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Spouse or partner violence, Physical, Confirmed, Initial encounterAdult physical abuse by nonspouse or nonpartner, Confirmed, SubsequentSpouse or partner violence, Physical, Confirmed, Subsequent encounterChild physical abuse, Confirmed, Initial encounterChild physical abuse, Confirmed, Subsequent encounterAdult sexual abuse by nonspouse or nonpartner, Confirmed, Initial encounter

Spouse or partner violence, Sexual, Confirmed, Initial encounterAdult sexual abuse by nonspouse or nonpartner, Confirmed, SubsequentNumerical Listing of DSM-5 Diagnoses and Codes (|CD-10-CM)Disorder, condition, or problemT76.32XD 255.9 256.82 256.9 259.0 259.1 259.2 259.3 259.4 259.5

Spouse or partner violence, Sexual, Confirmed, Subsequent encounterChild sexual abuse, Confirmed, Initial encounterChild sexual abuse, Confirmed, Subsequent encounterAdult psychological abuse by nonspouse or nonpartner, Confirmed, InitialSpouse or partner abuse, Psychological, Confirmed, Initial encounterAdult psychological abuse by nonspouse or nonpartner, Confirmed,Spouse or partner abuse, Psychological, Confirmed, Subsequent encounterChild psychological abuse, Confirmed, Initial encounterChild psychological abuse, Confirmed, Subsequent encounterSpouse or partner neglect, Suspected, Initial encounterSpouse or partner neglect, Suspected, Subsequent encounterChild neglect, Suspected, Initial encounterChild neglect, Suspected, Subsequent encounterAdult physical abuse by nonspouse or nonpartner, Suspected, Initial encounter

Spouse or partner violence, Physical, Suspected, Initial encounterAdult physical abuse by nonspouse or nonpartner, Suspected, SubsequentSpouse or partner violence, Physical, Suspected, Subsequent encounterChild physical abuse, Suspected, Initial encounterChild physical abuse, Suspected, Subsequent encounterAdult sexual abuse by nonspouse or nonpartner, Suspected, Initial encounter

Spouse or partner violence, Sexual, Suspected, Initial encounterAdult sexual abuse by nonspouse or nonpartner, Suspected, SubsequentSpouse or partner Violence, Sexual, Suspected, Subsequent encounterChild sexual abuse, Suspected, Initial encounterChild sexual abuse, Suspected, Subsequent encounterAdult psychological abuse by nonspouse or nonpartner, Suspected, InitialSpouse or partner abuse, Psychological, Suspected, Initial encounterAdult psychological abuse by nonspouse or nonpartner, Suspected,Spouse or partner abuse, Psychological, Suspected, Subsequent encounterChild psychological abuse, Suspected, Initial encounterChild psychological abuse, Suspected, Subsequent encounterProblem related to current military deployment statusOther problem related to employmentDiscord with neighbor, lodger, or landlordProblem related to living in a residential institutionLack of adequate food or safe drinking waterNumerical Listing of DSM-5 Diagnoses and Codes (|CD-10-CM) 895ICD-10-CM Disorder, condition, or problem 259.6 259.7 259 .9 260.0 260.2 260.3 260.4 260.5 260.9 262.29 262.810 262.810 262.811 262.812 262.820 262.891 262.898 263.0 263.4 263.5 263.8 264.0 264.1 264.4 265.0 265.1 265.2 265.3 265.4 265.4 265.5 265.8 265.8 265.9 269.010 269.010 269.010 269.010 269.011 269.011 269.011 269.011 269.020

Phase of life problemProblem related to living aloneTarget of (perceived) adverse discrimination or persecutionUnspecified problem related to social environmentPersonal history (past history) of physical abuse in childhoodPersonal history (past history) of sexual abuse in childhoodPersonal history (past history) of psychological abuse in childhoodPersonal history (past history) of neglect in childhoodRelationship distress with spouse or intimate partnerDisruption of family by separation or divorceProblems related to unwanted pregnancyProblems related to multiparityDiscord with social service provider, including probation officer, case manager, or social services worker

Problems related to release from prisonProblems related to other legal circumstancesVictim of crimeVictim of terrorism or tortureExposure to disaster, war, or other hostilitiesOther problem related to psychosocial circumstancesUnspecified problem related to unspecified psychosocial circumstancesEncounter for mental health services for victim of child abuse by parent

Encounter for mental health services for victim of child neglect by parent

Encounter for mental health services for victim of child psychological abuse by

Encounter for mental health services for victim of child sexual abuse by parent

Encounter for mental health services for perpetrator of parental child abuse

Encounter for mental health services for perpetrator of parental child neglect

Encounter for mental health services for perpetrator of parental child

Encounter for mental health services for perpetrator of parental child sexual abuse

Encounter for mental health services for victim of nonparental child abuse

Numerical Listing of DSM-S Diagnoses and Codes (|CD-10-CM) lCD-10-CM Disorder, condition, or problem 269.020 269.020 269.020 269.021 269.021 269.021 269.021 269.11 269.11 269.11 269.12 269.12 269.12 269.12 269.81 269.81 269.82 270.9 271.9 272.0 272.810 272.811 272.9 275.3 275.4 276.5 291.19 291.410 291.410 291.411 291.412 291.49 291.5 291.82 291.83 291.89

Encounter for mental health services for victim of nonparental child neglect

Encounter for mental health services for victim of nonparental child psycho-

Encounter for mental health services for victim of nonparental child sexual abuse

Encounter for mental health services for perpetrator of nonparental child abuse

Encounter for mental health services for perpetrator of nonparental child neglect

Encounter for mental health services for perpetrator of nonparental child

Encounter for mental health services for perpetrator of nonparental child

Encounter for mental health services for victim of spouse or partner neglect

Encounter for mental health services for victim of spouse or partner

Encounter for mental health services for victim of spouse or partner violence,

Encounter for mental health services for perpetrator of spouse or partner neglect

Encounter for mental health services for perpetrator of spouse or partner

Encounter for mental health services for perpetrator of spouse or partner violence, Physical

Encounter for mental health services for perpetrator of spouse or partner violence, Sexual

Encounter for mental health services for victim of nonspousal adult abuse

Encounter for mental health services for victim of spouse or partner violence,

Encounter for mental health services for perpetrator of nonspousal adult abuse

Tobacco use disorder, mildProblem related to lifestyleUnavailability or inaccessibility of health care facilitiesUnavailability or inaccessibility of other helping agenciesNonadherence to medical treatmentPersonal history (past history) of spouse or partner violence, Physical

Personal history (past history) of spouse or partner violence, Sexual

Personal history (past history) of spouse or partner psychological abuse

Personal history (past history) of spouse or partner neglectOther personal history of psychological traumaPersonal history of self-harmPersonal history of military deploymentWandering associated with a mental disorderAPA Board of Trustees DSM-5 Review CommitteesKenneth S. Kendler, M.D. (Chair)Robert Freedman, M.D. (Co—chair)Dan 6. Blazer, M.D., Ph.D., M.P.H.David Brent, M.D. (2011—)Ellen Leibenluft, M.D.Sir Michael Rutter, M.D. (-2011)Paul S. Summergrad, M.D.Robert J. Ursano, M.D. (—2011)Myrna Weissman, PhD. (2011—)Joel Yager, M.D.Jill L. Opalesky M.S. (Administrative Support)John S. McIntyre, M.D. (Chair)Joel Yager, M.D. (Co-chair)Anita Everett M.D.Cathryn A. Galanter, M.D.Jeffrey M. Lyness, MD.James E. Nininger, M.D.Victor I. Reus, M.D.Michael I. Vergare, M.D.Carolyn Robinowitz, M.D. (Chair)Mary Badaracco, M.D.Ronald Burd, M.D.Robert Freedman, M.D.Jeffrey A. Lieberman, M.D.Kyla Pope, M.D.Victor I. Reus, M.D.Daniel K. Winstead, M.D.Joel Yager, M.D.Glenn A. Martin, MD. (Chair)R. Scott Benson, M.D. (Speaker of theWilliam Cardasis, M.D.John M. de Figueiredo, M.D.Lawrence S. Gross, M.D.Brian 5. Hart, M.D.Stephen A. McLeod Bryant, M.D.Gregory A. Miller, M.D.Roger Peele, M.D.Charles S. Price, M.D.Deepika Sastry, M.D.John PD. Shemo, M.D.Eliot Sorel, M.D.Dilip V. Jeste, M.D. (Chair)R. Scott Benson, M.D.Kenneth S. Kendler, M.D.Helena C. Kraemer, PhD.David I. Kupfer, M.D.Jeffrey A. Lieberman, M.D.Glenn A. Martin, M.D.John S. McIntyre, M.D.John M. Oldham, M.D.Roger Peele, M.D.Darrel A. Regier, M.D., M.P.H.James H. Scully ]r., M.D.Joel Yager, M.D.Paul S. Appelbaum, M.D. (Consultant)Michael B. First, M.D. (Consultant)Robert D. Gibbons, PhD.Craig Nelson, M.D.Paul S. Appelbaum, M.D.Lama Bazzi, M.D.Alec W. Buchanan, M.D., PhD.Carissa Caban Aleman, M.D.Michael Champion, M.D.Jeffrey C. Eisen, M.D.Elizabeth Ford, M.D.Daniel T. Hackman, M.D.Mark Hauser, M.D.Steven K. Hoge, M.D., M.B.A.Debra A. Pinals, M.D.Guillermo Portillo, M.D.Patricia Recupero, M.D., ].D.Robert Weinstock, M.D.Cheryl Wills, M.D.Howard V. Zonana, M.D.Erin I. Dalder-AlpherLeah I. EngelElizabeth C. MartinRocio I. SalvadorEmil F. Coccaro, M.D.Deborah Dabrick, Ph.D.Prudence W. Fisher, Ph.D.Benjamin B. Lahey, Ph.D.Salvatore Mannuzza, Ph.D.Mary Solanto, Ph.D.I. Blake Turner, Ph.D.Eric Youngstrom, Ph.D.Anxiety, Obsessive-CompulsiveSpectrum, Posttraumatic, andLynn E. Alden, Ph.D.David B. Arciniegas, M.D.David H. Barlow, Ph.D.Katja Beesdo-Baum, Ph.D.Chris R. Brewin, Ph.D.Richard I. Brown, Ph.D.Timothy A. Brown, Ph.D.Richard A. Bryant, Ph.D.Joan M. Cook, Ph.D.loop de Jong, M.D., Ph.D.Paul F. Dell, Ph.D.Damiaan Denys, M.D.Bruce P. Dohrenwend, Ph.D.Brian A. Fallon, M.D., M.P.H.Edna B. Foa, Ph.D.Martin E. Franklin, Ph.D.Wayne K. Goodman, M.D.Jon E. Grant, ].D., M.D.Bonnie L. Green, Ph.D.Richard 6. Heimberg, Ph.D.Judith L. Herman, M.D.Devon E. Hinton, M.D., Ph.D.Stefan 6. Hofmann, Ph.D.Charles W. Hoge, M.D.Terence M. Keane, Ph.D.Nancy J. Keuthen, Ph.D.Dean 6. Kilpatrick, Ph.D.Katharina Kircanski, Ph.D.Laurence ]. Kirmayer, M.D.Donald F. Klein, M.D., D.Sc.Amaro J. Laria, Ph.D.Richard T. LeBeau, M.A.Richard J. Loewenstein, M.D.David Mataix-Cols, Ph.D.Thomas W. McAllister, M.D.Harrison 6. Pope, M.D., M.P.H.Ronald M. Rapee, Ph.D.Steven A. Rasmussen, M.D.Patricia A. Resick, Ph.D.Vedat Sar, M.D.Sanjaya Saxena, M.D.Paula P. Schnurr, PhD.M. Katherine Shear, M.D.Daphne Simeon, M.D.Harvey S. Singer, M.D.Melinda A. Stanley, Ph.D.James I. Strain, M.D.Kate Wolitzky Taylor, Ph.D.Onno van der Hart, Ph.D.Eric Vermetten, M.D., Ph.D.John T. Walkup, M.D.Sabine Wilhelm, Ph.D.Douglas W. Woods, Ph.D.Richard E. 2inbarg, Ph.D.Joseph Zohar, M.D.Adrian Angold, Ph.D.Deborah Beidel, Ph.D.David Brent, M.D.John Campo, M.D.Gabrielle Carlson, M.D.Prudence W. Fisher, Ph.D.David Klonsky, Ph.D.Matthew Nock, Ph.D.]. Blake Turner, Ph.D.Michael J. Devlin, M.D.Denise E. Wilfley, Ph.D.Susan 2. Yanovski, M.D.Boris Birmaher, M.D.Yeates Conwell, M.D.Ellen B. Dennehy, Ph.D.S. Ann Hartlage, Ph.D.Jack M. Hettema, M.D., Ph.D.Michael C. Neale, Ph.D.Gordon B. Parker, M.D., Ph.D., D.Sc.Roy H. Perlis, M.D. M.Sc.Holly 6. Prigerson, Ph.D.Norman E. Rosenthal, M.D.Peter ]. Schmidt, M.D.Mort M. Silverman, M.D.Meir Steiner, M.D., Ph.D.Mauricio Tohen, M.D., Dr.P.H., M.B.A.Sidney Zisook, M.D.Jiska Cohen-Mansfield, Ph.D.Vladimir Hachinski, M.D., C.M., D.Sc.Sharon Inouye, M.D., M.P.H.Grant Iverson, Ph.D.Laura Marsh, M.D.Bruce Miller, M.D.Jacobo Mintzer, M.D., M.B.A.Bruce Pollock, M.D., Ph.D.George Prigatano, Ph.D.Ron Ruff, Ph.D.Ingmar Skoog, M.D., Ph.D.Robert Sweet, M.D.Paula Trzepacz, M.D.Nickola Nelson, Ph.D.Diane Paul, Ph.D.Eva Petrova, Ph.D.Andrew Pickles, Ph.D.Ian Piek, Ph.D.Helene Polatajko, Ph.D.Alya Reeve, M.D.Mabel Rice, Ph.D.Joseph Sergeant, Ph.D.Bennett Shaywitz, M.D.Sally Shaywitz, M.D.Audrey Thurm, Ph.D.Keith Widaman, Ph.D.Warren Zigman, Ph.D.Eran Chemerinski, M.D.Thomas N. Crawford, Ph.D.Harold W. Koenigsberg, M.D.Kristian E. Markon, Ph.D.Rebecca L. Shiner, Ph.D.Kenneth R. Silk, M.D.Jennifer L. Tackett, Ph.D.David Watson, Ph.D.Kamaldeep Bhui, M.D.Manuel J. Cuesta, M.D., Ph.D.Richard Douyon, M.D.Paolo Fusar—Poli, Ph.D.John H. Krystal, M.D.Thomas H. McGlashan, M.D.Victor Peralta, M.D., Ph.D.Anita Riecher-Rt'issler, M.D.Mary V. Seeman, M.D.Stan E. Althof, Ph.D.Richard Balon, MD.John H.]. Bancroft, M.D., M.A., D.P.M.Howard E. Barbaree, Ph.D., M.A.Rosemary J. Basson, M.D.Sophie Bergeron, Ph.D.Anita L. Clayton, M.D.David L. Delmonico, Ph.D.Domenico Di Ceglie, M.D.Esther Gomez-Gil, M.D.Jamison Green, Ph.D.Richard Green, MD, JD.R. Karl Hanson, Ph.D.Lawrence Hartmann, M.D.Stephen J. Hucker, M.B.Eric S. Janus, JD.Patrick M. Iem, Ph.D.Megan S. Kaplan, Ph.D.Raymond A. Knight, Ph.D.Ellen T.M. Laan, Ph.D.Stephen B. Levine, M.D.Christopher 6. McMahon, M.B.Marta Meana, Ph.D.Michael H. Miner, Ph.D., M.A.William T. O’Donohue, Ph.D.Michael A. Perelman, Ph.D.Caroline F. Pukall, Ph.D.Robert E. Pyke, M.D., Ph.D.Vernon L. Quinsey, Ph.D. M.Sc.David L. Rowland, Ph.D., M.A.Michael Sand, Ph.D., M.P.H.Leslie R. Schover, Ph.D., M.A.Paul Stern, BS, ].D.David Thornton, Ph.D.Leonore Tiefer, Ph.D.Douglas E. Tucker, M.D.Jacques van Lankveld, Ph.D.Marcel D. Waldinger, M.D., Ph.D.Donald L. Bliwise, Ph.D.Daniel I. Buysse, M.D.Vishesh K. Kapur, M.D., M.P.H.Sanjeeve V. Kothare, M.D.Kenneth L. Lichstein, Ph.D.Mark W. Mahowald, M.D.Rachel Manber, Ph.D.Emmanuel Mignot, M.D., Ph.D.Timothy H. Monk, Ph.D., D.Sc.Thomas C. Neylan, M.D.Maurice M. Ohayon, M.D., D.Sc., Ph.D.Judith Owens, M.D., M.P.H.Daniel L. Picchietti, M.D.Stuart F. Quan, M.D.Thomas Roth, Ph.D.Daniel Weintraub, M.D.Theresa 8. Young, Ph.D.Phyllis C. Zee, M.D., Ph.D.Brenda Bursch, Ph.D.Kurt Kroenke, M.D.W. Curt LaFrance, Ir., M.D., M.P.H.Ion Stone, M.B., Ch.B., Ph.D.Lynn M. Wegner, M.D.Raymond F. Anton, Jr., M.D.Deborah A. Dawson, Ph.D.Roland R. Griffiths, Ph.D.Dorothy K. Hatsukami, Ph.D.John E. Helzer, M.D.Marilyn A. Huestis, Ph.D.John R. Hughes, M.D.Thomas R. Kosten, M.D.Nora D. Volkow, M.D.Christina Bryant, Ph.D.Amber Gum, Ph.D.Thomas Meeks, M.D.Jan Mohlman, Ph.D.Steven Thorp, Ph.D.Julie Wetherell, Ph.D.Neil K. Aggarwal, M.D., M.B.A., M.A.Sofie Béarnhielm, M.D., Ph.D.Iosé I. Bauermeister, Ph.D.James Boehnlein, M.D., M.Sc.Iaswant Guzder, M.D.Alejandro Interian, Ph.D.Sushrut S. Iadhav, M.B.B.S., M.D., Ph.D.Laurence J. Kirmayer, M.D.Alex J. Kopelowicz, M.D.Amaro J. Laria, Ph.D.Steven R. Lopez, Ph.D.Kwame J. McKenzie, M.D.John R. Peteet, M.D.Hans (I.6.B.M.) Rohlof, M.D.Cecile Rousseau, M.D.Mitchell 6. Weiss, M.D., Ph.D.Daniel L. Coury, M.D.Bernard P. Dreyer, M.D.Danielle Laraque, M.D.Lynn M. Wegner, M.D.Prudence W. Fisher, Ph.D.Martin Prince, M.D., M.Sc.Michael R. Von Korff, Sc.D.Prudence W. Fisher, Ph.D.Robert D. Gibbons, Ph.D.Ruben Gur, Ph.D.John E. Helzer, M.D.John Houston, M.D., Ph.D.Kurt Kroenke, M.D.Patrick E. Shrout, Ph.D.Erik Willcutt, Ph.D.Anxiety, Obsessive-CompulsiveSpectrum, Posttraumatic, andEric Hollander, M.D.Charlie Marmar, M.D.Mark w. Miller, Ph.D.Mark H. Pollack, M.D.Heidi S. Resnick, Ph.D.Grace T. Baranek, Ph.D.Colleen Jacobson, Ph.D.Maria Oquendo, M.D.Sir Michael Rutter, M.D.Nancy L. Zucker, Ph.D.Keith Hawton, M.Sc.David A. Jobes, Ph.D.Maria A. Oquendo, M.D.J. Eric Ahlskog, M.D., Ph.D.Allen J. Aksamit, M.D.Marilyn Albert, Ph.D.Guy Mckhann, M.D.Bradley Boeve, M.D.Helena Chui, M.D.Sureyya Dikmen, Ph.D.Douglas 6alasko, M.D.Harvey Levin, Ph.D.Mark Lovell, Ph.D.Jeffery Max, M.B.B.Ch.Ian McKeith, M.D.Cynthia Munro, Ph.D.Marlene Oscar—Berman, Ph.D.Alexander Troster, Ph.D.Anna Barnett, Ph.D.Martha Denckla, M.D.Jack M. Fletcher, Ph.D.Dido Green, Ph.D.Stephen Greenspan, Ph.D.Bruce Pennington, Ph.D.Ruth Shalev, M.D.Larry B. Silver, M.D.Lauren Swineford, Ph.D.Michael Von Aster, M.D.Patricia R. Cohen, Ph.D.Jaime L. Derringer, Ph.D.Lauren Helm, M.D.Christopher J. Patrick, Ph.D.Anthony Pinto, Ph.D.Scott W. Woods, M.D.Alan I. Riley, M.Sc.Ray C. Rosen, Ph.D.Jack D. Edinger, Ph.D.David Gozal, M.D.Hochang B. Lee, M.D.Tore A. Nielsen, Ph.D.Michael ]. Sateia, M.D.Jamie M. Zeitzer, Ph.D.Chuck V. Ford, M.D.Patricia 1. Rosebush, M.Sc.N., M.D.Sally M. Anderson, Ph.D.Julie A. Kable, Ph.D.Christopher Martin, Ph.D.Sarah N. Mattson, Ph.D.Edward V. Nunes, I11, M.D.Mary J. O’Connor, Ph.D.Heather Carmichael Olson, Ph.D.Blair Paley, Ph.D.Edward P. Riley, Ph.D.Tulshi D. Saha, Ph.D.Wim van den Brink, M.D., Ph.D.George E. Woody, M.D.Bruce Cuthbert, Ph.D.Aartjan Beekman Ph.D.Alistair Flint, M.B.David Sultzer, M.D.Ellen Whyte, M.D.Sergio Aguilar—Gaxiola, M.D., Ph.D.Kavoos 6. Bassiri, M.S.Venkataramana Bhat, M.D.Marit Boiler, M.P.H.Denise Canso, M.Sc.Smita N. Deshpande, M.D., D.P.M.Ravi DeSilva, M.D.Esperanza Diaz, M.D.Byron I. 600d, Ph.D.Simon 6roen, M.A.Ladson Hinton, M.D.Lincoln I. Khasakhala, Ph.D.Francis 6. Lu, M.D.Athena Madan, M.A.Anne W. Mbwayo, Ph.D.Oanh Meyer, Ph.D.Victoria N. Mutiso, Ph.D., D.Sc.David M. Ndetei, M.D.Andel V. Nicasio, M.S.Ed.Vasudeo Paralikar, M.D., Ph.D.Kanak Patil, M.A.Filipa I. Santos, H.B.Sc.Sanjeev B. Sarmukaddam, Ph.D., M.Sc.Monica 2. Scalco, M.D., Ph.D.Katie Thompson, M.A.Hendry Ton, M.D., M.Sc.Rob CJ. van Dijk, M.Sc.Johann M. Vega-Dienstmaier, M.D.Joseph Westermeyer, M.D., Ph.D.Daniel I. Balog, M.D.Charles C. Engel, M.D., M.P.H.Charles D. Motsinger, M.D.Cille Kennedy, Ph.D.Paul I. Pikonis, Ph.D.a Focus of Clinical AttentionWilliam E. Narrow, M.D., M.P.H., ChairRoger Peele, M.D.Lawson R. Wulsin, M.D.Charles H. Zeanah, M.D.Prudence W. Fisher, Ph.D., AdvisorStanley N. Caroff, M.D., Contributor/ConsultantJames B. Lohr, M.D., Contributor/ConsultantMarianne Wambolt, Ph.D., Contributor/ConsultantAllan Donner, Ph.D.Kenneth Altshuler, M.D.Pedro 6. Alvarenga, M.D.Diana 1. Antonacci, M.D.Richard Balon, M.D.David H. Barlow, Ph.D.L. Jarrett Bamhill, M.D.Katja Beesdo-Baum, Ph.D.Marty Boman, Ed.D.Iames Bourgeois, M.D.David Braff, M.D.Harry Brandt, M.D.Kirk Brower, M.D.Rachel Bryant—Waugh, Ph.D.Jack D. Burke Jr., M.D., M.P.H.Brenda Bursch, Ph.D.Joseph Camilleri, M.D.Patricia Casey, M.D.F. Xavier Castellanos, M.D.Eran Chemerinski, M.D.Wai Chen, M.D.Elie Cheniaux, M.D., D.Sc.Cheryl Chessick, MD,J. Richard Ciccone, M.D.Anita H. Clayton, M.D.Tihalia I. Coleman, Ph.D.John Csemansky, M.D.Manuel 1. Cuesta M.D., Ph.D.Joanne L. Davis, M.D.David L. Delmonico, Ph.D.Ray J. DePaulo, M.D.Dimitris Dikeos, M.D.Ina E. Djonlagic, M.D.C. Neill Epperson, M.D.Javier I. Escobar, M.D., M.Sc.Spencer Eth, M.D.David Fassler, M.D.Giovanni A. Fava, M.D.Robert Feinstein, M.D.Molly Finnerty, M.D.Mark H. Fleisher, M.D.Alessio Florentini, M.D.Laura Fochtmann, M.D.Marshal Forstein, M.D.William French, M.D.Maximillian Gahr, M.D.Cynthia Geppert, M.D.Ann Germaine, Ph.D.Marcia 60in, M.D.David A. Gorelick, M.D., Ph.D.David Graeber, M.D.Cynthia A. Graham, Ph.D.Andreas Hartmann, M.D.Victoria Hendrick, M.D.Merrill Herman, M.D.David Herzog, M.D.Mardi Horowitz, M.D.Ya-fen Huang, M.D.Anthony Kales, MDNiranjan S. Karnik, M.D., Ph.D.Jeffrey Katzman, M.D.Bryan King, M.D.Cecilia Kjellgren, M.D.Harold W. Koenigsberg, M.D.Richard B. Krueger, M.D.Steven Lamberti, M.D.Ruth A. Lanius, M.D.John Lauriello, M.D.Anthony Lehman, M.D.Michael Linden, M.D.Mark W. Mahowald, M.D.Marsha D. Marcus, Ph.D.Stephen Marder, M.D.Wendy Marsh, M.D.Michael S. McCloskey, Ph.D.Jeffrey Metzner, M.D.Robert Michels, M.D.Laura Miller, MD.Michael C. Miller, M.D.Frederick Moeller, M.D.Peter T. Morgan, M.D., Ph.D.Madhav Muppa, M.D.Philip Muskin, M.D.Joachim Nitschke, M.D.Abraham Nussbaurn, M.D.Ann Olincy, M.D. \Mark Onslow, Ph.D.Sally Ozonoff, Ph.D.John R. Peteet, M.D.Ismene L. Petrakis, M.D.Christophe M. Pfeiffer, M.D.Karen Pierce, M.D.Belinda Plattner, M.D.Franklin Putnam, M.D.Stuart F. Quan, M.D.John Racy, M.D.Phillip Resnick, M.D.Michele Riba, M.D.Ierold Rosenbaum, M.D.Stephen Ross, M.D.Lawrence Scahill, M.S.N., Ph.D.Daniel Schechter, M.D.Mary V. Seeman, M.D.Alessandro Serretti, M.D.Iianhua Shen, M.D.Ravi Kumar R. Singareddy, M.D.Ingmar Skoog, M.D., Ph.D.Gary Small, M.D.Paul Soloff, M.D.Christina Stadler, M.D., Ph.D.Nada Stotland, M.D.Neil Swerdlow, M.D.Kim Tillery, Ph.D.David Tolin, Ph.D.Jayne Trachman, M.D.Luke Tsai, M.D.Ming T. Tsuang, M.D., Ph.D.Richard Tuch, M.D.Johan Verhulst, M.D.B. Timothy Walsh, M.D.Michael Weissberg, M.D.Codehard Weniger, M.D.Keith Widaman, Ph.D.Thomas Wise, M.D.George E. Woods, M.D.Kimberly A. Yonkers, M.D.Alexander Young, M.D.David Geffen School of Medicine, University of California, Los Angeles

Helen Lavretsky, M.D., Principal InvestigatorJessica Brommelhoff, Ph.D.Xavier Cagigas, Ph.D.Paul Cemin, Ph.D.Linda Ercoli, Ph.D.Randall Espinoza, M.D.Helen Lavretsky, M.D.Jeanne Kim, Ph.D.David Merrill, M.D.Karen Miller, Ph.D.Christopher Nunez, Ph.D.Natalie St. Cyr, M.A., Lead ResearchNora Nazarian, B.A.Colin Shinn, M.A.Centre for Addiction and Mental Health, Toronto, Ontario, CanadaBruce 6. Pollock, M.D., Ph.D., Lead PrincipalR. Michael Bagby, Ph.D., Principal InvestigatorKwame I. McKenzie, M.D., PrincipalTony P. George, M.D., Co-investigatorLena C. Quilty, Ph.D., Co—investigatorPeter Voore, M.D., Co-investigatorDonna E. Al(man, Ph.D.R. Michael Bagby, Ph.D.Wayne C. V. Baici, M.D.Crystal Baluyut, M.D.Eva W. C. Chow, M.D., ].D., M.P.H.2. I. Daskalakis, M.D., Ph.D.Pablo Diaz-Hermosillo, M.D.George Foussias, M.Sc., M.D.Paul A. Frewen, Ph.D.Ariel 6raff-6uerrero, M.D., M.Sc., Ph.D.Margaret K. Hahn, M.D.Lorena Hsu, Ph.D.Justine Joseph, Ph.D.Sean Kidd, Ph.D.Kwame I. McKenzie, M.D.Mahesh Menon, Ph.D.Romina Mizrahi, M.D., Ph.D.Daniel J. Mueller, M.D., Ph.D.Lena C. Quilty, Ph.D.Anthony C. Ruocco, Ph.D.Jorge Soni, M.D.Aristotle N. Voineskos, M.D., Ph.D.George Voineskos, M.D.Peter Voore, Ph.D.Chris Watson, Ph.D.Ofer Agid, M.D.Ash Bender, M.D.Patricia Cavanagh, M.D.Sarah Colman, M.D.Vincenzo Deluca, M.D.Justin Geagea, MD.David S. Goldbloom, M.D.Daniel Greben, M.D.Malati Gupta, M.D.Ken Harrison, M.D.Imraan Ieeva, M.D.Joel Jeffries, M.B.Judith Laposa, Ph.D.Jan Malat, M.D.Shelley McMain, Ph.D.Bruce Pollock, M.D., Ph.D.Andriy V. Samokhvalov, M.D., Ph.D.Martin Strassnig, M.D.Albert H. C. Wong, M.D., Ph.D.Gloria I. Leo, M.A., Lead Research CoordinatorAnissa D. Bachan, B.A.Bahar Haji—Khamneh, M.A.Olga Likhodi, M.Sc.Eleanor J. Liu, Ph.D.Sarah A. McGee Ng, B.B.A.Susan E. Dickens, M.A., Clinical ResearchSandy Richards, B.Sc.N., SchizophreniaDallas VA Medical Center, Dallas, TexasCarol 5. North, M.D., M.P.E., PrincipalAlina Suris, Ph.D., A.B.P.P., PrincipalBarry Ardolf, Psy.D.Abila Awan, M.D.Joel Baskin, M.D.John Black, Ph.D.Jeffrey Dodds, Ph.D.Gloria Emmett, Ph.D.Karma Hudson, M.D.Iamylah Jackson, Ph.D., A.B.P.P.Lynda Kirkland-Culp, Ph.D., A.B.P.P.Heidi Koehler, Ph.D., A.B.P.P.Elizabeth Lewis, Psy.D.Aashish Parikh, M.D.Reed Robinson, Ph.D.Iheel Shah, M.D.Geetha Shivakumar, M.D.Sarah Spain, Ph.D., A.B.P.P.Lisa Thoman, Ph.D.Lia Thomas, M.D.Jamie Zabukovec, Psy.D.Mustafa Zaidi, M.D.Andrea 2artman, Ph.D.Robert Blake, L.M.S.W.Evelyn Gibbs, L.M.S.W.Michelle King-Thompson, L.M.S.W.Jeannie B. Whitman, Ph.D., Lead ResearchSunday Adewuyi, M.D.Elizabeth Anderson, B.A.Solaleh Azimipour, BS.Carissa Barney, B.S.Kristie Cavazos, B.A.Robert Devereaux, BS.Dana Downs, M.S., M.S.W.Sharjeel Farooqui, M.D.Julia Smith, Psy.D.Kun—Ying H. Sung, BS.School of Medicine, The University of Texas San Antonio,San Antonio. TexasMauricio Tohen, M.D., Dr.P.H., M.B.A.,Suman Baddam, Psy.D.Charles L. Bowden, M.D.Nancy Diazgranados, M.D., MS.Craig A. Dike, Psy.D.Dianne E. Dunn, Psy.D., M.P.H.Elena 6herman, M.D.Jodi M. Gonzalez, Ph.D.Pablo Gonzalez, M.D.Phillip Lai, Psy.D.Natalie Maples—Aguilar, M.A., L.P.A.Marlon P. Quinones, M.D.Ieslina J. Raj, Psy.D.David L. Roberts, Ph.D.Nancy Sandusky, R.N., F.P.M.H.N.P.-B.C.,Donna S. Stutes, M.S., L.P.C.Mauricio Tohen, M.D., Dr.PH, M.B.A.Dawn I. Velligan, Ph.D.Weiran Wu, M.D., Ph.D.Albana Dassori, M.D.Megan Frederick, M.A.Robert Gonzalez, M.D.Uma Kasinath, M.D.Camis Milam, M.D.Vivek Singh, M.D.Peter Thompson, M.D.Melissa Hernandez, B.A., Lead ResearchFermin Alejandro Carrizales, B.A.Martha Dahl, R.N., B.S.N.Patrick M. Smith, B.A.Nicole B. Watson, M.A.Michael E. DeBakey VA Medical Center and the Menninger Clinic,

Houston, Texas (Joint Study Site)Michael E. DeBakey VA Medical CenterLaura Marsh, M.D., Principal InvestigatorShalini Aggarwal, M.D.Su Bailey, Ph.D.Minnete (Helen) Beckner, Ph.D.Crystal Clark, M.D.Charles Delohn, M.D.Robert Garza, M.D.Aruna Gottumakkla, M.D.Janet Hickey, M.D.James Ireland, M.D.Mary Lois Lacey, A.P.R.N.Wendy Leopoulos, M.D.Laura Marsh, M.D.Deleene Menefee, Ph.D.Brian I. Miller, Ph.D.Candy Smith, Ph.D.Avila Steele, Ph.D.Jill Wanner, Ph.D.Rachel Wells, Ph.D.Kaki York-Ward, Ph.D.Sara Allison, M.D.Leonard Denney, L.C.S.W.Catherine Flores, L.C.S.W.Nathalie Marie, M.D.Christopher Martin, M.D.Sanjay Mathew, M.D.Erica Montgomery, M.D.Gregory Scholl, P.A.Iocelyn Ulanday, M.D., M.P.H.Sarah Neely Torres, 8.5., Lead ResearchKathleen Grout, M.A.Lea Kiefer, M.P.H.Iana Tran, M.A.Efrain Bleiberg, M.D., Principal InvestigatorJennifer Baumgardner, Ph.D.Elizabeth Dodd Conaway, L.C.S.W., B.C.D.Warren Christianson, D.O.Wesley Clayton, L.M.S.W.I. Christopher Fowler, Ph.D.Michael Croat, Ph.D.Edythe Harvey, M.D.Denise Kagan, Ph.D.Hans Meyer, L.C.S.W.Segundo Robert-Ibarra, M.D.Sandhya Trivedi, M.D.Rebecca Wagner, Ph.D.Harrell Woodson, Ph.D.Amanda Yoder, L.C.S.W.Iames Flack, MD.David Ness, M.D.Steve Herrera, B.S., M.T., Lead ResearchAllison Kalpakci, B.A.Mayo Clinic, Rochester, MinnesotaMark A. Frye, M.D., Principal InvestigatorGlenn E. Smith, Ph.D., Principal InvestigatorIeffrey P. Staab M.D., M.S., PrincipalOsama Abulseoud, M.D.Jane Cerhan, Ph.D.Julie Fields, Ph.D.Mark A. Frye, M.D.Manuel Fuentes, M.D.Yonas Geda, M.D.Maria Harmandayan, M.D.Reba King, M.D.Simon Kung, M.D.Mary Machuda, Ph.D.Donald McAlpine, M.D.Alastair McKean, M.D.Juliana Moraes, M.D.Teresa Rummans, M.D.James R. Rundell, M.D.Richard Seime, Ph.D.Glenn E. Smith, Ph.D.Christopher Sola, D.O.Jeffrey P. Staab M.D., MS.Marin Veldic, M.D.Mark D. Williams, M.D.Maya Yustis, Ph.D.Lisa Seymour, 85., Lead Research CoordinatorScott Feeder, M.S.Lee Gunderson, B.S.Sherrie Hanna, M.A., L.P.Kelly Harper, B.A.Katie Mingo, B.A.Cynthia Stoppel, A.S.Perelman School of Medicine, University of Pennsylvania,Philadelphia, PennsylvaniaMahendra T. Bhati, M.D., Principal InvestigatorMama S. Barrett, Ph.D., Co-investigatorMichael E. Thase, M.D., Co-investigatorPeter B. Bloom, M.D.Nicole K Chalmers L.C.S.W.Torrey A. Creed, Ph.D.Mario Cristancho, M.D.Amy Cunningham, Psy.D.John P. Dennis, Ph.D.Josephine Elia, M.D.Peter 6ariti, Ph.D., L.C.S.W.Philip Gehrman, Ph.D.Laurie Gray, M.D.Emily A.P. Haigh, Ph.D.Nora J. Johnson, M.B.A., M.S., Psy.D.Paulo Knapp, M.D.Yong-Tong Li, M.D.Bill Mace, Ph.D.Kevin S. McCarthy, Ph.D.Dimitri Perivoliot'is, Ph.D.Luke Schultz, Ph.D.Tracy Steen, Ph.D.Chris Tjoa, M.D.Nancy A. Wintering, L.C.S.W.Eleanor Ainslie, M.D.Kelly C. Allison, Ph.D.Rebecca Aspden, M.D.Claudia F. Baldassano, M.D.Vijayta Bansal, M.D.Rachel A. Bennett, M.D.Richard Bollinger, Ph.D.Andrea Bowen, M.D.Karla Campanella, M.D.Anthony Carlino, M.D.Noah Carroll, M.S.S.Alysia Cirona, M.D.Samuel Collier, M.D.Andreea Crauciuc, L.C.S.W.Pilar Cristancho, M.D.Traci D'Almeida, M.D.Kathleen Diller, M.D.Benoit Dubé, M.D.Ion Dukes, M.S.W.Lauren Elliott, M.D.Mira Elwell, B.A.Mia Everett, M.D.Lucy F. Faulconbridge, Ph.D.Patricia Furlan, Ph.D.Joanna Goldstein, L.C.S.W.Paul Grant, Ph.D.Jillian Graves, L.C.S.W.Tamar 6ur, M.D., Ph.D.Alisa Gutman, M.D., Ph.D.Nora Hymowitz, M.D.Sofia Jensen, M.D.Tiffany King, M.S.W.Katherine Levine, M.D.Alice Li, M.D.Janet Light, L.C.S.W.Iohn Listerud, M.DV Ph.D.Emily Malcoun, Ph.D.Donovan Maust, M.D.Adam Meadows, M.D.Michelle Moyer, M.D.Rebecca Naugle, L.C.S.W.Cory Newman, Ph.D.John Northrop, M.D., Ph.D.Elizabeth A. Ellis 0hr, Psy.D.John O'Reardon, M.D.Abraham Pachikara, M.D.Andrea Perelman, M.S.W.Diana Perez, M.S.W.Bianca Previdi, M.D.]. Russell Ramsay, Ph.D.Jorge Rivera-Colon, M.D.Ian Smedley, L.C.S.W.Katie Struble, M.S.W.Aita Susi, M.D.Yekaterina Tatarchuk, M.D.Ellen Tarves, M.A.Allison Tweedie, M.D.Holly Valerio, M.D.Thomas A. Wadden, Ph.D.Joseph Wright, Ph.D.Yan Xuan, M.D.David Yusko, Psy.D.Jordan A. Coello, B.A., Lead ResearchEric Wang, B.S.E.Jeannine Barker, M.A., A.T.R.Martekuor Dodoo, B.A.Laura Heller, B.A.Leah Hull-Rawson, B.A.Jacquelyn Klehm, B.A.Dante Proetto, B.S.Stanford University School of Medicine, Stanford, CaliforniaCarl Feinstein, M.D., Principal InvestigatorDebra Safer, M.D., Principal InvestigatorKari Berquist, Ph.D.Eric Clausell, Ph.D.Danielle Colbom, Ph.D.Whitney Daniels, M.D.Alison Darcy, Ph.D.Krista Fielding, M.D.Mina Fisher, M.D.Kara Fitzpatrick, Ph.D.Wendy Froehlich, M.D.Grace Gengoux, Ph.D.Anna Cassandra Golding, Ph.D.Lisa Groesz, Ph.D.Kyle Hinman, M.D.Rob Holaway, Ph.D.Matthew Holve, M.D.Rex Huang, M.D.Nina Kirz, M.D.Megan Klabunde, Ph.D.John Leckie, Ph.D.Naomi Leslie, M.D.Adrianne Lona, M.D.Ranvinder Rai, M.D.Rebecca Rialon, Ph.D.Beverly Rodriguez, M.D., Ph.D.Debra Safer, M.D.Mary Sanders, Ph.D.Jamie Scaletta, Ph.D.Norah Simpson, Ph.D.Manpreet Singh, M.D.Maria-Christina Stewart, Ph.D.Melissa Vallas, M.D.Patrick Whalen, Ph.D.Sanno Zack, Ph.D.Robin Apple, Ph.D.Victor Carrion, M.D.Carl Feinstein, M.D.Qhristine Gray, Ph.D.Antonio Hardan, M.D.Megan Jones, Psy.D.Linda Lotspeich, M.D.Lauren Mikula, Psy.D.Brandyn Street, Ph.D.Violeta Tan, M.D.Heather Taylor, Ph.D.Jacob Towery, M.D.Sharon Williams, Ph.D.Kate Amow, B.A., Lead Research CoordinatorNandini Datta, BS.Stephanie Manasse, B.A.Arianna Martin, M.S.Adriana Nevado, B.A.Children’s Hospital Colorado, Aurora, ColoradoMarianne Wamboldt, M.D., PrincipalGalia Abadi, M.D.Steven Behling, Ph.D.Jamie Blume, Ph.D.Adam Burstein, M.D.Debbie Carter, M.D.Kelly Caywood, Ph.D.Meredith Chapman, M.D.Paulette Christian, A.P.P.M.H.N.Mary Cook, M.D.Anthony Cordaro, M.D.Audrey Dumas, M.D.Guido Frank, M.D.Karen Frankel, Ph.D.Darryl Graham, Ph.D.Yael Granader, Ph.D.Isabelle Guillemet, M.D.Patrece Hairston, Ph.D.Charles Harrison, Ph.D.Tammy Herckner, L.C.S.W.Cassie Karlsson, M.D.Kimberly Kelsay, M.D.David Kieval, Ph.D.Megan Klabunde, Ph.D.Jaimelyn Kost, L.C.S.W.Harrison Levine, M.D.Raven Lipmanson, M.D.Susan Lurie, M.D.Asa Marokus, M.D.Idalia Massa, Ph.D.Christine McDunn, Ph.D.Scot McKay, M.D.Marissa Murgolo, L.C.S.W.Alyssa Oland, Ph.D.Lina Patel, Ph.D.Rheena I’ineda, Ph.D.6autam Rajendran, M.D.Diane Reichmuth, PhDMichael Rollin, M.D.Marlena Romero, L.C.S.W.Michelle Roy, Ph.D.Celeste St. John-Larkin, M.D.Elise Sannar, Ph.D.Daniel Savin, M.D.Claire Dean Sinclair, Ph.D.Ashley Smith, L.C.S.W.Mindy Solomon, Ph.D.Sally Tarbell, Ph.D.Helen Thilly, L.C.S.W.Sara Tlustos-Carter, Ph.D.l-Iolly Vause, A.P.P.M.I-I.NMarianne Wamboldt, M.D.Angela Ward, L.C.S.W.Jason Williams, Ph.D.Jason Willoughby, Ph.D.Brennan Young, Ph.D.Kelly Bhatnagar, Ph.D.Jeffery Dolgan, Ph.D.Jennifer Eichberg, L.C.S.W.Jennifer Hagman, M.D.James Masterson, L.C.S.W.Hy 6ia Park, M.D.Tami Roblek, Ph.D.Wendy Smith, Ph.D.David Williams, M.D.Laurie Burnside, M.S.M., C.C.R.C., LeadDarci Anderson, B.A., C.C.R.C.Heather Kennedy, M.P.H.Amanda Millar, B.A.Vanessa Waruinge, B.S.Elizabeth Wallace, B.A.Baystate Medical Center, Springfield, MassachusettsBruce Waslick, M.D., Principal InvestigatorCheryl Bonica, Ph.D., Co-investigatorJohn Fanton, M.D., Co-investigatorBarry Sarvet, M.D., Co-investigatorIulie Bermant, R.N., M.S.N., N.P.Cheryl Bonica, Ph.D.Jodi Devine, L.I.C.S.W.William Fahey, Ph.D.John Fanton, M.D.Stephane Jacobus, Ph.D.Barry Sarvet, M.D.Peter Thunfors, Ph.D.Bruce Waslick, M.D.Vicki Weld, L.I.C.S.W.Sara Wiener, L.I.C.S.W.Shadi Zaghloul, M.D.Sarah Detenber, L.I.C.S.W.Gordon Garrison, L.I.C.S.W.Jacqueline Humpreys, L.I.C.S.W.Noreen Mc6irr, L.I.C.S.W.Sarah Marcotte, L.C.S.W.Patricia Rogowski, R.N., C.N.S.Julie Kingsbury, C.C.R.P., Lead ResearchBrenda Martin, B.A.New York State Psychiatric Institute, New York, N.Y., Weill Cornell

Medical College, Payne Whitney and Westchester Divisions, New York and White Plains, N.Y., and North Shore Child and Family Guidance

Center, Roslyn Heights. NY. (Joint Study Site)Prudence W. Fisher, Ph.D., PrincipalJulia K. Carmody, B.A., Lead Research 2vi R. Shapiro, B.A., Lead Research

Part IBasic ConsiderationsBrunicardi_Ch01_p0001-p0026.indd 129/01/19 10:58 AMBrunicardi_Ch01_p0001-p0026.indd 229/01/19 10:58 AMThis page intentionally left blankLeadership in SurgeryStephen Markowiak, Hollis Merrick, Shiela Beroukhim, Jeremy J. Laukka, Amy Lightner, Munier Nazzal, Lee Hammerling, James R. Macho, and F. Charles Brunicardi 1chapterINTRODUCTIONThe field of surgery has evolved greatly from its roots, and sur-gical practice now requires the mastery of modern leadership principles and skills as much as the acquisition of medical knowledge and surgical technique. Historically, surgeons took sole responsibility for their patients and directed proceedings in the operating room with absolute authority, using a command-and-control style of leadership. Modern surgical practice has now evolved from single provider–based care toward a team-based approach, which requires collaborative leadership skills. Surgical care benefits from the collaboration of surgeons, anes-thesiologists, internists, radiologists, pathologists, radiation oncologists, nurses, pharmacists, social workers, therapists, hospital staff, and administrators. Occupying a central role on the healthcare team, surgeons1 have the potential to improve patient outcomes, reduce medical errors, and improve patient satisfaction through their leadership of the multidisciplinary team. Thus, in the landscape of modern healthcare systems, it is imperative that surgical training programs include formal instruction on leadership principles and skills to cultivate their trainees’ leadership capabilities.Many medical and surgical communities, including residency training programs, acknowledge the need for improved physician leadership. Specifically, surveyed surgical residents felt a lack of confidence in multiple areas of leadership, particularly in conflict resolution.2 Surgical trainees identify leadership skills as important, but they report themselves as “not competent” or “minimally competent” in this regard.2,3 While a small number of surgical training programs have implemented 1formal curricula focused on teaching leadership principles, it is now imperative that all surgical training programs teach these important skills to their trainees.4,5 Interviews of academic chairpersons identified several critical leadership success factors,6 including mastery of visioning, communication, change management, emotional intelligence, team building, business skills, personnel management, and systems thinking. These chairpersons stated that the ability of emotional intelligence was “fundamental to their success and its absence the cause of their failures,” regardless of medical knowledge.6 Thus, residency programs need to include leadership training to prepare future surgeons for success in modern healthcare delivery.In the United States, the Accreditation Council for Graduate Medical Education (ACGME) has established six core competencies—patient care, medical knowledge, prac-tice-based learning and improvement, interpersonal and com-munication skills, professionalism, and systems-based practice (Table 1-1)4—that each contain principles of leadership. The ACGME has mandated the teaching of these core competencies but has not established a formal guide on how to teach the lead-ership skills described within the core competencies. Therefore, this chapter offers a review of fundamental principles of leader-ship and an introduction of the concept of a leadership training program for future surgeons.DEFINITIONS OF LEADERSHIPMany different definitions of leadership have been described. Former First Lady Rosalynn Carter once observed that “A leader takes people where they want to go. A great leader takes people Introduction 3Definitions of Leadership 3Levels of Leadership / 4Fundamental Principles of  Leadership 4Vision / 5Generating Belief in Your Vision / 6Willingness / 7Time Management / 10Self-Care and Wellness / 11Recruitment / 11Creating a Culture of Empathy, Patient-Family-Centered Care, and Personalized Surgery / 11Why We Lead 11Choosing to Become a Leader / 11Leadership’s Effect on Healthcare Cost and Clinical Outcomes / 11The Importance of Diversity and Leadership 12Leadership Styles 12Formal Leadership Training  Programs in Surgery 13History of Leadership Training and the Multifactor Leadership Questionnaire / 13Designing the Program / 14Practicing Leadership Skills and Assessing Leadership Formally With Objective Structured Clinical Examination (OSCE) and Simulation / 14Evaluation of Surgeon Performance / 16Mentoring and Development 18Mentoring / 18Modeling Leadership for Medical Students and the “Hidden Curriculum” / 18Tools to Measure Leadership Outcomes in Healthcare / 19Leadership Training for the  Prospective Surgeon / 20Early Career Development and  Establishing Oneself 20Senior Faculty Development:  Transitioning to Departmental  Leadership and Legacy Building 21Conclusion 21Brunicardi_Ch01_p0001-p0026.indd 329/01/19 10:58 AM 4Table 1-1Accreditation Council for Graduate Medical Education core competenciesCORE COMPETENCYDESCRIPTIONPatient careTo be able to provide compassionate and effective healthcare in the modern-day healthcare environmentMedical knowledgeTo effectively apply current medical knowledge in patient care and to be able to use medical tools (i.e., PubMed) to stay current in medical educationPractice-based learning and improvementTo critically assimilate and evaluate information in a systematic manner to improve patient care practicesInterpersonal and communication skillsTo demonstrate sufficient communication skills that allow for efficient information exchange in physician-patient interactions and as a member of a healthcare teamProfessionalismTo demonstrate the principles of ethical behavior (i.e., informed consent, patient confidentiality) and integrity that promote the highest level of medical careSystems-based practiceTo acknowledge and understand that each individual practice is part of a larger healthcare delivery system and to be able to use the system to support patient careKey Points1 Effective surgical leadership improves patient care, safety, and clinical outcomes.2 A fundamental principle of leadership is to provide a vision that people can live up to, thereby providing direction and purpose to the constituency.3 Surgical leaders have the willingness to lead through an active and passionate commitment to the vision.4 Surgical leaders have the willingness to commit to lifelong learning.5 Surgical leaders have the willingness to communicate effec-tively and resolve conflict.6 Surgical leaders must practice effective time management.7 Different leadership styles are tools to use based on the team dynamic.8 Surgical trainees can be taught leadership principles in formal leadership training programs to enhance their ability to lead.9 Mentorship provides wisdom, guidance, and insight essen-tial for the successful development of a surgical leader.of business. In business, the processes of customer satisfaction, product development, and organization efficiency are the equiva-lent of patient satisfaction, medical advancement, and efficient delivery of care. Jim Collins, author of Good to Great, studied the success and leadership styles of Fortune 500 companies over a 30-year period. He found that leadership is strongly correlated with corporate success, and most importantly for our study, that leadership strength can be broken down by level and characteristic (See figure 1-1).8Of 11 particularly outstanding organizations identified, great leadership was the single major defining characteristic that distinguished them from their peers. These organizations were led by what Collins called the “Level 5 Leader,” one whose per-sonal humility and professional will drove team success. Under this system of leadership study, surgeon-leaders begin at the bottom level and, through study, hard work, and professional development, advance to the ultimate level of leadership.8FUNDAMENTAL PRINCIPLES OF LEADERSHIPLeadership is a complex concept. Surgeons should strive to adopt leadership qualities that provide the best outcomes for their patients, based on the following fundamental principles: vision, willingness, time management, conflict resolution, where they don’t necessarily want to go, but where they ought to be.” Leadership does not always have to come from a position of authority. Former American president John Quincy Adams stated, “If your actions inspire others to dream more, learn more, do more, and become more, you are a leader.” Another defini-tion is that leadership is the process of using social influence to enlist the aid and support of others in a common task.7Levels of LeadershipWhen working toward organizational success, strong leader-ship is a critical component. The best study of the relationship between leadership skill and organizational success is in the field LEVEL 5 EXECUTIVEBuilds enduring greatnessthrough a paradoxical combinationof personal humility plus professional will.LEVEL 4 EFFECTIVE LEADERCatalyzes commitment to and vigorous pursuitof a clear and compelling vision; stimulatesthe group to high performance standards.LEVEL 3 COMPETENT MANAGEROrganizes people and resources toward the effectiveand efficient pursuit of predetermined objectives.LEVEL 2 CONTRIBUTING TEAM MEMBERContributes to the achievement of groupobjectives; works effectively with others in a group setting.LEVEL 1 HIGHLY CAPABLE INDIVIDUALMakes productive contributions through talent, knowledge,skills, and good work habits.Figure 1-1. Levels of leadership as defined by Jim Collins in Good to Great. (Reproduced with permission from Collins J: Good to Great. Boston, MA: Harper Collins; 2011.)Brunicardi_Ch01_p0001-p0026.indd 429/01/19 10:58 AM 5LEADERSHIP IN SURGERYCHAPTER 1recruitment, and culture (See Table 1-2). Surgeon-leaders will develop a team of faculty, residents, and other healthcare per-sonnel who are aligned on mission, vision, and values. The team and leader must be willing to address complex problems with honest communication and well-developed conflict resolution skills. A culture must be established where faculty and staff will work towards the advancement of the medical arts and the greater good of society.9VisionThe first and most fundamental principle of leadership is to establish a vision that people can live up to, thus providing direction and purpose to the constituency. Creating a vision is a declaration of the near future that inspires and conjures motivation.10 A classic example of a powerful vision that held effective impact is President Kennedy’s declaration in 1961 that “. . . this nation should commit itself to achieving the goal, before this decade is out, of landing a man on the moon and returning him safely to the earth.” Following his declaration of this vision with a timeline to achieve it, the United Sates mounted a remarkable unified effort, and by the end of the decade, Neil Armstrong took his famous walk and the vision had been accomplished (Fig. 1-2).On a daily basis, surgeons are driven by a powerful vision: the vision that our surgical care will improve patients’ lives. The great surgical pioneers, such as Hunter, Lister (Fig. 1-3), Halsted, von Langenbeck, Billroth, Kocher (Fig. 1-4), Carrel, Gibbon, Blalock, Wangensteen, Moore, Rhoads, Huggins, Murray, Kountz, Longmire, Starzl, and DeBakey (Fig. 1-5), each possessed a vision that revolutionized the field of surgery. In the 19th century, Joseph Lister changed the practice of surgery with his application of Pasteur’s germ theory. He set a young boy’s open compound leg fracture, a condition with a 90% mortality 2Figure 1-2. Apollo 11 Lunar Module moon walk. Astronaut Edwin “Buzz” Aldrin walks by the footpad of the Apollo 11 Lunar Module, July 1969. (Reproduced with permission from AP Photo/NASA. © 2018 The Associated Press.)Figure 1-3. Joseph Lister directing use of carbolic acid spray in one of his earliest antiseptic surgical operations, circa 1865. (Used with permission from Getty Images.)rate at that time, using carbolic acid dressings and aseptic surgical technique. The boy recovered, and Lister gathered nine more patients. His famous publication on the use of aseptic technique introduced the modern era of sterile technique. Emil Theodor Kocher was the first to master the thyroidectomy, thought to be an impossible operation at the time, and went on to perform thousands of thyroidectomies with a mortality of less than 1%. He was awarded the Nobel Prize in Physiology or Medicine in 1909 for describing the thyroid’s physiologic role in metabolism. Michael E. DeBakey’s powerful vision led to the development of numerous groundbreaking procedures that helped pioneer the field of cardiovascular surgery. For example, envisioning an artificial artery for arterial bypass operations, Dr. DeBakey invented the Dacron graft, which has helped millions of patients suffering from vascular disease and enabled the development of endovascular surgery. Dr. Frederick Banting, the youngest recipient of the Nobel Prize in Physiology or Medicine, had a vision to discover the biochemical link between diabetes and glucose homeostasis. His vision and perseverance led to the discovery of insulin.11 In retrospect, the power and clarity of their visions were remarkable, and their willingness and dedication were inspiring. By studying their careers and accomplishments, surgical trainees can be inspired by the potential impact of a well-developed vision.Table 1-2The fundamental principles of leadershipLEADERSHIP SKILLDESCRIPTION AND APPLICATION IN THE FIELD OF MEDICINEVisionThe act of establishing tangible goals of care for patients on both a daily basis as well as for long-term purposes.Effective communicationEstablishing an open, respectful, and nonjudgmental forum for communication among different members of the healthcare team and with the patient.Willingness to leadTaking on full responsibility for the care of patients and remaining ethical, professional, and committed despite the especially challenging rigors of joining the field of surgery.Willingness to learnA commitment to lifelong learning of the latest scientific, medical, and surgical updates to deliver optimized patient care.Conflict resolutionThe art of resolving conflicts in a peaceful and ethical manner in team settings.Brunicardi_Ch01_p0001-p0026.indd 529/01/19 10:58 AM 6BASIC CONSIDERATIONSPART IFigure 1-5. Michael E. DeBakey. (Reproduced with permission from AP Photo/David J. Phillip. © 2018 The Associated Press.)Generating Belief in Your VisionSurgical leaders with great visions will inevitably require help from colleagues, other healthcare professionals, scientists, administrators, patients, and nonmedical personnel. To get this help, surgical leaders must inspire their team and understand motivation. For the surgeon-leader, it is critical to know that people do not follow leaders because of what they do; people follow leaders because of why they do what they do. The people who help the leader execute the vision are motivated by the leader’s beliefs and attitudes more than the leader’s policy or agenda. This concept, based on Simon Sinek’s Start With Why, is rooted in understanding of the anatomy and function of the human brain.13 See figure 1-6.For example, take a surgeon-leader who wants to imple-ment a new perioperative checklist to reduce surgical errors. The “what” is very simple: a checklist to reduce errors. The operating room team may make a rational decision to adapt the checklist; however, it is also possible that the checklist may be perceived as “another piece of paperwork” and rejected, or that the checklist may have its implementation fought, undermined, delayed, or ignored. A surgeon-leader who does not understand how people are motivated might argue rationally, telling the team that the checklist was created with great care, that all of the best evidence was incorporated in its creation, and that the checklist is short and efficient. This is the “how,” and once again it appeals to the rational and analytical side of the team. With these arguments, the surgeon-leader’s vision remains susceptible to rejection for many of the same reasons. A leader who understands how to motivate a team towards a vision will start with “why.” Before ever discussing the checklist in detail with the team, the leader will speak of their shared mission to offer the best patient care possible, ask the team to imagine how they might want a family member treated, and emphasize that a careless error could lead to patient harm and embarrassment for the team. With these argu-ments, which constitute an emotional appeal to the team’s belief system, the leader can expect this vision for better patient care via a new surgical checklist to be adapted by the team. The team will be receptive to implementing a new checklist, not because they believe in the checklist as a tool, but because they believe in the surgeon-leader’s vision for optimizing patient care.There is a biological reason why this concept works. “Why,” “how,” and “what” are correlated to the functions Figure 1-4. Emil Theodor Kocher. (Reproduced with permission from the National Library of Medicine.)Leaders must learn to develop a vision to provide direction for their team. The vision can be as straightforward as provid-ing quality of care or as lofty as defining a new field of sur-gery, such as atomic surgery and personalized medicine. One can start developing such vision by brainstorming the answers to two simple questions: “Which disease needs to be cured?” and “How can it be cured?”12 The answers represent a vision and should be recorded succinctly in a laboratory notebook or journal. Committing pen to paper enables the surgical trainee to define his or her vision in a manner that can be shared with others.WhatHowWhyNeocortexLimbic BrainWhen a leader's vision appeals to “why,” it triggers an emotional response in the limbic brain and increases the likelihood that a vision will be embraced. Persuasion using “what” and “how” appeals to the neocortex and is more easily rejected.Figure 1-6. When leaders seek to generate belief in their vision, it is best to appeal to the team with “why” statements. (Data from Sinek S. Start with why: how great leaders inspire everyone to take action. London: Portfolio/Penguin; 2013.)Brunicardi_Ch01_p0001-p0026.indd 629/01/19 10:58 AM 7LEADERSHIP IN SURGERYCHAPTER 1of separate anatomical levels in the human brain. The neo-cortex is, evolutionarily, the newest area of our brains, and it is responsible for the analytical and rational thoughts and decisions that we make. It corresponds to the “what” and the “how.” When the surgeon-leader in the previous example started with the checklist and its rational arguments, the leader was appealing to their team’s neocortex, and the vision was rejected. However, when the surgeon started with the “why,” the vision for better patient care was emotionally accepted by the team, who became receptive to the checklist as a tool for achieving the vision.13Surgery is a field that requires extraordinary dedication and great personal sacrifice. The very nature of vision—steps forward into a better future—implies that change and difficult work will be required of the leader. See figure 1-7. For this reason, surgeon-leaders should establish visions about which they are deeply pas-sionate and committed so that when obstacles are encountered the leader has the strength of will to progress forward. Leaders should be selective about which options they pursue. Each oppor-tunity and idea requires great effort to execute; ultimately only a few can be brought to completion. Therefore, leaders should understand what drives their organization’s economic engine: the ideas and opportunities that will bring patients better care, bring the organization more patients, and create new treatments, etc. Thousands of hospitals, companies, innovators, and physicians are addressing many of the same problems in healthcare, such as growing burdens of chronic disease, an aging population, and ris-ing health costs. The best opportunities lie where talent and ability align, so leaders and organizations should be cognizant of choos-ing projects for which they have the potential to be the “best in the world” at doing. Once the vision is set and the project is chosen, it is up to the leader to generate momentum.Momentum is either a cumulative effect of continuous steps towards improvement or, alternatively, in the negative sense, movements towards failure or stagnation. The “flywheel effect,” depicted in Fig. 1-8, demonstrates the building of momentum with (a) initial steps forward, (b) an accumulation of visible results, (c) realignment of the team in the new direc-tion (accounting for new information and data), and then (d) an accumulation of momentum followed by more steps forward. Careful attention to the aforementioned principles is essential in building a successful surgical career, department, or division.8The Flywheel Effect of Building and SustainingMomentumStepsforwardVisibleresultsMomentumbuildsThe Teamaligns andadjustsFigure 1-8. The “flywheel effect.” (Data from Collins J: Good to Great. Boston, MA: Harper Collins; 2011.)WHAT YOU ARE DEEPLYPASSIONATE ABOUTWHAT DRIVESYOURECONOMICENGINEWHAT YOU CANBE THE BEST INTHE WORLD ATFigure 1-7. Leaders should be selective about where they expend their efforts, as demonstrated by Jim Collins in “Good to Great.” (Reproduced with permission from Collins J: Good to Great. Boston, MA: Harper Collins; 2011.)WillingnessThe Willingness Principle represents the active commitment of the leader toward his or her vision. To do so, a surgical leader must be willing to lead, commit to lifelong learning, communi-cate effectively, and resolve conflict.To Lead. A key characteristic of all great leaders is the will-ingness to serve as the leader. Dr. Martin Luther King Jr, who championed the civil rights movement with a powerful vision of equality for all based on a commitment to nonviolent methods,14 did so at a time when his vocalization of this vision ensured harassment, imprisonment, and threats of violence against him-self, his colleagues, and his family and friends (Fig. 1-9). King, a young, highly educated pastor, had the security of employ-ment and family, yet was willing to accept enormous respon-sibility and personal risk and did so in order to lead a nation toward his vision of civil rights, for which he was awarded the Nobel Peace Prize in 1964.Willingness to lead is a necessity in any individual who desires to become a surgeon. By entering into the surgical the-ater, a surgeon accepts the responsibility to care for and operate on patients, despite the risks and burdens involved. They do so, believing fully in the improved quality of life that can be achieved. Surgeons must embrace the responsibility of leading surgical teams that care for their patients, as well as leading sur-gical trainees to become future surgeons. A tremendous sacrifice is required for the opportunity to learn patient care. Surgical trainees accept the hardships of residency with its accompanying steep learning curve, anxiety, long work hours, and time spent away from family and friends. The active, passionate commit-ment to excellent patient care reflects a natural willingness to lead based on altruism and a sense of duty toward those receiving care. Thus, to ensure delivery of the utmost level of care, surgical trainees should commit to developing and refining leadership skills. These skills include a commitment to lifelong learn-ing, effective communication, and conflict resolution.To Learn. Surgeons and surgical trainees, as leaders, must possess willingness to commit to continuous learning. Modern surgery is an ever-changing field with dynamic and evolving healthcare systems and constant scientific discovery and inno-vation. Basic and translational science relating to surgical care is growing at an exponential rate. The sequencing of the human 3Brunicardi_Ch01_p0001-p0026.indd 729/01/19 10:58 AM 8BASIC CONSIDERATIONSPART Igenome and the enormous advances in molecular biology and signaling pathways are leading to the transformation of pre-cision medicine and personalized surgery in the 21st century (see Chapter 15).15 Performing prophylactic mastectomies with immediate reconstruction for BRCA1 mutations and thyroidecto-mies with thyroid hormone replacement for RET proto-oncogene mutations are two of many examples of genomic information guiding surgical care. Technologic advances in minimally inva-sive surgery and robotic surgery as well as electronic records and other information technologies are revolutionizing the craft of surgery. The expansion of minimally invasive and endovas-cular surgery over the past three decades required surgeons to retrain in new techniques using new skills and equipment. In this short time span, laparoscopy and endovascular operations are now recognized as the standard of care for many surgical diseases, resulting in shorter hospital stay, quicker recovery, and a kinder and gentler manner of practicing surgery. Remarkably, during the last century, the field of surgery has progressed at an exponential pace and will continue to do so with the advent of using genomic analyses to engineer cancer cells with molecular imaging agents that will guide personalized surgery, which will transform the field of surgery during this century. Therefore, surgical leadership training should emphasize and facilitate the continual pursuit of knowledge.Willingness to learn encompasses the surgeon’s commit-ment to lifelong learning. This has been exemplified by the surgeons of the past several decades who have dedicated their peak practicing years to perfecting minimally invasive surgical Figure 1-9. Dr. Martin Luther King Jr acknowledges the crowd at the Lincoln Memorial for his “I Have a Dream” speech during the March on Washington, D.C., August 28, 1963. (Reproduced with permission from AP Photo. © 2018 The Associated Press.)techniques, including the use of robotic surgery. The field con-tinues to advance, offering many advantages to patients includ-ing faster recovery, sometimes decreased pain depending on procedure type, and shorter hospital stays.16-18Fortunately, surgical organizations and societies provide surgeons and surgical trainees a means to acquire new knowl-edge on a continuous basis. There are numerous local, regional, national, and international meetings of surgical organizations that provide ongoing continuing medical education credits, also required for the renewal of most medical licenses. The American Board of Surgery requires all surgeons to complete meaningful continuing medical education to maintain certification.19 These societies and regulatory bodies enable surgeons and surgical trainees to commit to continual learning and ensure their competence in a dynamic and rapidly growing field.Surgeons and trainees now benefit from the rapid expan-sion of web-based education as well as mobile handheld tech-nology. These are powerful tools to minimize nonproductive time in the hospital and make learning and reinforcement of medical knowledge accessible. Currently web-based resources provide quick access to a vast collection of surgical texts, lit-erature, and surgical videos. Surgeons and trainees dedicated to continual learning should be well versed in the utilization of these information technologies to maximize their education. The next evolution of electronic surgical educational materials will likely include simulation training similar to laparoscopic and Da Vinci device training modules. The ACGME, acknowl-edging the importance of lifelong learning skills and moderniza-tion of information delivery and access methods, has included them as program requirements for residency accreditation.To Communicate Effectively. The complexity of modern healthcare delivery systems requires a higher level and collab-orative style of communication. Effective communication directly impacts patient care. In 2000, the U.S. Institute of Medi-cine published To Err Is Human: Building a Safer Health System, which raised awareness concerning the magnitude of medical errors. This work showcased medical errors as the eighth leading cause of death in the United States with an estimated 100,000 deaths annually.20 Subsequent studies examining medical errors have identified communication errors as one of the most com-mon causes of medical error.21-23 In fact, the Joint Commission identifies miscommunication as the leading cause of sentinel events. Information transfer and communication errors cause delays in patient care, waste surgeon and staff time, and cause serious adverse patient events.23 Effective communication among surgeons, nurses, ancillary staff, and patients is not only a crucial element to improved patient outcomes, but it also leads to less medical litigation.24-26 A strong correlation exists between communication and patient outcomes.Establishing a collaborative atmosphere is important since communication errors leading to medical mishaps are not simply failures to transmit information. Communication errors “are far more complex and relate to hierarchical differences, concerns with upward influence, conflicting roles and role ambiguity, and interpersonal power and conflict.”22,27-29 Errors frequently originate from perceived limited channels of com-munication and hostile, critical environments. To overcome these barriers, surgeons and surgical trainees should learn to communicate in an open, universally understood manner and remain receptive to any team member’s concerns. A survey of physicians, nurses, and ancillary staff identified effective communication as a key element of a successful leader.30 As 45Brunicardi_Ch01_p0001-p0026.indd 829/01/19 10:58 AM 9LEADERSHIP IN SURGERYCHAPTER 1leaders, surgeons, and surgical trainees who facilitate an open, effective, and collaborative style of communication can reduce errors and enhance patient care. A prime example is that suc-cessful communication of daily goals of patient care from the team leader improves patient outcomes. In one recent study, the modest act of explicitly stating daily goals in a standard-ized fashion significantly reduced patient length of intensive care unit stay and increased resident and nurse understanding of goals of care.31 Implementing standardized daily team briefings in the wards and preoperative units led to improvements in staff turnover rates, employee satisfaction, and prevention of wrong-site surgery.27 In cardiac surgery, improving communication in the operating room and transition to the postanesthesia care unit was an area identified to decrease risk for adverse outcomes.32 Behaviors associated with ineffective communication, including absence from the operating room when needed, playing loud music, making inappropriate comments, and talking to others in a raised voice or a condescending tone, were identified as patient hazards; conversely, behaviors associated with effec-tive collaborative communication, such as leading the time-out process and closed-loop communication technique, resulted in improved patient outcomes.One model to ensure open communication is through standardization of established protocols. A commonly accepted protocol is the “time out” that is now required in the modern operating room. During the time-out protocol, all team mem-bers introduce themselves and state a body of critical informa-tion needed to safely complete the intended operation. This same standardization can be taught outside the operating room. Within the Kaiser system, certain phrases have been given a uni-versal meaning: “I need you now” by members of the team is an understood level of urgency and generates a prompt physician response 100% of the time.27 As mentioned earlier, standardized forms can be useful tools in ensuring universally understood communication during sign-out. The beneficial effect of stan-dardized team communication further demonstrates how effec-tive communication can improve patient care and is considered a vital leadership skill.Effective communication with patients in the mod-ern era, necessitates understanding that many patients access health information via the internet and that patients are often ill equipped to evaluate the individual source.33,34 Discrepancies exist between surgeon’s self-perceived ability to communicate and patient’s actual satisfaction. A patient’s perceived interac-tion with their physician has an enormous impact on patient health outcomes, malpractice, and financial reimbursement;35-40 specifically, the association between poor doctor–patient com-munication and a patient’s perception that their doctor does not care about them. Good bedside manner has been shown to decrease litigation even in situations of error or undesirable out-come.39-40 Physicians who demonstrate concern, actively know their patients, and share responsibility for decision-making are more likely to be trusted by their patients.26,41,42 Strong doctor–patient relationships and effective communication skills have been incentivized by the Agency for Healthcare Research and Quality and the Centers for Medicare & Medicaid Services through their Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) and Clinical and Group Consumer Assessment of Healthcare Providers and Systems (CGCAHPS) programs, which measure patient satisfaction.43To Resolve Conflict. Great leaders are able to achieve their vision through their ability to resolve conflict. Delivery of modern surgical care is complex; numerous conflicts arise on a daily basis when surgeons and surgical trainees provide high-quality care. Therefore, the techniques for conflict resolution are essential for surgical leaders.To properly use conflict resolution techniques, it is impor-tant for the surgeon and surgical trainee to always remain objec-tive and seek personal flexibility and self-awareness. The gulf between self-perception and the perception of others can be profound; in a study of cooperation and collaboration among operating room staff, the quality of their own collaboration was rated at 80% by surgeons, yet was rated at only 48% by oper-ating room nurses.44 Systematic inclusion of modern conflict resolution methods that incorporate the views of all members of a multidisciplinary team help maintain objectivity. Reflection is often overlooked in surgical residency training, but it is a critical component of learning conflict resolution skills. Introspection allows the surgeon to understand the impact of his or her actions and biases. Objectivity is the basis of effective conflict resolu-tion, which can improve satisfaction among team members and help deliver optimal patient care.Modern conflict resolution techniques are based on objec-tivity, willingness to listen, and pursuit of principle-based solu-tions.45 For example, an effective style of conflict resolution is the utilization of the “abundance mentality” model, which attempts to achieve a solution that benefits all involved and is based on core values of the organization, as opposed to the uti-lization of the traditional fault-finding model, which identifies sides as right or wrong.46 Application of the abundance mental-ity in surgery elevates the conflict above the affected parties and focuses on the higher unifying goal of improved patient care. “Quality Improvement” (previously or alternatively “Morbidity and Mortality”) conferences are managed in this style and have the purpose of practice improvement and improving overall quality of care within the system, as opposed to placing guilt or blame on the surgeon or surgical trainees for the complication being reviewed. The traditional style of command-and-control technique based on fear and intimidation is no longer welcome in any healthcare system and can lead to sanctions, lawsuits, and removal of hospital privileges or position of leadership.Another intuitive method that can help surgical trainees learn to resolve conflict is the “history and physical” model of conflict resolution. This model is based on the seven steps of caring for a surgical patient that are well known to the surgical trainee47: (a) the “history” is the equivalent of gathering subjec-tive information from involved parties with appropriate empa-thy and listening; (b) the “laboratory/studies” are the equivalent of collecting objective data to validate the subjective informa-tion; (c) a “differential diagnosis” is formed out of possible root causes of the conflict; (d) the “assessment/plan” is developed in the best interest of all involved parties; the plan, including risks and benefits, is openly discussed in a compassionate style of com-munication; (e) “preoperative preparation” includes the acquisi-tion of appropriate consultations for clearances, consideration of equipment and supplies needed for implementation, and the “informed consent” from the involved parties; (f) the “operation” is the actual implementation of the agreed-upon plan, including a time-out; (g) and “postoperative care” involves communicat-ing the operative outcome, regular postoperative follow-up, and the correction of any complications that arise. This seven-step method is an example of an objective, respectful method of con-flict resolution.47 Practicing different styles of conflict resolu-tion and effective communication in front of the entire group of Brunicardi_Ch01_p0001-p0026.indd 929/01/19 10:58 AM 10BASIC CONSIDERATIONSPART Isurgical trainees attending the leadership training program is an effective means of teaching conflict resolution techniques.Time ManagementIt is important for leaders to practice effective time management. Time is the most precious resource, as it cannot be bought, saved, or stored. Thus, management of time is essential for a productive and balanced life for those in the organization. The effective use of one’s time is best done through a formal time management program to improve one’s ability to lead by setting priorities and making choices to achieve goals. The efficient use of one’s time helps to improve both productivity and quality of life.48-50It is important for surgeons and surgical trainees to learn and use a formal time-management program. There are ever-increasing demands placed on surgeons and surgical trainees to deliver the highest quality care in highly regu-lated environments. Furthermore, strict regulations on limita-tion of work hours demand surgical trainees learn patient care in a limited amount of time.48-50 All told, these demands are enormously stressful and can lead to burnout, drug and/or alcohol abuse, and poor performance.48-50 A time-motion study of general surgery trainees analyzed residents’ self-reported time logs to determine resident time expenditure on educa-tional/service-related activities (Fig. 1-10).50 Surprisingly, senior residents were noted to spend 13.5% of their time on low-service, low-educational value activities. This time, prop-erly managed, could be used to either reduce work hours or improve educational efficiency in the context of new work hour restrictions. It is therefore critical that time be used wisely on effectively achieving one’s goals.Parkinson’s law, proposed in 1955 by the U.K. politi-cal analyst and historian Cyril Northcote Parkinson, states that work expands to fill the time available for its completion, thus leading individuals to spend the majority of their time on insignificant tasks.51 Pareto’s 80/20 principle states that 80% of goals are achieved by 20% of effort and that achieving the final 20% requires 80% of their effort. Therefore, proper planning for undertaking any goal needs to include an analysis of how much effort will be needed to complete the task.49 Formal time management programs help surgeons and surgical trainees bet-ter understand how their time is spent, enabling them to increase productivity and achieve a better-balanced lifestyle.Various time allocation techniques have been described.49 A frequently used basic technique is the “prioritized list,” also known as the ABC technique. Individuals list and assign relative 6Low educationLow serviceHigh serviceHigh educationTime Motion StudyLow education, lowservice value (Ex: Waiting duringmandatory in-house call)High education, lowservice value (Ex: Teaching conferences)High education, highservice value (Ex: Operating with a mentor)Low education,high service value (Ex: Repeatedly performing History & Physicals)values to their tasks. The use of the lists and categories serves solely as a reminder, thus falling short of aiding the user in allo-cating time wisely. Another technique is the “time management matrix technique.”49 This technique plots activities on two axes: importance and urgency, yielding four quadrants (Fig. 1-11). Congruous with the Pareto’s 80/20 principle and Parkinson’s law, the time management matrix technique channels efforts into quadrant II (important but nonurgent) activities. The activi-ties in this quadrant are high yield and include planning, creative activity, building relationships, and maintaining productivity. Too often, surgeons spend a majority of their time attending to quadrant I (important and urgent) tasks. Quadrant I tasks include emergencies and unplanned or disorganized situations that require intensive and often inefficient effort. While most surgeons and surgical trainees have to deal with emergencies, they often develop the habit of inappropriately assigning activi-ties into quadrant I; excess time spent on quadrant I tasks leads to stress or burnout for the surgeon and distracts from long-term goals. Efficient time management allows surgeons and surgical trainees to be proactive about shifting energy from quadrant I tasks to quadrant II, emphasizing preplanning and creativity over always attending to the most salient issue at hand, depend-ing on the importance and not the urgency.Finally, “the six areas of interest” is an alternative effec-tive time management model that can help surgeons and surgi-cal trainees achieve their goals, live a better-balanced lifestyle, and improve the quality of their lives.49 The process begins by performing a time-motion study in which the activities of 6-hour increments of time over a routine week are chronicled. At the end of the week, the list of activities is analyzed to determine how the 168 hours in 1 week have been spent. The surgical trainee then selects six broad categories of areas of interest ImportantUrgentQuadrant IQuadrant IIIQuadrant IIQuadrant IVNonurgentTime Management MatrixNonimportantFigure 1-11. Time management. (Data from Covey S. The Seven Habits of Highly Effective People. New York, NY: Simon & Schuster; 1989.)Figure 1-10. Surgery resident time-motion study.Brunicardi_Ch01_p0001-p0026.indd 1029/01/19 10:58 AM 11LEADERSHIP IN SURGERYCHAPTER 1(i.e., family, clinical care, education, health, community service, hobbies) and sets a single activity goal in each category every day and monitors whether those goals are achieved. This tech-nique is straightforward and improves one’s quality of life by setting and achieving a balanced set of goals of personal inter-est, while eliminating time-wasting activities.A formal time management program is essential for modern leadership. The practice and use of time management strategies can help surgeons and surgical trainees achieve and maintain their goals of excellent clinical care for their patients, while maintaining a more balanced lifestyle.Self-Care and WellnessThe challenges of practicing medicine place unique stresses on surgeons. A departmental program for improving wellness and teaching self-care can help alleviate these stresses. Acknowl-edging these stresses is an important step for any leader to help peers at risk. Quality of life surveys have identified individual protective factors that can be implemented prophylactically. These factors for improving self-care and wellness include regu-lar exercise programs, maintenance of routine medical care, and health screening. The following may not apply to all physicians; however, religious practices, reflective writing, and maximizing work-life balance have also been demonstrated to be protective.52Surgeons and physicians overall experience increased rates of suicide, depression, substance abuse, marital and family prob-lems, and other stress-related health effects as compared to the general population. Suicide rates in physicians are higher among those who are divorced, widowed, or never married. Depression is a common challenge, with rates as high as 30% among trainees, and higher when lifetime risk is considered. Drug and alcohol abuse among physicians mirrors the general population; however, physicians have higher rates of prescription drug abuse. The abil-ity to self-medicate likely contributes to prescription drug abuse by physicians. Divorce and marriage unhappiness among physi-cians has been attributed to the “psychology of postponement,” compulsive personality traits that are reinforced and selected for during medical training, and lack of work-life balance. Residents, due to their inexperience, may be at higher risk than practicing physicians. For physicians who do not seek professional help, fear of losing their medical license is the most commonly provided reason. Departmental wellness programs may provide an alterna-tive source of support for these surgeons.52-54The past 10 years have seen a significant increase in atten-tion to the issue of physician wellness. Physician wellness has become an issue transcending specialties and resulting in signif-icant research. The creation of wellness and self-care programs within departments represents an opportunity for surgeons to demonstrate leadership qualities.52-54RecruitmentThe challenges of modern medicine and ever-larger medical centers have created a reality where no single surgeon-leader can exercise complete control—it takes a team of leaders with shared vision, mission, and goals. To this end, the previously discussed “level 5 leader” who embodies personal humility and professional will is essential.8 Previous generations whose lead-ers and departments were composed of self-proclaimed giants dominated and suppressed alternative points of view, com-munication, and innovation. In recent years, there has been a change to building teams with authentic leaders who have high ethical standards and well-developed nontechnical skills, who lead by example, and who never compromise excellence. The surgeon-leader must build a team where talented individuals are placed in the right job for their skills. The essence of a leader is one who enables others to succeed. Team work is imperative to change, and trust is the make-or-break component. Simply put, teams that trust each other work well, and teams that do not trust each other do not work well.9Creating a Culture of Empathy, Patient-Family-Centered Care, and Personalized SurgeryCreating the right culture is the most challenging of all the sur-geon-leader’s tasks. Modern surgical departments should focus on creating a culture of empathy, patient–family-centered care, and personalized surgery. Instilling a positive culture requires both discipline and consistency because it may take consider-able time to change how people think, feel, and behave.9,55,56 Organizational culture is built around the leader’s vision and values. Coming up with strong values requires genuine com-mitment. A leader should realize that staying true to his or her values can be challenging when conflicts arise.57WHY WE LEADChoosing to Become a LeaderThere are many benefits to becoming a leader. Humankind has pondered the question of whether leaders are born or made for millennia. The best evidence to date indicates that leaders are both born and made. Leadership potential is a skill that all per-sons are born with, to some degree, and that can be formally trained, learned through observation, and honed with practice.13 The positive effects of a leader on others are innumerable, including a leader’s positive influence on innovation, diversity, culture, and quality. For modern surgeons, leadership skills are essential for the delivery of quality patient care; therefore, it is the duty of the surgeon to study leadership.For the surgeon studying to be a better leader, effective leadership also has many individual benefits, including rec-ognition from one’s peers, promotion, and autonomy. Mod-ern leaders are increasingly required to be humble about their accomplishments in order to be successful and effective.8 Beyond recognition, promotion, and autonomy there are more selfless reasons for surgeons to desire leadership. Leadership is a tool to help make a difference. Leadership is a good path towards a career as an educator, which offers the leader a sense of accomplishment and satisfaction in seeing others succeed. Some choose to become leaders out of a sense of selfless ser-vice, taking on leadership for the benefit of others, or out of a desire to solve problems. Leadership may come with material rewards, including wealth and power, which motivate some.Whatever the motivation, surgeons, in their role as lead-ers of patient care teams, have a duty to develop some skill in leadership. It would be best for individuals, departments, and patients if all surgeons sought to develop leadership skills and experience in some area of administration, patient care, educa-tion, or research. The benefits to the individual are numerous.Leadership’s Effect on Healthcare Cost and Clinical OutcomesMuch attention has rightly been paid to historical leaders’ impact on humanity. Surgical leaders of the past have made great contributions on which we may build. All surgeons have a responsibility to be leaders, whether at the team level or in Brunicardi_Ch01_p0001-p0026.indd 1129/01/19 10:58 AM 12BASIC CONSIDERATIONSPART Ian administrative or organizational capacity. To that end, it is worth noting the benefits of formal leadership education.Large observational studies using trained observers assessed the effects of different surgical leadership styles on operative cases. Team cohesion and collective efficiency were reduced when leaders utilized abusive supervision or over-controlling methods. Abusive supervision alone was associated with decreased “psychological safety.”58 Surgeons perceived as having positive leadership characteristics by their staff have lower 30-day all-cause mortality.59 This is likely due to creating a culture of safety where the staff can speak up if they notice an error and feel they have the latitude to do what is best for the patient quickly and autonomously.59,60With increased recognition and attention on human error, nontechnical skills, including leadership, play a role in patient safety. The landmark study, “To Err Is Human,” estimated that almost 100,000 people die each year due to medical errors.20 In the surgical setting, 40% to 50% of errors may be attributed to communication breakdown. The Multifactor Leadership Ques-tionnaire scores subjects on their demonstration of transforma-tional leadership behaviors. Transformational leaders exhibit the qualities of charisma, inspired motivation, intellectual stimulation, and individualized consideration. In video analysis of complex surgical operations, surgeons scoring even a single point higher on the transformational leadership score exhibited 3 times more information sharing behaviors, 5 times more posi-tive voice behaviors, and 10 times more supportive behaviors, all while displaying poor behaviors 12.5 times less frequently than their peers.60 Exhibiting the characteristics of transforma-tional leadership clearly has much to offer the surgeon-leader in preventing serious errors.58-60The field of trauma contains the largest body of formal study demonstrating the positive effects of leadership on clini-cal results. Strong leadership skills improve both the speed of resuscitation and completion of the initial trauma evaluation.61-63 There is no one optimal style of leadership covering all situa-tions; some call for a more empowering leadership style while others call for a more directive style. The optimal style of lead-ership varies based on team composition, with less experienced teams better responding to the directive style, while more expe-rienced teams work faster with trust and an empowering style. The formally educated surgical leader should be able to switch easily between styles based on the situation at hand.56,58,60-64Leadership styles affect responses to patient safety con-cerns and protect the organization as a whole. The surgical leader adopts a supervisory capacity while creating a culture of safety. In detail, frontline staff must be encouraged to partici-pate in safety improvement. Staff ownership of safety must be established and upheld. In order to assure this outcome, whistle-blowers must be protected. A culture of psychological safety, organizational fairness, and continuous learning is required. Subordinates require appropriate authority, autonomy, and lati-tude to do their jobs and care for patients.60Formal leadership training has been well studied within the Veteran’s Health Administration system using the Surgical Care Improvement Program. The Medical Team Training Pro-gram, for instance, has been shown to result in a 18% decrease in 30-day mortality65 and a 17% decrease in 30-day morbidity.66Also at the organizational level, leaders using an empowering style may improve process of care protocols and increase efficiency. Operating room turnover times specifically have been shown to be reducible.67 Value-based purchasing benchmarks, such as hospital-acquired infections, which affect reimbursement, can be reduced or eliminated depending on the measure.68,69 Medical errors may be reduced, and significant medical errors may have their effects mitigated. Patient satis-faction may be improved. The overall financial performance of the institution can be affected in a positive manner.69,70There are positive correlations between mutual respect, clinical leadership, and surgical safety. Traditional command and control style leadership negatively impacts psychological safety resulting in the development of more modern leadership styles. The best clinical processes have the potential to break down when there is a toxic work environment and lack of psy-chological safety within the team.The Importance of Diversity and LeadershipThe past quarter century has seen a steady increase in diversity within the field of surgery. Women, as of 2015, represent 38% of surgical trainees and 10% of academic professors currently, but have doubled their representation in the past 20 years.71 Some fields, such as head and neck surgery and plastic surgery72 have studied their own subspecialty groups with similar find-ings. African Americans comprise both 6% of medical school graduates, 6% surgical trainees, and 2% to 4% of professors of surgery nationwide.73 Hispanics represent 5% of graduat-ing medical students, 9% of general surgery trainees, and 4% to 5% of persons at all levels of academic surgery.73 Physician diversity is crucial and may help to address disparities in social determinants of health.74Studies indicate that the bottleneck in diversity occurs at the level of the medical school application pool, which in turn is caused by educational deficiencies at the primary, secondary, and collegiate level.73,75-78 As an attempted solution, the University of Michigan developed a “pipeline” program that pairs grade-school and high-school students with physicians for experiential learn-ing and the development of mentoring, presentation skills, and networking.75 It is important for departments of surgery to develop a diversity program for recruitment of residents and faculty. Multi-institutional blinded studies indicate that the implementa-tion of formal leadership and diversity training improves diversity leadership and strategic human resource management.74,78LEADERSHIP STYLESThe principles of leadership can be practiced in a variety of styles. Just as there are many definitions of leadership, many classifications of styles exist as well. A landmark study by Daniel Goleman in Harvard Business Review identified six distinct leadership styles, based on different components of emotional intelligence.79 Emotional intelligence is the ability to recognize, understand, and control the emotions in others and ourselves. By learning different styles, surgeons and trainees can recognize their own leadership style and the effect on the team dynamic. Furthermore, it teaches when the situation may demand change in style for the best outcome. The six leadership styles identified are coercive, authoritative, affiliative, demo-cratic, pacesetting, and coaching.The coercive leader demands immediate compliance. This style reflects the command and control style that has histori-cally dominated surgery. Excessive coercive leadership erodes team members’ sense of responsibility, motivation, sense of participation in a shared vision, and ultimately, performance. The phrase, “Do what I tell you!” brings to mind the coercive leader. However, it is effective in times of crisis to deliver clear, Brunicardi_Ch01_p0001-p0026.indd 1229/01/19 10:58 AM 13LEADERSHIP IN SURGERYCHAPTER 1concise instruction. This style should be used sparingly and is best suited for emergencies.The authoritative leader embodies the phrase “Come with me,” focusing on mobilizing the team toward a common, grand vision. This type of leader allows the team freedom to innovate, experiment, and devise its own means. Goleman’s research indicates this style is often the most effective. These leaders display self-confidence, empathy, and proficiency in initiating new ideas and leading people in a new direction. This is best used when a shift in paradigm is needed.The affiliative leader creates harmony and builds emo-tional bonds. This requires employment of empathy, building relationships, and emphasis on communication. An affiliative leader frequently gives positive feedback. This style can allow poor performance to go uncorrected if too little constructive/critical advice is given. Affiliative leadership is most useful when motivating people during stressful circumstances or heal-ing rifts in a team.The coaching style of leadership focuses on developing people for the future. Coaching is leadership through mentor-ship. The coach gives team members challenging tasks, coun-sels, encourages, and delegates. Unlike the affiliative leader who focuses on positive feedback, the coach helps people iden-tify their weaknesses and improve their performance, and ties their work into their long-term career aspirations. This leader-ship style builds team capabilities by helping motivated learners improve. However, this style does not work well when team members are defiant and unwilling to change or learn, or if the leader lacks proficiency.The democratic leader forges consensus through participa-tion. This leadership style listens to and values each member’s input. It is not the best choice in an emergency situation, when time is limited, or when teammates cannot contribute informed guidance to the leader. It can also be exasperating if a clear vision does not arise from the collaborative process. This style is most appropriate when it is important to obtain team consensus, quell conflict, or create harmony.The pacesetter leader sets high standards for performance and exemplifies them. These leaders identify poor performers and demand more from them. However, unlike the coach, the pacesetter does not build the skills of those who are not keep-ing up. Rather, a pacesetter will either take over the task him-self or delegate the task to another team member. This style can be summed up best by the phrase, “Do as I do, now.” This leadership style works well when it is important to obtain high-quality results and there is a motivated, capable team. However, pacesetters can easily become micromanagers who have diffi-culty delegating tasks to team members, which leads to burn out on the part of the leader. Additionally, team members can feel overwhelmed and demoralized by the demands for excellence without an empathic counter balance.Each of the above styles of leadership has strengths and weakness. Importantly, leaders who are the most successful do not rely only on one leadership style alone. They use sev-eral of them seamlessly depending on the situation and the team members at hand. Therefore, the more styles a leader has mastered, the better, with particular emphasis on the authorita-tive, affiliative, democratic, and coaching styles. Each leader-ship style is a tool that is ultimately employed to guide a team to realizing a vision or goal. Thus, leadership training programs should teach the proper use of all leadership styles while adher-ing to the principles of leadership.7FORMAL LEADERSHIP TRAINING PROGRAMS IN SURGERYHistory of Leadership Training and the Multifactor Leadership QuestionnaireSince it has been shown that effective leadership can improve patient outcomes, leadership principles and skills should be taught to surgical trainees using formal leadership training programs. The importance of teaching leadership skills is reflected by the ACGME mandated core competencies (see Table 1-1). However, surgical trainees, most notably chief residents, find themselves in various leadership roles without ever having experienced formal-ized leadership training, which has been shown to result in a self-perceived lack of leadership ability.2 When surveyed on 18 core leadership skills (Table 1-3), 92% of residents rated all 18 skills as important, but over half rated themselves as “minimally” or “not competent” in 10 out of 18 skills.2 Increasingly, residents and junior faculty are requesting leadership training and wish to close the gap between perceived need for training and the implementa-tion of formal leadership training programs.80-86A number of leadership workshops have been created. Extracurricular leadership programs have been designed mostly Table 1-3Eighteen leadership training modulesSKILLSIMPORTANCE MEAN SCORECOMPETENCE MEAN SCORE*Academic program development3.22.4*Leadership training3.82.3*Leadership theory3.22.1*Effective communication3.72.7*Conflict resolution3.83*Management principles3.72.7*Negotiation3.72.8*Time management42.8*Private or academic practice, managed care3.62*Investment principles3.52.2*Ethics3.63.2Billing, coding, and compliance3.51.7*Program improvement32*Writing proposals3.32.2*Writing reports3.42.4*Public speaking3.72.7*Effective presentations3.72.7*Risk management3.52.1*Total3.62.5**P <0.001 by Student t-test between mean importance and mean competence scores.Reproduced with permission from Itani KMF, Liscum K, Brunicardi FC: Physician leadership is a new mandate in surgical training, Am J Surg. 2004 Mar;187(3):328-331.Brunicardi_Ch01_p0001-p0026.indd 1329/01/19 10:58 AM 14BASIC CONSIDERATIONSPART Ifor physicians with an MBA or management background but have not been incorporated into the core residency training program.80 Also, there are many institutions that have published experiences with leadership retreats or seminars for residents or young physicians.81-84 The ACGME hosts multiple leader-ship skills workshops for chief residents, mostly targeted toward pediatricians, family practitioners, and psychiatrists.85 Similarly, the American College of Surgeons leads an annual 3-day lead-ership conference focusing on leadership attributes, consensus development, team building, conflict resolution, and translation of leadership principles into clinical practice.86-87 These pro-grams were all received well by participants and represent a call for a formal leadership program for all surgical trainees.An innovative leadership curriculum first implemented in 2000, prior to work-hour restrictions, taught general surgery trainees’ collaborative leadership skills at a time when the tradi-tional command-and-control leadership style predominated.2,89,90 Surgical residents participated in 18-hour-long modules based on the leadership principles and skills listed in Table 1-2, taught by the surgical faculty. A number of leadership techniques, including time management techniques and applied conflict resolution techniques described earlier, were designed and implemented as part of this leadership training program. Within 6 months of implementation, residents’ self-perceived total commitment to the highest personal and professional standards, communication skills, visualization of clear missions of patient care, and leadership of others toward that mission increased sig-nificantly.2,89,90 Remarkably, the positive impact of this leader-ship curriculum was significant when measured using tools, such as the Multifactor Leadership Questionnaire (MLQ), social skills inventory, personality inventory, and internal strength scorecard.2,89,90 The MLQ is a well-validated instrument that objectively quantifies leadership beliefs and self-perceived out-comes across medical and nonmedical disciplines. Based on the MLQ, surgical residents more often use a passive-avoidance style of leadership that emphasizes taking corrective action only after a problem is “significant and obvious.” This tool can also be used to track progress toward more effective, collaborative styles of leadership. These studies demonstrated the ability to measure leadership behavior of surgical trainees in a standard-ized, quantifiable format.2,89,90 Taken together, these studies sup-port the concept that leadership skills can and should be taught to surgical trainees, and there are validated tools to measure outcomes.Designing the ProgramSuccess in designing a formal leadership development program can be achieved through the following method. First, select the right participants at the right time in their career. Junior sur-geons new to practice are ideal; however, they should be given a chance to get their clinical and research interests off the ground before they are asked to lead others. Candidates, should be open to taking on leadership roles and have the right combination of introspection and humility that lends to professional develop-ment. High-quality speakers from the business, legal, creative, and medical worlds should be brought as guest speakers. Topics could include leadership overall, strategy, finance, management skills, feedback, and coaching. Constructive criticism is essential because prospective leaders will need guidance and mentoring. Surgeons who have been through a formal leadership training program will become proficient at team-building skills and man-agement and will become self-empowered individuals.918Formal leadership training is not restricted to faculty alone. Leadership training should begin early and continue throughout residency. Surgical residents’ leadership styles have been studied in environments where they are given an assistant to supervise, as if they were an attending. Most residents were able to adapt to difficult operative challenges, in this setting, by providing a more directed style of leadership to their assistants. When faced with a less challenging task, or when the surgery resident’s confidence was particularly high, their leadership score was also high. For the surgical resident preparing to move on to the attending level, such skills are necessary to develop.92Nontechnical surgical skills, such as leadership, demon-strate a number of desired effects for the operative team. Patient safety, including all cause 30-day mortality, is improved by stronger nontechnical skills.59 Development of clear and effec-tive communication, situational awareness, team skills, and decision-making all are correlated with reduced surgical errors. Interruptions, such as needing to answer a page during an opera-tion, are the only nontechnical factors in surgical error that are not directly attributable to leadership style.93Surgical leaders have a responsibility to make ethical deci-sions. At this time, there is no standard curriculum to formally train surgical residents in ethics, despite interest from a majority of residency program directors.94-97 Several solutions have been proposed. A case-based approach to ethics training appears to have some merit, where monthly hour long ethical dilemmas are discussed in an informal, nonhierarchical setting.98 In another study, an ICU-based simulation model demonstrated promise for teaching compassion and end-of-life ethics to surgical resi-dents. In this model, surgery residents have their first end-of-life conversations with standardized patients simulating the surgical ICU environment.99,100Practicing Leadership Skills and Assessing Leadership Formally With Objective Structured Clinical Examination (OSCE) and SimulationThe past decade has seen a demonstrable increase in our knowl-edge of how to develop leadership skills, particularly through simulation, as well as leadership evaluation through OSCE and other tools. Multiple groups have assessed multidisciplinary teams, typically composed of nurses, anesthesia groups, and surgeons for the leadership associated nontechnical skills of communication, teamwork, and situational awareness. Through increasingly validated instruments and assessment tools, these nontechnical skills have been found to be trainable.101 The OSCE has been established as the gold standard102 for the train-ing and assessment of a wide range of clinical and nontechnical skills with high reliability and validity.103-106The OSCE was developed by Harden, at the Ninewells Hospital in Dundee, Scotland, and first published in 1975.107 He subsequently coined the term “OSCE” in his 1979 publica-tion “Assessment of Clinical Competence Using an Objective Structured Clinical Examination (OSCE).”108 The purpose of the OSCE was to address the lack of a reliable method to evalu-ate the clinical abilities of physicians and featured a compre-hensive assessment of history-taking and physical examination skills. Early versions also assessed nontechnical skills, patient interaction, and professionalism. Since its inception, the OSCE has matured, been subjected to rigorous tests of reliability and validity, and has seen widespread adoption.109-111OSCEs remain a critical portion of resident evaluation. They have been well validated for teaching leadership skills in Brunicardi_Ch01_p0001-p0026.indd 1429/01/19 10:58 AM 15LEADERSHIP IN SURGERYCHAPTER 1trauma and interacting with simulated patients in difficult sce-narios. OSCEs can be tailored to a variety of circumstances, including practicing breaking bad news or discussing end of life care, dealing with angry or aggressive patients, and simulating disagreements with other providers or family members.109-112 The potential for OSCEs to train, test, and perfect nontechnical skills, such as leadership, is extraordinary.A pilot project for the Medical Council of Canada was conducted by the University of Toronto and published in 1988 describing the use of an OSCE for evaluating the clinical skills of international medical graduates applying to Canadian resi-dency.113 Effective communication and language proficiency have been key components since the beginning. A compre-hensive review of this program 2 years later confirmed the reliability and validity of using an OSCE for this purpose.114 The Medical Council of Canada has subsequently mandated a requirement for an OSCE evaluation of all international gradu-ates applying for positions in Canada. In place for the past two decades, the program has ensured a baseline proficiency of skill, attitude, knowledge, and other nontechnical skills.115OSCEs quickly gained acceptance as an established tool to assess learners in a comprehensive manner and became the inspiration for the creation of the USMLE Step 2 Clinical Skills (CS) examination, required for all U.S. medical students prior to licensure.116 Indeed, medical students whose schools use OSCE as practice do better on USMLE Step 2.117 The USMLE Step 2 CS examination meets the criteria, discussed in the following section, for a thorough and well-designed OSCE examination, due to its 12-station design which takes 8 hours to complete. It has been found to be a valid and comprehensive evaluation of a student’s clinical abilities, admittedly at massive expense to medical students.118 In the United States, osteopathic medical students take the OSCE-style Level 2 Performance Evaluation.119Although station number and total duration are not com-pletely agreed upon, data indicate that the OSCE examination should be between 3 and 6 hours and 8 to 10 stations in length in order to obtain reliable (r = ≥0.7) communication, history, and physical examination skills. A guideline was that at least seven cases are needed in any domain to achieve reliability. The testing period may be spread over several sessions making up an aggregate score in order to maintain validity. Many medical schools prepare their students for clinical practice with OSCE-style examinations throughout the year, which, taken together, are summative of a high-quality, multistation, valid OSCE. Checklists are typically the standard scoring tools; however, checklists alone may not be as reliable as a more comprehen-sive review by more experienced clinicians—particularly when assessing more advanced students and residents.120 All of the licensure examinations, discussed previously, meet the criteria for a well-designed OSCE based on number of stations and time duration.Beginning in 2003, the ACGME mandated the use of OSCEs within residency programs. At the time, residents were wary of its adoption, particularly fearing its use as a tool for determining promotion. Residents’ perceptions of the examina-tion, over time, did change to reflect an acceptance of its use for grading both technical and nontechnical skills.121-123In the United States, the OSCE assesses technical and nontechnical skills in an accurate and valid fashion. The OSCE demonstrates a rapid progression of technical skills highly cor-related to a postgraduate year, whereas clinical skills improve at a more moderate rate121 (Fig. 1-12).10.5123PGY Level45z score0–0.5–1Technical stationsClinical stationsFigure 1-12. Resident assessment by year of training by OSCE. Technical skills assessment demonstrates a rapid and continual pro-gression through 5 years of training, whereas clinical evaluations show only modest improvement over the same time period. (Data from Turner JL, Dankoski ME. Objective structured clinical exams: a critical review, Fam Med. 2008 Sep;40(8):574-578.)The past 2 to 3 years has seen an explosion in simula-tion technology and research. In one particularly strong study, multiple teams were assessed for hemorrhage and airway emer-gencies. The Non-Technical Skills for Surgeons (NOTSS) tool was used to assess teams prior to and during simulation. For surgeons, higher NOTSS scores were associated with a quicker resolution of the simulation crisis.125 Advances are being made in using simulation to solve difficult to teach physical examina-tion skills such as breast lump detection and prostate or rectal cancers.126,127 Studies assessing these new simulation tools have also indicated that many attending level surgeons would benefit from continued simulation practice both for keeping operative skills fresh and preventing the decline of physical exam skills, for instance during dedicated research time.126-128The Objective Structured Assessment of Technical Skills (OSATS) was initially developed as a bench station examination. It was later applied to intraoperative skill assessment, and appears to be an additional option for programs seeking a validated and reliable method for mixing technical skills assessment into simu-lations of nontechnical exercises to create a more “real world” simulation.129-133 With recent focus on milestones and proficiency-based promotion, as compared to time-based promotion of resi-dents, there is a need to reliably assess intraoperative skill.134 Digitization and modern computing have created new opportu-nities for simulation and education. One proposed method is a real-time, mobile web system featuring consistent and accurate assessment of the residents’ performance. The platform enabled timely recording of data, was efficient in terms of how much fac-ulty time it took to complete an assessment (average 2 minutes), and from a validity standpoint did trend well overall with resident postgraduate year. The system itself fulfilled the ACGME and American Board of Surgery mandate for program assessment of resident performance in the operating room.134Nontechnical skills often erode during stressful events, particularly in surgery where bleeding, complexity of the opera-tion, time-constraints, and equipment problems can have a nega-tive effect. Additionally, roadblocks with insurance and other third parties, critical illness, and delivering bad news add differ-ent kinds of stress.135 Indeed, video analysis of real operations indicates that attending surgeons typically take over, change their style of leadership, and decrease their teaching in the oper-ating room once unintended events occur.136Brunicardi_Ch01_p0001-p0026.indd 1529/01/19 10:58 AM 16BASIC CONSIDERATIONSPART IBy using simulated patients, patient-centered models, and intensive and immersive training, nontechnical skills including communication can improve interview techniques.137,138 Post com-munication skills training at the 12-month follow-up demonstrated that the training was effective, and with real clinical practice after the training communication skills had improved even more.139Lastly, there appears to be a positive feedback loop tying nontechnical leadership skills with self-perceived operating room prowess. Those surgeons who rate their own technical skills highly are also more likely to engage in positive leader-ship skills, including teaching in the operating room, handle difficult situations, and provide more clear instructions.140 Simulation may be particularly critical for preventing techni-cal skill decline in residents on dedicated research time or for attending surgeons whose research, clinic, or administrative duties decrease the amount of time they can spend in the operating room. Simulation represents the future of medicine and an excellent opportunity for research and development. Medicine, including surgery, has much ground to make up in regards to simulation training compared to other high-risk fields, such as the military, space, and aeronautics. Modern surgical leaders should recognize surgical simulation as criti-cal to their organization’s success.Evaluation of Surgeon PerformanceMultiple organizations are evaluating the technical and nontechnical skills of surgeons in a real-time basis. We have included this com-prehensive list of organizations (Table 1-4) with a brief description of their purpose and mechanisms of evaluation. Several of these involve technical skills evaluations and most involve nontechnical Table 1-4Multiple organizations have been created to evaluate both the technical and nontechnical skills of surgeons141ORGANIZATION NAMEDESCRIPTIONMAIN SKILLS, CONDITIONS, OR QUALITIES EVALUATEDEVALUATION OF TECHNICAL SKILLS?EVALUATION OF NONTECHNICAL SKILLS?Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS)A public reporting initiative that measures patient perspectives on and satisfaction with hospital care based on qualities of healthcare that patients view as important.Communication with nurses, communication with doctors, responsiveness of hospital staff, pain management, communication about medicines, discharge information, care transitionNoYesClinical and Group Consumer Assessment of Healthcare Providers and Systems (CGCAHPS)A public reporting initiative that measures patient perspectives on and satisfaction with care provided in an office setting based on qualities of healthcare that patients view as important.Access to care, provider communication, test results, office staff, overall provider ratingNoYesDatix, Incident ReportingA database of incidents that improves reliability of physicians by improving rates of reporting, promoting ownership of mistakes, and improving patient safety.System issues, patient safety and quality issues, provider behavior, leadership styleYesYesPatient Advocacy Reporting System (PARS)A system that compiles patient complaints into a complaint index for each physician for comparison with other medical group members and to help identify high-malpractice-risk physicians who may benefit from peer intervention.Unprofessional behavior deemed as disrespectful and rudeNoYesCo-worker Observation Reporting SystemA system in which physicians document coworker unprofessional conduct in order to provide nonjudgmental and timely feedback and to encourage self-reflection and change.Unprofessional behavior deemed as disrespectful and unsafeYesYes(Continued)Brunicardi_Ch01_p0001-p0026.indd 1629/01/19 10:58 AM 17LEADERSHIP IN SURGERYCHAPTER 1Table 1-4Multiple organizations have been created to evaluate both the technical and nontechnical skills of surgeons141ORGANIZATION NAMEDESCRIPTIONMAIN SKILLS, CONDITIONS, OR QUALITIES EVALUATEDEVALUATION OF TECHNICAL SKILLS?EVALUATION OF NONTECHNICAL SKILLS?American Board of Surgery (ABS) Maintenance of Certification (MOC) ProgramA program that documents a surgeon’s ongoing commitment to professionalism, lifelong learning, and practice improvement through self-report.Restrictions on medical license, restrictions on hospital privileges, continuing medical education, self-assessment of continuing medical education, cognitive expertise, ongoing participation in quality assessment program relevant to the surgeon’s practiceYesYesHospital CompareA database that is part of the Centers for Medicare & Medicaid Services (CMS) Hospital Quality Initiative and provides information on hospital performance and quality of care based on consumer perspectives so that patients can assess and compare hospitals.Hospital Compare is based on data from HCAHPS and evaluates hospitals by the same guidelines as HCAHPSNoYesFederation of State Medical Boards (FSMB)An organization representing all state medial and osteopathic boards in the United States that license physicians and sponsors the United States Medical Licensing Examination.Medical knowledge, patient complaints, violations of the lawYesYesInternet clinical scoresA database of direct patient opinions of physicians, provided through various sources, including Healthgrades.com, RateMDs.com, and Yelp.Professionalism, communication, timelinessNoYesHospital-Acquired Condition Reduction ProgramA government program that provides incentives for hospitals to reduce the number of undesirable patient conditions resulting from their stay in the hospital and that could have been avoided by adjusting hospital reimbursement rates accordingly.Foreign objects retained after surgery, air embolism, blood incompatibility, pressure ulcers, falls, poor glycemic control, catheter-associate infections, surgical site infections, deep vein thrombosis, pulmonary embolism, pneumothoraxYesNoAmerican College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP)A program that collects information on and provides a risk-adjusted ranking of preventable surgical complication rates to encourage providers to improve care.Surgical complications rates, surgical site infections, urinary tract infections, readmission rates, surgical outcomesYesNoCenters for Medicare & Medicaid Services Surgical Care Improvement Project (CMS SCIP)A collaborative healthcare organization that collects data on surgical complication rates based on established guidelines.Rates of infection, cardiac, venous thromboembolism, vascular, and respiratory, complications of surgeryYesNo(Continued)Brunicardi_Ch01_p0001-p0026.indd 1729/01/19 10:58 AM 18BASIC CONSIDERATIONSPART Iskills. Additionally, most have been tied to performance evalua-tions and even salary and discipline up to and including loss of licensure. To our knowledge, this is the first comprehensive listing of the various agencies that evaluate surgeon performance.141MENTORING AND DEVELOPMENTMentoringA formal leadership training program for surgical trainees should include mentoring. Mentoring is the active process by which an experienced, empathetic person guides another indi-vidual in the development and self-recognition of their own vision, learning, core competencies, and professional develop-ment. Halstead established the concept of a surgical mentor who directly provided the trainees with professional and technical guidance. Halstead’s concept went beyond a simple preceptor-ship by emphasizing clinical decision making based on scien-tific evidence. His goal was to develop surgeons who would go on to become outstanding leaders and innovators in the field. Although surgery has changed dramatically since Halstead’s era, mentorship remains crucial in surgical training. In addition to teaching technical skills, clinical judgment, and scientific inquiry, modern-day mentors must also model effective com-munication, empathy, humanism, and the prioritization of com-peting professional and personal activities.The mentor must also be an experienced and trusted advi-sor committed to the success of the mentee. A greater level of trust and commitment distinguishes the mentor from the teacher. More than a teacher, a mentor is a coach. The goal of a teacher is to pass on a defined level of knowledge for each stage of a student’s education. The underlying premise is a limited level of advancement for the student. The coach, on the other hand, has the sole purpose to make his or her student the best at their game, with an unlimited level of advancement. Modern men-torship implies a partnership between the mentor and the men-tee. Surgical residency program chairs and program directors must recruit and develop faculty “coaches” to mentor residents to optimize their potential. Emeritus Chair of the University of California, Los Angeles Head and Neck Surgery, Dr. Paul Ward, said it best: “We strive to produce graduates of our resi-dency program who are among those who change the way we think and practice.”142 Having more than 25 former residents become chairs of academic head and neck surgical programs, Dr. Ward embodied the role as a surgeon’s coach. The respon-sibilities of an effective mentor are summarized by Barondess: “Mentoring, to be effective, requires of the mentor empathy, maturity, self-confidence, resourcefulness, and willingness to commit time and energy to another. The mentor must be able to offer guidance for a new and evolving professional life, to stimulate and challenge, to encourage self-realization, to fos-ter growth, and to make more comprehensible the landscape in which the protégé stands.”143One of the major goals of mentors is to assess the aptitudes and abilities of mentees with regard to the appropriateness of their vision for their surgical career. Proper selection of the appropriate mentor can bring to the mentee much needed wisdom, guidance, and resources and can expand the scope of his or her vision. In addition, the mentor can refine the leadership skills taught to mentees in formal training programs. Highly successful surgeons most often have had excellent surgical mentors. It is impressive to note that more than 50% of United States’ Nobel laureates have served under other Nobel laureates in the capacity of student, postdoctoral fellow, or junior collaborator.144 In academic medicine, evidence-based studies have shown benefits to the mentees that include enhanced research productivity, higher likelihood of obtaining research grants, and greater success in obtaining desired positions in practice or at academic institutions.145 Mentoring provides benefits to the mentors themselves, including refinement of their own personal leadership skills and a strong sense of satisfaction and accomplishment.Mentorship is essential to accomplish the successful development of surgical trainees and to help cultivate their vision. Therefore, formal leadership training programs that have a goal of training the future leaders in surgery should include mentoring.Modeling Leadership for Medical Students and the “Hidden Curriculum”Medical students enter school with great empathy, excitement, optimism, and an idealistic vision. They have self-selected to enter a profession of healing and achieved entry into a highly coveted graduate training program with centuries of tradition. Yet, these medical students are naive to the actual practice of medicine and its professional norms. Along the way to becoming a doctor, many medical students lose some of the optimism, empathy, and excite-ment, particularly during their first and third years of school. Some students come to see the patient-physician relationship as an after-thought to providing care.145,146 Through the “hidden curriculum,” formal leadership training, and modeling of professional behavior, surgical residents, and attendings can help medical students to real-ize their vision of becoming empathic physicians.Traditionally, medical schools and professors have unknowingly relied on a hidden curriculum to mold these ide-alistic students into capable professionals. The hidden curricu-lum is the informal social norms learned by students implicitly, based on their observations of resident and attending behavior. The hidden curriculum has always been present in education, for better or worse, and may be unmasked and studied, but cannot be eliminated. Medical students actively engage in seeking out mentors, and naturally and subconsciously look to their men-tors for cues on how to conduct themselves as physicians, the same way in which a child learns how to behave from a parent or older sibling. Whether or not the witnessed behavior is a positive example of professionalism, the student will begin to perceive that behavior as normal and acceptable. For better or worse, the professional norms of medicine (the Hippocratic oath, respect to patients and colleagues, ethical conduct, personal accountability, empathy, and altruism) are modeled in every personal encounter. It is imperative that all resident and attending surgeons under-stand that the medical students are observing them closely. When resident and attending surgeons model professional behavior, the hidden curriculum becomes a useful tool for professional devel-opment.147-150 This consistent modeling of professional behavior is one necessary component of leadership.During their clinical years, medical students experience both an exponential growth in knowledge and a measurable decline in empathy towards their patients. Initially, medical stu-dents are filled with excitement and wonder during their first patient encounters. The rapid pace of clinical work, acquisition of knowledge, and intense experiences create stress for the stu-dent, both positively and negatively. Scrubbing into the operat-ing room, witnessing the passing of a patient, helping deliver a baby, and studying for boards are impactful milestones that each student experiences in a matter of months. Due to the 9Brunicardi_Ch01_p0001-p0026.indd 1829/01/19 10:58 AM 19LEADERSHIP IN SURGERYCHAPTER 1challenges of their work, students naturally have doubts about their own career choices and abilities, even as they experience growth and success. However, as students gain knowledge and abilities, they also come to see commonly encountered clinical problems as routine work. As familiarity and comfort with clini-cal problems increases, the excitement and wonder experienced by the student decreases. It is during this time that a decline in student empathy occurs, typically in their third year of medical school.151 In medicine, even routine clinical work still requires extraordinary attention to detail, and compassionate care must be delivered to every patient, every time. This attention to detail and compassionate delivery of care are the hallmark of the true professional. It is important that surgical residents and attend-ings always model positive behavior.Previously, medical schools instructed students in anat-omy, physiology, pathology, and clinical medicine, but left the acquisition of professionalism to the informal hidden curricu-lum. The Carnegie Report, published in 2010 at the 100-year anniversary of the Flexner Report, called for medical education to promote “the progressive formation of the physician’s profes-sional identity.”152 To this end, many medical schools nation-wide emphasize early professional education and an integrated curriculum. The Liaison Committee on Medical Education (LCME) sets standards for administrative and faculty leader-ship that manage the curricular model and educational affairs of students; however, formal leadership education is not explicitly required at this time. However, career exploration, mentoring, and advising are instrumental responsibilities of each medical school and a requirement of the LCME. Establishing a leader-ship program that is perpetual and coexists within an integrated curriculum will support this endeavor.153 A longitudinal lead-ership program beginning at the onset of medical school can establish a pattern of ethical behavior, professionalism, balance, Table 1-5Leadership assessment toolboxMETHOD OF LEADERSHIP MEASUREMENTDESCRIPTIONMultifactor Leadership Questionnaire (MLQ)The MLQ is a questionnaire based on the differences between transformation and transactional approaches of leadership. It identifies leadership qualities through the rater’s beliefs about effective leadership.NEO Five-Factor Personality Inventory (NEO)NEO explores different facets of five different personality traits—neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness—through a questionnaire.Surgeon’s Leadership Inventory (SLI)The SLI is a questionnaire based on literature on leadership in surgery and surgeon’s leadership behaviors observed in the operating room. It includes eight elements of surgeon’s leadership in the operating room, which are maintaining standards, managing resources, making decisions, directing, training, supporting others, communicating, and coping with pressure.Patient feedbackPatient complaints are inversely related to leadership effectiveness and can thus be used as opportunities to improve and as a measure of leadership.Objective Structured Clinical Examination (OSCE)The OSCE can be administered in a controlled environment with attending feedback on various aspects of leadership tackled in the practice cases. Videotaped sessions provide further opportunities for improvement as residents will be able to later observe their own behaviors and reflect on ways to improve their approach to the case presented.Consumer Assessment of Healthcare Providers and Systems (CAHPS)CAHPS surveys are based on aspects of healthcare that matter most to patients, such as physician communication. The results are made public and can be used to shed light on areas of leadership physicians can improve on to work towards a patient-centered approach to care.Reproduced with permission from Jacobs LA: Practical Ethics for the Surgeon. Philadelphia, PA: Wolters Kluwer; 2018.wellness, and strong character. Indeed, many medical schools are shifting to a new, integrated style curriculum with early pro-fessional development as the standard.154This chapter has emphasized, in an intentional way, the importance of establishing a vision and goals. Throughout the process of becoming a physician, medical students will trade some of their idealism and optimism for a refined vision and a set of goals that become a part of their professional identity. This newly matured vision will guide the future these students create. The future leaders of medicine and surgery are current medical students. To foster a climate of professionalism and empathy, medical students should be taught in an environment of formal leadership training, from the first day of medical school through graduation. In addition to leadership training, medical students will inevitably acquire some of the traits and habits of their resi-dent and attending mentors through the hidden curriculum. In this way, the modeling of professional behaviors by surgical residents and attendings can serve to reinforce professionalism and may help to ward off the empathy decline experienced by medical students in their clinical years.Tools to Measure Leadership Outcomes in HealthcareThere is evidence that leadership training improves healthcare quality. The ACGME, via its core competencies, has recognized technical skills, surgical judgement, and nontechnical skills as qualities essential to develop in residents.155,156 The objec-tive measurement of nontechnical skills is difficult. Table 1-5 includes a list of methods for assessing nontechnical skills cur-rently in use by some residency programs. The Consumer Assess-ment of Healthcare Providers and Systems (CAHPS) survey is in the early phases of being applied to individual physicians, but it has been applied to hospitals as a whole for several years.Brunicardi_Ch01_p0001-p0026.indd 1929/01/19 10:58 AM 20BASIC CONSIDERATIONSPART ILeadership can be evaluated through instruments such as the Multifactor Leadership Questionnaire, the NEO Five–Factor Inventory, and the Surgeon’s Leadership Inventory. The Mul-tifactor Leadership Questionnaire (MLQ) analyzes leadership aptitude as either a transactional or a transformational style.157 Leadership based on transaction focuses on completing and rewarding the tasks, whereas leadership based on transforma-tion focuses more on the motivation for completing the tasks and emphasizes a positive and encouraging working environ-ment for the team.158,159 In a study applying the questionnaire to five surgeons in a single hospital, surgeons who scored higher on the transformational section were more focused on promot-ing an open environment for all the attendings, residents, nurses and other staff in the operating room. This transformational style correlated with greater communication. These findings are important in showing that lack of communication is often a leading factor in surgical errors.The use of an MLQ in 2008 studying surgical residents showed a significant association between transformational lead-ership and overall perceived team effectiveness and resident sat-isfaction.158-159 The questionnaire also found that the residents, as leaders, placed less value on the individual needs of their colleagues, possibly reflecting a high sense of independence and frequent changes in teams due to rotations among services. This finding helped identify an area of leadership training on which the program can focus to help further develop a more supportive team atmosphere amongst the residents. In 2011, a study administered the NEO Five-Factor Personality Inventory (NEO) to a group of surgical residents. NEO, which assesses personality on five broad strokes, including neuroticism, open-ness, agreeableness, extroversion, and conscientiousness, found that the surgeons scored above the national average on most of the factors tested but below average on agreeableness. This is a measure of altruism and tolerance, among other related factors. This result corresponded with the MLQ administered to the same group of residents and therefore highlighted areas of lead-ership that required modification.158,159The Surgeon’s Leadership Inventory (SLI) is a helpful guide for residency programs.160 The SLI grades surgeons on eight different elements of leadership, as listed in Table 1-6. As with the MLQ and NEO questionnaires, the SLI can be used to assess the growth of leadership ability in surgery residents. Table 6 provides a list and description of the different elements assessed by the SLI.141LEADERSHIP TRAINING FOR THE PROSPECTIVE SURGEONProspective surgeons such as medical students and premedical students may have no better source for developing the personal attributes necessary for a successful career than current surgical attending surgeons and current residents. When surveyed, these doctors emphasized accountability, resilience, and high personal standards for oneself as critical tools. Prospective surgeons are advised to pursue perfectionism and be self-critical, cautioning against taking these traits to far towards neurotic behavior. Criti-cal leadership skills of teamwork and learning to take initiative are mandatory in modern medicine and must be learned early. Innovation is highly desirable.162Residents, on the other hand, are closer to becoming inde-pendent. To some extent, they have already been selected for their leadership, innovation, and resiliency through the process Table 1-6Surgeons Leadership Inventory (SLI)ELEMENTDESCRIPTIONMaintaining standardsPracticing safe and quality patient care by following established protocols and asking for help when neededMaking decisionsMaking informed judgments and communicating decisions with relevant personnelManaging resourcesAppropriately assigning resources and tasks to team membersDirectingClearly communicating expectations and instructions and demonstrating confidence in leadership abilityTrainingEducating and training team members when the opportunity arisesSupporting othersOffering assistance where appropriate and encouraging open communicationCommunicatingSharing information in a timely manner and encouraging input from othersCoping with pressureShowing flexibility when required to meet goalsData correlating patient complaints in a large number of hospitals show that improved leadership is associated with better hospital climate, improved performance, and a lower number of complaints.161Reproduced with permission from Jacobs LA: Practical Ethics for the Surgeon. Philadelphia, PA: Wolters Kluwer; 2018.of the match. During training their progression from novice to expert is necessarily rapid. A graded tool for all procedure based specialties including surgery – OpTrust – has been recently vali-dated to facilitate the resident’s transition to leadership across five domains including questioning, planning, instruction, prob-lem solving, and leadership.163As emphasized throughout this chapter, the concept of training leadership skills early applies particularly to junior fac-ulty and residents. The resident-surgeon-manager conference is one model for integrating department members of various experience levels into a results-based leadership conference. In this conference, various stakeholders including attorneys, per-sons with business experience, and risk management experts are brought in as guest participants. Exercises were immersive and included case-based discussions, role-playing, simulation, and interactive lecture. Topics included teamwork, learning negoti-ating techniques, time management, risk management, balance, giving feedback, and creating immediate, goal-oriented action plans.86EARLY CAREER DEVELOPMENT AND ESTABLISHING ONESELFA variety of methods have been proposed for the professional development of new attending surgeons. “Speed Mentoring”— 10-minute pairings of senior and junior surgeons answering pre-set questions—have been studied at national conferences with promising results. These sessions could be spread out over several days and integrated into a busy surgeon’s schedule.164Brunicardi_Ch01_p0001-p0026.indd 2029/01/19 10:58 AM 21LEADERSHIP IN SURGERYCHAPTER 1A study of department chairs and award-winning surgeon-scientists identified perseverance and team leadership skills as critical factors for development in the young attending surgeon. Chairs advocated protected time for research, financial support, and mentorship as departmental level support that the surgeon scientist should actively seek out in their first position. The sur-geon-scientist compared to the pure clinician faces a different set of challenges, particularly the financial challenge of funding research and clinical duties competing for time and attention with research interests.165One study addressed surgeon behavior in the operating room to assess the leadership style most associated with strong leadership. Based off of this study, surgeons who are trained to collaborate, consult others appropriately, be polite (simple “please” and “thank you”), and create a safe space for their operating room staff to voice concerns will demonstrate good leadership. However, surgeons who demonstrate nonconstruc-tive criticism, destructive humor, steer conversation away from the current case, and express frustration will be perceived as demonstrating poor leadership. Under this system, surgeon behavior can be categorized—conductor, elucidator, delegator, engagement facilitator, tone setter, being human, and safe space maker—in order to provide individual feedback for professional development.166SENIOR FACULTY DEVELOPMENT: TRANSITIONING TO DEPARTMENTAL LEADERSHIP AND LEGACY BUILDINGThe presence of experienced, senior academic surgeons within a department represents an opportunity. The formal develop-ment of a plan for late career transitioning through departmental leadership roles all the way to emeritus status naturally initi-ates a constructive process when thought out years in advance. The plan should be agreeable to the senior faculty member in question as well as departmental leadership and hospital stakeholders. Once in place, the senior academic surgeon and department will both thrive thanks to a shared vision, mutual understanding, and clear goals and transition points. Depart-mental leadership can use the transition plan to look ahead at the future of their department years down the line.167Recognition of senior academic surgeons with departmen-tal leadership, promotions, and emeritus status is a privilege earned by the academician over a lifetime of work; however, for the department it represents an opportunity to shape the values and culture of the faculty body as a whole. The continued vis-ibility, model, and influence of such leaders will have a trickle-down effect on the rest of the department. Surgical leaders are part of a large and extraordinary network facilitated by men-torship and decades of professional collaboration. Exceptional senior academic surgeons may often experience the “multiplier-effect” whereby one excellent leader trains several, who go on to train several more until the culture of surgery nationwide is influenced.168Although there are no mandatory ages for which surgeons must retire as in other professions, such as airline pilots, the issue of aging and when to cease practice has been controver-sial. There are some, however few, reports of physicians prac-ticing after the decline of their skill and becoming dangerous. As a whole, the profession has been unable to prevent this. Nationwide, from 1975 to 2015, the number of physicians prac-ticing after age 65 has increased by 374%. Some hospitals and healthcare organizations have implemented mandatory cognitive and physical evaluations as a condition of continued practice. In the absence of more robust professional initiatives our field may see legislative oversight in the future.169 The authors believe that a formally planned transition emphasizing the values of leader-ship and legacy-building offers a more palatable alternative.CONCLUSIONAlthough there are several definitions of leadership and a vari-ety of leadership styles, all share the common goal of improving patient care in the modern era. All forms of leadership require a vision and willingness—the willingness to assume the respon-sibility to lead, continue learning, practice effective commu-nication styles, and resolve conflict. Effective leadership can change surgical departments and improve patient care through innovation. A growing body of evidence suggests the mastery of leadership requires practice through intentional curricula and reinforcement through mentorship.Surgical leadership is bred through its training programs. 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The underrepresentation of women physicians among recogni-tion award recipients from medical specialty societies. PM R. 2017;9(8);804-815. 73. Derck J, Zahn K, Finks JF, Mand S, Sandhu G. Doctors of tomorrow: an innovative curriculum connecting underrep-resented minority high school students to medical school. Educ Health (Abingdon). 2016;29(3):259-265. 74. Marrast LM, Zallman L, Woolhandler S, Bor DH, McCormick D. Minority physicians’ role in the care of underserved patients: diversifying the physician workforce may be key in addressing health disparities. JAMA Intern Med. 2014;174:289-291. 75. Silva AK, Preminger A, Slezak S, Phillips LG, Johnson DJ. Melting the plastic ceiling: overcoming obstacles to foster leadership in women plastic surgeons. Plast Reconstr Surg. 2016;138(3):721-729. 76. Abelson JS, Symer MM, Yeo HL. Surgical time out: our counts are still short on racial diversity in academic surgery. Am J Surg. 2018;215(4):542-548. 77. Fernald A, Marchman VA, Weisleder A. 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Transformational, transactional, and passive-avoidant leadership charac-teristics of a surgical resident cohort: analysis using the multifactor leadership questionnaire and implications for improving surgical education curriculums. J Surg Res. 2008;148:49-59. 84. Ackerly DC, Sangvai DG, Udayakumar K, et al. Training the next generation of physician-executives: an innovative residency pathway in management and leadership. Acad Med. 2011;86:575-579. 85. Accreditation Council for Graduate Medical Education. Leadership skills for chief residents. Available at: http://www .acgme.org/acgmeweb/. Accessed June 15, 2018. 86. Hanna WC, Mulder D, Fried G, et al. Training future surgeons for management roles: the resident-surgeon-manager confer-ence. Arch Surg. 2012;147:940-944. 87. American College of Surgeons. Surgeons as leaders: from operating room to boardroom. Available at: http://www.facs.org/education/surgeonsasleaders.html. Accessed June 15, 2018. 88. Awad SS, Hayley B, Fagan SP, Berger DH, Brunicardi FC. The impact of a novel resident leadership training curriculum. Am J Surg. 2004;188:481-484. 89. Horwitz IB, Horwitz S, Brandt ML, Brunicardi FC, Awad SS. Assessment of communication skills of surgical residents using the Social Skills Inventory. Am J Surg. 2007;194:401-405. 90. Horwitz IB, Horwitz S, Brunicardi FC, Awad SS. Improving comprehensive surgical resident training through use of the NEO Five-Factor Personality Inventory: results from a cohort-based trial. Am J Surg. 2011;201:828-834. 91. Dimick JB, Mulholland MW. Design principles for build-ing a leadership development program in a department of surgery. Ann Surg. 2018;267(1):39-41.Brunicardi_Ch01_p0001-p0026.indd 2329/01/19 10:58 AM 24BASIC CONSIDERATIONSPART I 92. Gannon SJ, Law, KE, Ray RD, et al. Do resident’s leader-ship skills relate to ratings of technical skill? J Surg Res. 2016;206(2):466-471. 93. Gillespie BM, Harbeck E, Kang E, Steel C, Fairweather N, Chaboyer W. Correlates of non-technical skills in surgery: a prospective study. BMJ Open. 2017;7(1):e014480. 94. Downing MT, Way DP, Caniano DA. Results of a national sur-vey on ethics education in general surgery residency programs. Am J Surg. 1997;174(3):364-368. 95. Helft PR, Eckles RE, Torbeck L. Ethics education in surgical residency programs: a review of the literature. J Surg Educ. 2009;66(1):35-42. 96. Kavarana MN, Sade RM. Ethical issues in cardiac surgery. Future Cardiol. 2012;8(3):451-465. 97. Reitsma AM, Moreno JD. Ethics of innovative surgery: US surgeons’ definitions, knowledge, and attitudes. J Am Coll Surg. 2005;200(1):103-110. 98. Klingensmith ME. Teaching ethics in surgical train-ing programs using a case-based format. J Surg Educ. 2008;65(2):126-128. 99. Holloran SD, Starkey GW, Burke PA, Steele G Jr, Forse RA. An educational intervention in the surgical intensive care unit to improve ethical decisions. 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Ann Surg. 2014;260(1):65-71. 105. Sloan DA, Donnelly MB, Schwartz RW, Strodel WE. The objective structured clinical examination; the new gold stan-dard for evaluating postgraduate clinical performance. Ann Surg. 1995;222(6):735-742. 106. Cohen R, Reznick RK, Taylor BR, Provan J, Rothman A. Reliability and validity of an objective structured clini-cal examination in assessing surgical residents. Am J Surg. 1990;160(3):302-305. 107. Harden RM, Stevenson M, Downie WW, Wilson GM. Assessment of clinical competence using objective struc-tured examinations. Br Med J. 1975;1(5955):447. 108. Harden RM, Gleeson FA. Assessment of clinical compe-tence using an objective structured clinical examination (OSCE). Med Educ. 1979;13(1):41-54. 109. Hochberg MS, Berman RS, Kalet AL, Zabar S, Gillespie C, Pachter HL. Professionalism training for surgical residents: documenting the advantages of a professionalism curriculum. Ann Surg. 2016;264(3):501-507. 110. Merrick HW, Nowacek GA, Boyer J, et al. Ability of the objective structured clinical examination to differentiate surgical residents, medical students, and physician assis-tant students. J Surg Res. 2002;106(2):319-322. 111. Sudan R, Lynch TG, Risucci DA, Blair PG, Sachdeva AK. American College of Surgeons Resident Objective Structured Clinical Examination: a national program to assess clinical readiness of entering postgraduate year 1 surgery residents. Ann Surg. 2014;260(1):65-71. 112. Yudkowsky R, Alseidi A, Cintron J. Beyond fulfilling the core competencies: an objective structured clinical examination to assess communication and interpersonal skills in a surgical residency. Curr Surg. 2004;61(5):499-503. 113. Cohen R, Rothman AI, Ross J. A comprehensive assessment of graduates of foreign medical schools. Ann R Coll Phys Surg Can. 1988;21(7):505-509. 114. Reznick R, Smee S, Rothman A, et al. An objective struc-tured clinical examination for the licentiate: a report of the pilot project of the Medical Council of Canada. Acad Med. 1992;67(8):487-494. 115. Medical Council of Canada. NAC Overview. Available at: http://mcc.ca/examinations/nac-overview/. Accessed June 16, 2018. 116. McGaghie WC, Cohen ER, Wayne DB. Are United States Medical Licensing Exam Step 1 and 2 scores valid measures for postgraduate medical residency selection decisions? Acad Med. 2011;86(1):48-52. 117. Simon SR, Bui A, Day S, Berti D, Volkan K. The relation-ship between second-year medical students’ OSCE scores and USMLE Step 2 scores. J Eval Clin Pract. 2007;13(6):901-905. 118. Lehman EP 4th, Guercio JR. The Step 2 Clinical Skills exam—a poor value proposition. N Engl J Med. 2013;368(10):889-891. 119. National Board of Osteopathic Medical Examiners. COM-LEX-USA Level 2-PE. Available at: https://www.nbome.org/exams-assessments/comlex-usa/comlex-usa-level-2-pe/. Accessed June 16, 2018. 120. Cerilli GJ, Merrick HW, Staren ED. Objective Structured Clin-ical Examination technical skill stations correlate more closely with postgraduate year level than do clinical skill stations. Am Surg. 2001;67(4):323-326; discussion 326-327. 121. Turner JL, Dankoski ME. Objective structured clinical exams: a critical review. Fam Med. 2008;40(8):574-578. 122. Zyromski NJ, Staren ED, Merrick HW. Surgery residents’ perception of the Objective Structured Clinical Examination (OSCE). Curr Surg. 2003;60(5):533-537. 123. Schwartz RW, Witzke DB, Donnelly MB, Stratton T, Blue AV, Sloan DA. Assessing residents’ clinical performance: cumula-tive results of a four-year study with the Objective Structured Clinical Examination. Surgery. 1998;124(2):307-312. 124. Doumouras AG, Hamidi M, Lung K, Tarola CL, Tsao MW, Scott JW, Yule S. Non-technical skills of surgeons and anaes-thetists in simulated operating theatre crises. Br J Surg. 2017;104(8):1028-1036. 125. Nicksa GA, Anderson C, Fidler R, Stewart L. Innovative approach using interprofessional simulation to educate sur-gical residents in technical and nontechnical skills in high-risk clinical scenarios. JAMA Surg. 2015;150(3):201-207. 126. Laufer S, Ray RD, D’Angelo AL, Jones GF, Pugh CM. Use of simulators to explore specialty recommendation for a palpable breast mass. Am J Surg. 2015;210(4):618-623. 127. Laufer S, Cohen ER, Kwan C, et al. Sensor technology in assess-ments of clinical skill. N Engl J Med. 2015;372(8):784-786. 128. D’Angelo AL, Ray RD, Jenewein CG, Jones GF, Pugh CM. Residents’ perception of skill decay during dedicated research time. J Surg Res. 2015;199(1):23-31. 129. Martin JA, Regehr G, Reznick R, et al. Objective Structured Assessment of Technical Skill (OSATS) for surgical residents. Br J Surg. 1997;84(2):273-278. 130. Hatala R, Cook DA, Brydges R, Hawkins R. Constructing a validity argument for the Objective Structured Assess-ment of Technical Skills (OSATS): a systematic review of validity evidence. Adv Health Sci Educ Theory Pract. 2015;20(5):1149-1175. 131. Reznick R, Regehr G, MacRae H, Martin J, McCulloch W. Testing technical skill via an innovative “bench station” exam-ination. Am J Surg. 1997;173(3):226-230.Brunicardi_Ch01_p0001-p0026.indd 2429/01/19 10:58 AM 25LEADERSHIP IN SURGERYCHAPTER 1 132. Hopmans CJ, den Hoed PT, van der Laan L, et al. Assessment of surgery residents’ operative skills in the operating theater using a modified Objective Structured Assessment of Techni-cal Skills (OSATS): a prospective multicenter study. Surgery. 2014;156(5):1078-1088. 133. Glarner CE, McDonald RJ, Smith AB, et al. Utilizing a novel tool for the comprehensive assessment of resident operative performance. J Surg Educ. 2013;70(6):813-820. 134. Wagner JP, Chen DC, Donahue TR, et al. Assessment of resident operative performance using a real-time mobile Web system: preparing for the milestone age. J Surg Educ. 2014;71(6):e41-e46. 135. 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Brunicardi_Ch01_p0001-p0026.indd 2629/01/19 10:58 AMThis page intentionally left blankSystemic Response to Injury and Metabolic SupportSiobhan A. Corbett This chapter is dedicated to Dr. Stephen Lowry, my mentor and friend.2chapterOVERVIEW: INJURY-ASSOCIATED SYSTEMIC INFLAMMATORY RESPONSEThe inflammatory response to injury occurs as a consequence of the local or systemic release of “damage-associated” molecules to mobilize the necessary resources required for the restoration of homeostasis. Minor host insults result in a localized inflam-matory response that is transient and, in most cases, benefi-cial. Major host insults follow a different trajectory. A subset of these patients will die within 24 hours of hospital admis-sion, succumbing to overwhelming tissue injury and immediate organ damage. With advances in prehospital care and improved trauma management, these numbers have diminished. A second subgroup of patients who suffer a major host insult succumb to secondary organ damage remote from the injury site and die later (weeks) in their hospital course. They form an increasing percentage of the in hospital trauma-related deaths. A dysreg-ulated, overwhelming systemic inflammatory response to the injury/hemorrhage and associated ischemia/reperfusion events has been implicated as the cause of multiple organ failure in these patients. Moreover, it has been linked to immune suppres-sion that increases the risk of infectious complications and poor outcome. Finally, a third subgroup, characterized by extended length of stay in the ICU, complicated postdischarge courses, and failure to regain/recover to their preinjury status, has been described and also linked to persistent inflammation and sup-pressed host protective immunity. The term persistent inflamma-tion, immunosuppression, and catabolism syndrome (PICS) has Overview: Injury-Associated Systemic  Inflammatory Response 27The Detection of Cellular Injury 28The Detection of Injury is Mediated by Members of the Damage-Associated Molecular Pattern Family / 28DAMPs Are Ligands for Pattern Recognition Receptors / 32Central Nervous System Regulation  of Inflammation in Response to  Injury 34Neuroendocrine Response to Injury / 35The Cellular Stress Responses 39Reactive Oxygen Species and the Oxidative Stress Response / 39The Unfolded Protein Response / 39Autophagy / 40Apoptosis / 40Necroptosis / 40Pyroptosis / 41Mediators of Inflammation 42Cytokines / 42Eicosanoids / 47Plasma Contact System / 48Serotonin / 50Histamine / 50Cellular Response to Injury 50Cytokine Receptor Families and Their Signaling Pathways / 50JAK-STAT Signaling / 50Suppressors of Cytokine Signaling / 50Tumor Necrosis Factor Superfamily / 51Transforming Growth Factor-β Family of Receptors / 51Transcriptional and Translational  Regulation of The Injury  Response 52Transcriptional Events Following Blunt Trauma / 52Transcriptional Regulation of Gene Expression / 52Epigenetic Regulation of Transcription / 53Translation Regulation of Inflammatory Gene Expression / 53Cell-Mediated Inflammatory  Response 54Neutrophils / 54Monocyte/Macrophages / 54Lymphocytes and T-Cell Immunity / 55Dendritic Cells / 55Platelets / 56Mast Cells / 56Endothelium-Mediated Injury 56Vascular Endothelium / 56Neutrophil-Endothelium Interaction / 56Chemokines / 57Nitric Oxide / 58Prostacyclin / 58Endothelins / 59Platelet Activating Factor / 59Natriuretic Peptides / 60Surgical Metabolism 60Metabolism During Fasting / 60Metabolism After Injury / 62Lipid Metabolism After Injury / 63Ketogenesis / 64Carbohydrate Metabolism / 65Protein and Amino Acid Metabolism / 66Nutrition in The Surgical Patient 66Estimation of Energy Requirements / 66Vitamins and Minerals / 68Overfeeding / 68Enteral Nutrition 68Rationale for Enteral Nutrition / 68Early vs. Late Feeding / 68Intermittent vs. Continuous Enteral Feeding / 69Enteral Formulas / 69Access for Enteral Nutritional Support / 71Parenteral Nutrition 72Rationale for Parenteral Nutrition / 73Total Parenteral Nutrition / 73Peripheral Parenteral Nutrition / 73Initiation of Parenteral Nutrition / 73Complications of Parenteral Nutrition / 74Brunicardi_Ch02_p0027-p0082.indd 2701/03/19 6:49 PM 28been applied to this group.1 Recent data suggest that severely injured patients who are destined to die from their injuries, whether late in their hospital course or after discharge, differ from survivors only in the degree and duration of their dysregu-lated acute inflammatory response.1-3As trauma is the leading cause of mortality and morbidity for individuals under age 45, understanding the complex path-ways that regulate the local and systemic inflammatory response following severe traumatic injury is necessary to develop appro-priate and targeted therapeutic strategies that will improve out-comes for these patients.In this chapter, we will review what is known about the soluble and cellular effectors of the injury-induced inflamma-tory response, how the signals are sensed, transduced, and mod-ulated, and how their dysregulation is associated with alterations in the immune system. We will also discuss how these events are monitored regulated by the central nervous system. Finally, we will review how injury reprograms cellular metabolism, in an attempt to mobilize energy and structural stores to meet the challenge of restoring homeostasis.THE DETECTION OF CELLULAR INJURYThe Detection of Injury is Mediated by Members of the Damage-Associated Molecular Pattern FamilyTraumatic injury activates the innate immune system to pro-duce a systemic inflammatory response (SIR) in an attempt to limit damage and to restore homeostasis. It includes two general responses: (a) an acute proinflammatory response resulting from innate immune system recognition of ligands, and (b) an anti-inflammatory response that may serve to modulate the proin-flammatory phase and direct a return to homeostasis (Fig. 2-1). This is accompanied by a suppression of adaptive immunity.4 Rather than occurring sequentially, recent data indicate that all three responses are simultaneously and rapidly induced follow-ing severe traumatic injury.3The degree of the systemic inflammatory response follow-ing trauma is proportional to injury severity and is an inde-pendent predictor of subsequent organ dysfunction and resultant 1mortality. Recent work has provided insight into the mecha-nisms by which immune activation in this setting is triggered. The clinical features of the injury-mediated systemic inflamma-tory response, characterized by increased body temperature, heart rate, respirations, and white blood cell count, are similar to those observed with infection (Table 2-1). However, it is widely accepted that systemic inflammation following trauma is sterile, resulting from endogenous molecules that are produced as a consequence of tissue damage or cellular stress.5 Termed damage-associated molecular patterns (DAMPs) or alarmins, DAMPs interact with specific cell receptors that are located both on the cell surface and intracellularly.6Trauma DAMPs are structurally diverse endogenous mol-ecules that are immunologically active. Table 2-2 includes a par-tial list of DAMPs that are released either passively from necrotic/damaged cells or actively from physiologically “stressed” cells by upregulation or overexpression. Once they are outside the cell, DAMPs promote the activation of innate immune cells, as well as the recruitment and activation of antigen-presenting cells, which are engaged in host defense.7 The best-characterized DAMP with significant preclinical evidence for posttrauma release, as well as a direct link to the systemic inflammatory response, is high-mobility group protein B1 (HMGB1). Additional evidence for other important DAMP molecules that participate in postin-jury inflammation is also presented.High-Mobility Group Protein B1. The best-characterized DAMP in the context of the injury-associated inflamma-tory response is high-mobility group B1 (HMGB1) protein. HMGB1 is highly conserved across species. It is a constitutively expressed, nonhistone chromosomal protein that participates in a variety of nuclear events, including DNA repair and transcrip-tion. Inflammatory signaling can redirect HMGB1 to the cytosol in both monocytes and macrophages, as a result of posttransla-tional modification. HMGB1 is released passively from dam-aged or necrotic cells and is detected rapidly in the circulation within 30 minutes post injury. It can also be actively secreted from immune-competent cells stimulated by bacterial-derived lipoproteins (e.g., endotoxin) or by inflammatory cytokines (e.g., tumor necrosis factor). For example, macrophages release HMGB1 following the activation of the inflammasomes.8,9 Key Points1 Endogenous damage-associated molecular patterns (DAMPs) are produced following tissue and cellular injury. These molecules interact with immune and nonimmune cell receptors to initiate a “sterile” systemic inflammatory response following severe traumatic injury.2 In many cases, DAMP molecules are sensed by pattern rec-ognition receptors (PRRs), which are the same receptors that cells use to sense invading pathogens. This explains in part, the similar clinical picture of systemic inflammation observed in injured and/or septic patients.3 The central nervous system receives information with regard to injury-induced inflammation via soluble mediators as well as direct neural projections that transmit informa-tion to regulatory areas in the brain. The resulting neuro-endocrine reflex plays an important modulatory role in the immune response.4 Inflammatory signals activate key cellular stress responses (the oxidative stress response; the heat shock protein response; the unfolded protein response; autophagy; pyroptosis), which serve to mobilize cellular defenses and resources in an attempt to restore homeostasis.5 The cells, mediators, signaling mechanisms, and pathways that comprise and regulate the systemic inflammatory response are closely networked and tightly regulated by tran-scriptional events as well as by epigenetic mechanisms, post-translational modification, and microRNA synthesis.6 Management of critically ill and injured patients is optimized with the use of evidence-based and algorithm-driven therapy.7 Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients.Brunicardi_Ch02_p0027-p0082.indd 2801/03/19 6:49 PM 29SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2MOFPICSInjuryImmunehomeostasisEarly deathDischarge to LTACPoor quality of lifeIndolent deathCatabolic statePersistence inflammationProgressive immunosuppressionAnti-inflammatoryPro-inflammatoryRapid recoveryChronic critical illnessTimeUncomplicatedclinical courseFigure 2-1. Postinjury systemic response can follow multiple trajectories. MOF = multiple organ failure; PICS = persistent inflammation, immunosuppression, and catabolism syndrome; LTAC = long-term acute care facility. (Reproduced with permission from Loftus TJ, Mira JC, Ozrazgat-Baslanti T, et al: Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospec-tive cohort study of sepsis in critically ill surgical patients, BMJ Open. 2017 Aug 1;7(7):e015136.)Table 2-1Clinical spectrum of infection and systemic inflammatory response syndrome (SIRS)TERMDEFINITIONInfectionIdentifiable source of microbial insultSIRSTwo or more of following criteria are met: Temperature ≥38°C (100.4°F) or ≤36°C (96.8°F) Heart rate ≥90 beats per minute Respiratory rate ≥20 breaths per minute or Paco2 ≤ 32 mmHg or mechanical ventilation Abnormal white blood cell count (≥12,000/μL or ≤4000/μL or ≥10% immature band forms)SepsisIdentifiable source of infection + SIRSSevere sepsisSepsis + organ dysfunctionSeptic shockSepsis + cardiovascular collapse (requiring vasopressor support)Paco2 = partial pressure of arterial carbon dioxide.Table 2-2Damage-associated molecular patterns (DAMPs) and their receptorsDAMP MOLECULEPUTATIVE RECEPTOR(S)HMGB-1TLRs (2,4,9), RAGEHeat shock proteinsTLR2, TLR4, CD40, CD14,SiglecsS100 proteinTLR4, RAGEMitochondrial DNATLR9HyaluranTLR2, TLR4, CD44BiglycanTLR2 and TLR4Formyl peptides (mitochondrial)Formyl peptide receptor 1IL-1αIL-1 receptorOnce outside the cell, HMGB1 has been shown to signal via the Toll-like receptors (TLR2, TLR4, TLR9), the receptor for advanced glycosylation end products (RAGE), CD24, and others. The activation of TLRs by HMGB1 occurs mainly in myeloid cells, whereas RAGE is thought to be the receptor tar-get for HMGB1 in endothelial cells.The diverse proinflammatory biological responses that result from HMGB1 signaling include: (a) the release of cytokines and chemokines from macrophage/monocytes and dendritic cells; (b) neutrophil activation and chemotaxis; (c) alterations in epithelial barrier function, including increased permeability; and (d) increased procoagulant activity on plate-let surfaces; among others.10 In addition, HMGB1 binding to TLR4 triggers the proinflammatory cytokine release that medi-ates “sickness behavior.”11The biologic function of HMGB1 is regulated by its redox state. For example, a thiol at C106 is required for HMGB1 to promote macrophage TNF release, while a disulfide bond between C23 and C45 confers proinflammatory properties. With all three cysteines in the thiol (reduced) state, HMGB1 loses its DAMP function, but gains the capacity to serve as a chemotactic mediator. Importantly, shifts between the redox states have been demonstrated and indicate that redox state dynamics are impor-tant regulators of HMGB1.12Brunicardi_Ch02_p0027-p0082.indd 2901/03/19 6:49 PM 30BASIC CONSIDERATIONSPART IHMGB1 levels in human subjects following injury corre-late with the Injury Severity Score and complement activation, as well as with increases in circulating inflammatory mediators such as tumor necrosis factor.13 Exogenous administration of HMGB1 to normal animals produces fever, weight loss, epithe-lial barrier dysfunction, and, possibly, death. Further supporting the HMGB1 role in sterile inflammation, traumatic brain injury (TBI) induced by a cortical injury model has been shown to result in acute lung injury with increased alveolar hemorrhage, neutrophil infiltration, and poor oxygenation. This acute lung injury (ALI) was accompanied by a doubling in serum HMGB1 concentrations along with evidence that neocortical brain cells were a source of HMGB1 following TBI.14 More recently, in an animal model of hemorrhagic shock, HMGB1 release from intestinal epithelium was linked to acute lung injury.15 Finally, increased plasma levels of HMGB1 have been shown to cor-relate with immune suppression and increased infection risk in patients undergoing major surgical procedures.16 The identifica-tion of the receptor for advanced glycation end products as the receptor for HMGB1 in this setting has identified new therapeu-tic strategy to ameliorate ALI following TBI.17A Role for Mitochondrial DAMPs in the Injury-Mediated Inflammatory Response. Mitochondrial proteins and/or DNA can act as DAMPs by triggering an inflammatory response to cellular necrosis and stress. Specifically, mitochondrial DNA (mtDNA) released from damaged or dysfunctional mitochon-dria leads both to inflammasome activation and activation of the stimulator of interferon gene pathway (STING).18Cell-free mtDNA (cf-mtDNA) has been shown to be thousands of times higher in trauma patients when compared to normal volunteers. In addition, direct injection of mitochon-dria lysates in an animal model causes remote organ damage, including liver, and lung inflammation.19 These data suggest that with cellular stress or tissue injury, cf-mtDNA released from damaged/stressed mitochondria contribute to the sterile inflammatory response in injured patients. From an evolution-ary perspective, given that eukaryotic mitochondria derive from bacterial origin, it would make sense that they retain bacterial features capable of eliciting a strong response that is typically associated with a pathogen trigger. In addition, the mitochon-drial transcription factor A (TFAM), a highly abundant mito-chondrial protein, is functionally and structurally homologous to HMGB1. It has also been shown be released in high amounts from damaged cells where it acts in conjunction with mtDNA to activate TLR9 signaling.20Following trauma, cf-mtDNA levels appear to be higher in nonsurvivors when compared to survivors and correlate with the development of both SIRS and sepsis post injury.21,22 Cf-mtDNA has also been linked both ex vivo and in vivo to the formation of neutrophil extracellular traps, which are also associated with sterile inflammation and are a possible cause of secondary tissue injury.23,24 Reducing cf-mtDNA, perhaps by targeting enzymes capable of digesting circulating mtDNA is an attractive therapeutic option to prevent development of inflam-matory complications of trauma.25Heat-Shock Proteins as DAMPs. Heat shock proteins (HSPs) are a large and diverse family of intracellular proteins that are expressed during times of inflammation and oxidative stress or following tissue injury.26 Very highly conserved across species, HSPs function as molecular chaperones to monitor and maintain appropriate protein folding.27 They accomplish this task through the promotion of protein refolding, the targeting of misfolded proteins for degradation, or the sequestering of partially folded proteins for movement to appropriate membrane compartments. HSPs are also capable of binding foreign proteins and thereby function as intracellular chaperones for ligands such as bacterial DNA and endotoxin.HSPs are presumed to protect cells from the effects of traumatic stress and, when released by damaged cells, alert the immune system of the tissue damage by activating both innate and acquired immunity.28 HSPs are also released from intact cells via a nonclassical secretory pathway, both via “secretory lysosomes” as well as the exosomal pathway. For example, HSP70-containing exosomes have been implicated in postshock inflammation.29 Once outside the cell, free HSPs can bind to pattern-recognition receptors (PRR) as well as other cell surface receptors to modu-late the inflammatory response. Recently, the role of free HSP-mediated proinflammatory properties via TLR2 and TLR4 has been questioned, as it has been suggested that the presence of con-taminating endotoxin in bacterially-produced HSP preparations may explain at least some of these inflammatory effect results.30 However, the additional evidence suggests that the immunos-timulatory properties may be dependent on how HSPs arrive outside the cell. In the context of massive cell damage or large exosome release, HSPs may serve as proinflammatory DAMPs. In contrast, HSPs released by active secretion may exert anti-inflammatory immune dampening signals (Table 2-3).31,32 New receptors for HSP have been identified that are members of the sialic acid-binding immunoglobulin-like lectins (siglecs), which may explain these effects. Two members of the family, Siglec-5 and Siglec-14, with similar binding sites for HSP70, exhibit oppo-site intracellular events in response to HSP binding, being either pro-(Siglec-14) or anti-(Siglec-5) inflammatory.33,34From a clinical perspective, extracellular HSPs have been demonstrated to be elevated almost immediately post injury in polytraumatized patients (up to 10 times normal) with the degree of elevation being correlated with the severity of illness.35 Moreover, in the setting of polytrauma, plasma HSP70 levels have been shown to correlate inversely with HLA-DRA expression, a marker of immunosuppression.36Extracellular Matrix Molecules Act as DAMPs. Recent work has explored the role of extracellular matrix (ECM) proteins in the TLR-mediated inflammatory response that follows tissue injury. These molecules, which are sequestered under normal conditions, can be released in a soluble form with proteolytic digestion of the ECM. Proteoglycans, glycosaminoglycans, and glycoproteins such as fibronectin have all been implicated as key players in the DAMP/TLR interaction. Proteoglycans, in particu-lar, have also been shown to activate the intracellular inflamma-somes that trigger sterile inflammation. These molecules, which consist of a protein core with one or more covalently attached glycosaminoglycan chains, can be membrane-bound, secreted, or proteolytically cleaved and shed from the cell surface.Biglycan is one of the first proteoglycans to be described as a TLR ligand.37 It consists of a protein core containing leucine-rich repeat regions, with two glycosaminoglycan (GAG) side-chains (chondroitin sulfate or dermatan sulfate). While biglycan typically exists in a matrix bound form, with tissue injury it is released from the ECM in a soluble form where it interacts with TLR2 or TLR4 to generate an immediate inflammatory response.Various proinflammatory cytokines and chemokines includ-ing tumor necrosis factor (TNF)-α and interleukin (IL)-1β are Brunicardi_Ch02_p0027-p0082.indd 3001/03/19 6:49 PM 31SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2downstream effector molecules of biglycan/TLR2/4 signaling. Among these, the mechanism of biglycan-mediated autonomous synthesis and secretion of mature IL-1β is unique. Usually, release of mature IL-1β from the cell requires two signals: one that is needed to initiate synthesis (TLR2/4-mediated), and the other to process pro-IL-1β to its mature form (inflammasome-mediated). How is it possible for biglycan to provide both signals? Current evidence indicates that when soluble biglycan binds to the TLR, it simultaneously serves as a ligand for a purinergic receptor, which facilitates the inflammasome activation required for IL-1β processing.38 These data support the idea that DAMP-mediated signals can initiate a robust inflammatory response.S100 Proteins as DAMPs. S100 proteins are a group of cal-cium-binding proteins that participate in the regulation of intra-cellular calcium. There are at least 25 members identified to date, with diverse functions that are cell-type dependent. While regulation and management of calcium storage is a primary function of S100 proteins, additional specialized roles include cytoskeletal organization, protein trafficking and transcriptional regulation. They are loosely grouped according to their func-tional capability: those that work exclusively inside the cell, outside the cell, or in both locations.8,39Similar to both HMGB1 and HSP, S100 proteins are released passively from damaged cells as well as actively via nonclassical protein secretion mechanisms. For example, S100A8/A9 (also called calprotectin) is released by activated neutrophils and macrophages, although the exact mechanisms that regulate the active release of S100 proteins remain unclear.40 In addition, S100A8/A9 secretion is linked to the release of neu-trophil extracellular traps (NETs), a fibrillar matrix of DNA and granule proteins that are extruded from activated neutrophils and that serve an antimicrobial function.41 Similar to HMGB1, S100 protein functions can be modulated by their redox state.Extracellular S100A8/A9 functions as an endogenous agonist to bind TLR4 and RAGE, serving as a strong proin-flammatory mediator. It can induce both inflammatory cytokine production and activation of leukocyte migration, as well as pro-mote apoptosis and autophagy in distinct cell types. S100A8/A9 is increased following polytrauma, and in some studies, higher levels of S100A8/A9 have been correlated with patient survival.9 More recent work in a second severely injured patient cohort (median ISS of 39) showed that the most seriously injured patients demonstrated a significantly smaller overall increase in S100A8/A9 when compared to the other patients, and that lower S100A8/A9 levels were associated with infectious risk.42A second S100 family protein, S100B, is highly expressed in astrocytes and is an important biomarker for traumatic brain injury. When assessed within 3 hours of injury, it is a highly sensitive marker that is helpful in identifying those patients with mild TBI who do not require imaging.43 In a recent cohort of 100 patients with severe traumatic brain injury, serum S100B levels were significantly higher in those patients who had an unfavorable outcome 3 months post injury compared with those who had made a good recovery. The patients who died also had significantly higher S100B levels than the survivors.8,44Heme as DAMP. Heme is the oxygen-binding moiety found in hemoglobin and other hemoproteins in the muscle and mito-chondria. It is a very highly conserved molecule composed of a tetrapyrrole ring surrounding a single iron. When red blood cells are damaged, hemoglobin is released, where it is bound by plasma proteins such as haptoglobin. In turn, the hemoglobin-haptoglobin complexes are scavenged by the reticuloendothelial system in the liver and spleen to form bilirubin as the ultimate end product. When the amount of free hemoglobin exceeds the binding capacity of haptoglobin and other specialized binding proteins, it is loosely bound to other plasma proteins where it can be readily oxidized. Ultimately, this can result in the release of the prosthetic heme group from hemoglobin, generating labile heme, which is a pro-oxidant.45In vitro experiments demonstrate that labile heme induces cell activation, via both TLR4-dependent processes and the inflammasome, resulting in cytokine release.46,47 Moreover, Table 2-3The immunomodulatory functions of heat shock proteins (HSPs)CELL LOCATIONRECOGNIZED AS DAMPIMMUNOMODULATORY FUNCTIONHSP90Cytoplasm, endoplasmic reticulumCan function both inside and outside the cellMay act as DAMP chaperone to activate innate immune responseBinds and optimizes RNA polymerase II action to regulate gene transcriptionStabilizes glucocorticoid receptor in the cytoplasmImportant for processing and membrane expression of TLRChaperones include IKKFacilitates antigen presentation to dendritic cellsHSP70Can function both inside and outside the cellEndoplasmic reticulum homolog is BiPExogenous HSP70 elicits cellular calcium flux, NF-κB activation, cytokine productionCan have anti-inflammatory actions when expression is increasedInhibits TLR-mediated cytokine production via NF-κBReduces dendritic cell capacity for T-cell stimulationBiP sequesters proteins important to the unfolded protein responseHSP60MitochondriaExogenous HSP60 inhibits NF-κB activationPlays a role in intracellular protein traffickingModulates cytokine synthesisBiP = binding immunoglobulin protein; DAMP = damage-associated molecular pattern; IKK = IκB kinase; NF-κB, nuclear factor-κB; TLR = Toll-like receptorBrunicardi_Ch02_p0027-p0082.indd 3101/03/19 6:49 PM 32BASIC CONSIDERATIONSPART Iheme-induced neutrophils activation leads to extracellular traps (NETs) release through a mechanism dependent on reactive oxygen species.48 However, unlike the other DAMPs discussed, labile heme can also have direct cytotoxic effects on cells by a direct interaction with membrane phospholipids and the catal-ysis of membrane lipid peroxidation, leading to programmed cell death. In macrophages, labile heme can induce necroptosis, rather than apoptosis.45DAMPs Are Ligands for Pattern Recognition ReceptorsThe inflammatory response that occurs following traumatic injury is similar to that observed with pathogen exposure. Not surprisingly, surface and cytoplasmic receptors that medi-ate the innate immune response to microbial infection have also been implicated in the activation of sterile inflamma-tion. In support of this idea, genes have been identified that are dysregulated acutely both in response to a microbial ligand administered to human volunteers and in response to traumatic injury in a large patient population.49 The classes of receptors that are important for sensing damaged cells and cell debris are part of the larger group of germ-line encoded pattern recogni-tion receptors (PRRs). The best described ligands for these receptors are microbial components, the pathogen-associated molecular patterns (PAMPs). The PRRs of the innate immune system are varied and include Toll-like receptors (TLRs), calcium-dependent (C-type) lectin receptors (CLRs), the nucleotide-binding domain, leucine-rich repeat–containing (NBD-LRR) proteins (NLRs; also nucleotide-binding and oligomerization domain [NOD]-like receptors), receptors for advanced glycation end-products (RAGE), and retinoic acid–inducible gene (RIG)-I-like receptors (RLRs). Following receptor ligation, intracel-lular signaling modulates transcriptional and posttranslational events necessary for host defense by coordinating the synthesis and release of cytokines and chemokines to either initiate or suppress the inflammatory response. The best described of these receptors, the TLRs, NLRs, CLRs and RAGE, are dis-cussed in the following section.Toll-Like Receptors. The Toll-like receptors are evolutionarily conserved type 1 transmembrane proteins that are the best-char-acterized PRRs in mammalian cells. They were first identified in Drosophila, where a mutation in the Toll gene led to its iden-tification as a key component in their immune defense against fungal infection. The first human TLR, TLR4, was identified shortly thereafter. Now, more than 10 human TLR family mem-bers have been identified, with distinct ligands that include lipid, carbohydrate, peptide, and nucleic-acid components of various pathogens. TLRs are expressed by both immune and nonimmune cells. At first, the expression of TLR was thought to be isolated to professional antigen-presenting cells such as dendritic cells and macrophages. However, mRNA for TLR family members have been detected in most cells of myeloid lineage, as well as NK cells.50 In addition, activation of T cells increases their TLR expression and induces their survival and clonal expan-sion. Direct engagement of TLR in Treg cells promotes their expansion and reprograms them to differentiate into T helper cells, which in turn provides help to effector cells. In addition, B cells express a distinct subset of the TLR family that deter-mines their ability to respond to DAMPs; however, the signifi-cance of restricted TLR expression in these cells is not yet clear.All TLRs consist of a ligand-binding domain, char-acterized by multiple leucine-rich repeats (LRRs), and a carboxy-terminal, intracellular Toll/interleukin (IL) 1 recep-tor (TIR) domain. The LRR domains recognize bacterial and viral PAMPs in the extracellular environment (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11) or in the endolysosomes (TLR3, TLR7, TLR8, TLR9, and TLR10). While the role of TLRs in sepsis has been well described, more recent data indi-cate that a subset of the TLRs—TLR4 in particular—also rec-ognize DAMPs released from injured cells and tissues.51 Among the DAMP ligands for surface TLR are HMGB1, HSPs, S100 proteins, and several others. Endosomal TLR ligands include mtDNA and other mitochondrial proteins.What we know about TLR signaling events has largely been derived from the TLR-mediated response to bacterial pathogens. However, it is largely accepted that the intracellu-lar adaptors required for signal transmission by TLRs are con-served and utilized for “damage” sensing of endogenous (“self”) ligands as well.52,53 The intracellular domain structure of TLRs is highly conserved and is characterized by a cytoplasmic Toll/IL-1R homology (TIR) domain. Binding of ligand to the recep-tor results in a receptor dimer, either a homodimer (e.g., TLR4/TLR4) or heterodimer (e.g., TLR2/TLR1), which recruits a number of adaptor proteins to the TIR domains through TIR-TIR interaction.54 With one exception (TLR3), the universal adaptor protein central to the TLR signaling complex is myeloid dif-ferentiation factor 88 (MyD88), a member of the interleukin-1 receptor subfamily. MyD88 works through the recruitment of a second TIR-containing adaptor, MyD88 adaptor-like protein (Mal, also termed Toll/interleukin-1 receptor-containing adaptor protein, or TIRAP) in the context of TLR4 and TLR2 signaling, which serves as a bridge between MyD88 and activated TLRs to initiate signal transduction. It is interesting that Mal’s adaptor function requires cleavage of the carboxy-terminal portion of the protein by caspase-1, a key effector of the inflammasome.55 This finding suggests an important synergy between TLRs and the inflammasome that may potentiate TLR-mediated signaling.Signaling through the MyD88-dependent pathway occurs once the receptor is ligated at the cell surface.54 Receptor liga-tion, dimerization, and recruitment of the MyD88/Mal com-plex results in the activation of numerous cytoplasmic protein kinases, including IL-1 receptor–associated kinases, resulting in an interaction with tumor necrosis factor receptor–associated factor 6 (TRAF6). TRAF6, an E3 ubiquitin ligase, forms a com-plex with two other proteins, which together activate the com-plex that subsequently phosphorylates IκB kinase (IKK)-β and the MAP kinases (MAPKs). Ultimately, the phosphorylation of IκB leads to its degradation, which frees NF-κB and allows its translocation to the nucleus and the transcription of NF-κB tar-get genes. Simultaneously, MAP kinase activation is critical for activation of the activator protein-1 (AP-1) transcription factor, and thus production of inflammatory cytokines.Two other TIR domain-containing adaptor proteins, TIR-domain-containing adapter-inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM), are important to TLR-signaling events that are involved in the MyD88-independent sig-naling pathways, activated by TLR3 and TLR4. One distinction of MyD88-dependent and -independent TLR signaling is that TLR4/TRIF transduction begins after the signaling complex is internalized into endosomes. The MyD88-independent pathway acts through TRIF to activate NF-κB, similar to the MyD88-dependent pathway. However, TRIF can also recruit other sig-naling molecules to phosphorylate interferon-regulatory factor 3 (IRF3), which induces expression of type I IFN genes.5422Brunicardi_Ch02_p0027-p0082.indd 3201/03/19 6:49 PM 33SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2The initiation of transcription by TLR activation leads to the upregulation of a large cohort of target genes that include interferons α and β (IFNα/β), nitric oxide synthase 2 (NOS2A), and tumor necrosis factor (TNF), which play critical roles in initiating innate immune responses to cellular injury and stress. Given the importance of TLR triggering of the innate immune response to immune homeostasis, it is no surprise that the pro-cess is tightly regulated. TLR signaling is controlled at multiple levels, both posttranscriptionally via ubiquitination, phosphory-lation, and micro RNA actions that affect mRNA stability, and by the localization of the TLRs and their signaling complexes within the cell.TLR expression is significantly increased following blunt traumatic injury.50,51 A recent study of patients undergoing “high-risk” surgical procedures examined immune parameters, includ-ing TLR expression, that were associated with the development of SIRS. The investigators demonstrated that patients who developed postoperative SIRS exhibited increased TLR4 and TLR5 expres-sion on a subgroup of CD14+ monocytes when compared to those patients with an uneventful recovery.56 Moreover, the upregulation of TLR in these patients was associated with increased expression of IL-6. Interestingly, the authors hypothesize that preoperatively, a subset of monocytes may already be primed to act in this way and thus may identify a vulnerable patient group.Nucleotide-Binding Oligomerization Domain (NOD)-like Receptor (NLR) Family. The nucleotide-binding oligo-merization domain-like receptors (NLR) are a large family of proteins composed of intracellular PRRs that sense both endog-enous (DAMPs) and exogenous (PAMPs) molecules to trigger innate immune activation. The best characterized of the NLRs is the NLR family pyrin domain-containing 3 (NLRP3), which is highly expressed in peripheral blood leukocytes. It forms the key “sensing” component of the larger, multiprotein inflamma-some complex, which is composed of NLRP3; the adapter pro-tein apoptosis-associated speck-like protein containing a CARD (ASC); and the effector protein, caspase 1.57 Activation of the NLRP3 inflammasome is tightly regulated, both transcription-ally and at the posttranslational level. An initial priming event (typically via TLR/nuclear factor [NF]-κB signals) upregulates NLRP3 expression. The receptor then resides in the cytoplasm in an inactive form due to an internal interaction between two adjacent domains. When phagocytosed DAMPs are sensed by NLRP3, this second event releases the self-repression. The pro-tein can then oligomerize and recruit other complex members. The net result is the auto-activation of pro-caspase 1 to caspase 1. This event is pivotal to all known inflammasome signaling pathways.57,58 The caspase-1 products assemble to form the IL-1 converting enzyme (ICE), which cleaves the proforms of IL-1β, IL-18, and IL-33 to form their active, mature forms required for secretion from the cell.59The inflammasome-activated cytokines, IL-1β and IL-18, are potent proinflammatory molecules that promote key immune responses essential to host defense. Both IL-1β and IL-18 lack a signal sequence, which is usually necessary for the secretion of cellular proteins. More than 20 proteins in addition to IL-1β and IL-18 undergo unconventional protein secretion independent of the ER and Golgi, including a number of the DAMP molecules.60 Currently, the mechanisms responsible for unconventional protein secretion are not understood; however, the process is also evident in yeast under conditions of cellular stress. It makes evolutionary sense that a mechanism for rapid secretion of stored proteins essential to the stress response is highly conserved.Evidence suggests that genetic variations in the NLRP3 gene might affect the magnitude of immune inflammatory responses following trauma. Single nucleotide polymor-phisms within the NLRP3 gene were found to be associated with increased risk of sepsis and MODS in patients with major trauma.61 In an animal model of burn injury, early inflamma-some activation has been detected in a variety of immune cells (NK cells, CD4/ CD8 T cells, and B cells), as determined by the assessment of caspase 1 cleavage by flow cytometry.62 Further, inhibition of caspase 1 activity in vivo results in increased burn mortality, suggesting that inflammasome activation may play an unanticipated protective role in the host response to injury that may be linked to increased production of specific cytokines.CNS trauma induces inflammasome activation in the ner-vous system. Moreover, exosomes containing inflammasome protein cargo are secreted into cerebral spinal fluid and can be detected in patients with TBI.63 In an animal model of TBI, controlled cortical impact, exosomes containing inflammasome proteins are detected in the serum and appear to be linked to TBI-related acute lung injury.64C-Type Lectin and Lectin-Like Receptors. Macrophages and dendritic cells possess receptors that detect molecules released from damaged or dying cells in order to retrieve and process antigens for T cell presentation. A key family of receptors that directs this process is the C-type lectin (CLR) and C-type lec-tin-like (CTLR) receptor family that includes the selectin and the mannose receptor families. CLR and CTLR bind carbohy-drates in both a calcium-dependent (CLR) and -independent (CTLR) fashion. Best described for their sensing of PAMPs, the CLRs can also act to promote the endocytosis and clear-ance of cell debris, which can be processed and presented to T cells.65,66 CTLR receptor recognition of DAMPs of intracellular origin, such as F-actin and the ribonucleoprotein SAP-130, can trigger multiple signaling pathways leading to NF-κB, type I interferon (IFN), and/or inflammasome activation. Expression of the CTLR, MINCLE (macrophage-inducible C-type lectin), is increased after exposure to proinflammatory stimuli or cell stress. When MINCLE senses self-damage in association with ischemia-reperfusion injury, it promotes proinflammatory cyto-kine, chemokine, and nitric oxide production.67Receptor for Advanced Glycation End Products (RAGE).  Another key player in the sterile inflammatory response to injury is the transmembrane receptor, the receptor for advanced glycation endproducts, or RAGE. Highly conserved across spe-cies, RAGE is a member of the immunoglobulin superfamily that is constitutively expressed at high levels in the lung, with low/absent expression in other adult cell types. However, pro-inflammatory stimuli and the presence of RAGE ligands can increase RAGE expression on immune cells such as neutrophils, macrophages, and lymphocytes.68 RAGE also exists as a solu-ble form (sRAGE) composed only of the extracellular domain, which can bind to and sequester RAGE ligands, without conse-quent signaling events.RAGE binds diverse ligands, including HMGB1 and S100, as well as components of the extracellular matrix such as collagen. As a receptor, RAGE recognizes the three-dimensional structure of its ligands that allow it to bind a diverse reper-toire of molecules, independent of their amino acid sequence. Brunicardi_Ch02_p0027-p0082.indd 3301/03/19 6:49 PM 34BASIC CONSIDERATIONSPART ISignaling via RAGE is mediated via multiple pathways lead-ing to transcriptional activation and release of proinflammatory mediators.69 Animal models have linked RAGE to acute lung injury in ischemia-reperfusion models.70 In clinical studies, high sRAGE levels have be linked to prolonged mechanical ventila-tion post lung transplant as well as worse outcomes following TBI-associated acute lung injury.42 These events likely represent a role for an HMGB1-RAGE axis in these pathologic processes.Soluble Pattern Recognition Molecules: The Pentraxins.68  Soluble pattern recognition molecules (PRMs) are a molecu-larly diverse group of molecules that share a conserved mode of action defined by complement activation, agglutination and neutralization, and opsonization. The best described of the PRMs are the pentraxins. PRMs can be synthesized at sites of injury and inflammation by macrophages and dendritic cells, while neutrophils can store PRMs and release them rapidly fol-lowing activation. In addition, epithelial tissues (the liver in par-ticular) serve as a reservoir source for systemic mass release. The short pentraxin, C-reactive protein (CRP), was the first PRM to be identified. Serum amyloid protein (SAP), which has 51% sequence similarity to human CRP, also contains the pentraxin molecular signature. CRP and SAP plasma levels are low (≤3 mg/L) under normal circumstances. However, CRP is synthesized by the liver in response to interleukin-6, increasing serum levels more than a 1000-fold. Thus, CRP is considered part of the acute-phase protein response in humans. For this reason, C-reactive protein has been studied as a marker of the proinflammatory response in many clinical settings, includ-ing appendicitis, vasculitis, and ulcerative colitis. CRP and SAP are ancient immune molecules that share many functional properties with antibodies: they bind bacterial polysaccharides, ECM components, apoptotic cells, and nuclear materials, as well as all three classes of Fcγ receptors (FcγR). Both molecules also participate in the activation and regulation of complement pathways. In this way, short pentraxins can link immune cells to the complement system.71Finally, there is significant data to support a role for pen-traxin 3 (PTX3), a long pentraxin family member, in the “sterile” inflammatory response associated with cellular stress. While CRP is produced solely in the liver, PTX3 is produced by vari-ous cells in peripheral tissues, including immune cells. PTX3 plasma concentrations increase rapidly in various inflammatory conditions, including sepsis. Further, in a recent prospective study of polytraumatized patients, serum PTX3 concentrations were highly elevated, peaking at 24 hours. Further, PTX3 con-centrations at admission were associated with injury severity, while higher PTX3 serum concentrations 24 hours after admis-sion correlated with lower probability for survival.72CENTRAL NERVOUS SYSTEM REGULATION OF INFLAMMATION IN RESPONSE TO INJURYThe central nervous system (CNS) communicates with the body through ordered systems of sensory and motor neurons, which receive and integrate information to generate a coordinated response. Rather than being an immune-privileged organ, recent work indicates that the CNS receives information with regard to injury-induced inflammation both via soluble media-tors as well as direct neural projections that transmit informa-tion to regulatory areas in the brain (Fig. 2-2). How does the TNFIL-1Central nervous systemACTHglucocorticoidsSensory vagusSympatheticParasympathetic(Motor vagus)AcetylcholineInjuryinflammationInflammatorycascadeInjury siteEPI, NOREPIFigure 2-2. Neural circuit relaying messages of localized injury to the brain (nucleus tractus solitarius). The brain follows with a hor-mone release (adrenocorticotropic hormone [ACTH], glucocorticoids) into the systemic circulation and by sympathetic response. The vagal response rapidly induces acetylcholine release directed at the site of injury to curtail the inflammatory response elicited by the activated immunocytes. This vagal response occurs in real time and is site specific. EPI = epinephrine; IL-1 = interleukin-1; NOREPI = norepinephrine; TNF = tumor necrosis factor. (Adapted with permission from Tracey KJ: The inflammatory reflex, Nature. 2002 Dec 19-26;420(6917):853-859.)Brunicardi_Ch02_p0027-p0082.indd 3401/03/19 6:49 PM 35SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2CNS sense inflammation? DAMPs and inflammatory molecules convey stimulatory signals to the CNS via multiples routes. For example, soluble inflammatory signaling mol-ecules from the periphery can reach neurons and glial cells directly through the fenestrated endothelium of the circumven-tricular organs (CVO) or via a leaky blood-brain barrier in path-ological settings following a traumatic brain injury.73 In addition, inflammatory stimuli can interact with receptors located on the brain endothelial cells to generate a variety of proinflammatory mediators (cytokines, chemokines, adhesion molecules, proteins of the complement system, and immune receptors) that directly impact the brain parenchyma. Not surprising, this response is countered by potent anti-inflammatory signaling, a portion of which is provided by the HPA axis and the release of systemic glucocorticoids. Inflammatory stimuli in the CNS result in behavioral changes, such as increased sleep, lethargy, reduced appetite, and the most common feature of infection, fever.Information regarding peripheral inflammation and tis-sue damage can also be signaled to the brain via afferent neu-ral fibers, particularly those of the vagus nerve.74 These afferent fibers can interconnect with neurons that project to the hypo-thalamus to modulate the HPA axis. In addition, afferent vagal nerve impulses modulate cells in the brain stem, at the dorsal motor nucleus of the vagus, from which efferent pregangli-onic parasympathetic originate. Axons from these cells, which comprise the visceromotor component of the vagus nerve, form an “inflammatory reflex” that feeds back to the periphery to regulate inflammatory signaling events.75 Mechanistic insight into the “inflammatory reflex” was provided by the observa-tion in several experimental model systems, that vagal stimu-lation reduced proinflammatory cytokine production from the spleen.75,76 This effect was dependent on both vagal efferent signals and on splenic catecholaminergic nerve fibers that origi-nated in the celiac plexus and terminated in the T cell–rich area of the spleen. The vagal efferent fibers that terminated within the celiac ganglion were found to synapse on the cell bodies of the catecholaminergic splenic nerves. Vagal stimulation resulted in the firing of these adrenergic nerves, resulting in the activation of β2-adrenergic receptors on a subset of acetylcholine (ACh)-producing T cells. The ACh released from this T cell popula-tion targets α-7 nicotinic ACh receptors (a7nAChR) expressed by splenic macrophages.77 Macrophage ACh receptor ligation blocks cell activation, inhibiting cytokine production and shifting the macrophages towards an M2 anti-inflammatory phenotype. Moreover, ACh-receptor binding inhibits intracellular signaling including the nuclear translocation of NF-κB and the activation of the inflammasome. In a rat model of hemorrhagic shock with reperfusion, vagal nerve stimulation post injury resulted in a decrease in the inflammatory response to hemorrhage.78Neuroendocrine Response to InjuryTraumatic injury results in complex neuroendocrine signaling from the brain that serves to enhance immune defense and rap-idly mobilize substrates necessary to meet essential energy and structural needs. The two principle neuroendocrine pathways that orchestrate the host response are the hypothalamic-pitu-itary-adrenal (HPA) axis, which results in the release of gluco-corticoid hormones, and the sympathetic nervous system, which results in release of the catecholamines, epinephrine (EPI), and norepinephrine (EPI). Virtually every hormone of the HPA axis influences the physiologic response to injury and stress (Table 2-4), but some with direct influence on the inflammatory 3Table 2-4Hormones regulated by the hypothalamus, pituitary, and autonomic systemHypothalamic RegulationCorticotropin-releasing hormoneThyrotropin-releasing hormoneGrowth hormone–releasing hormoneLuteinizing hormone–releasing hormoneAnterior Pituitary RegulationAdrenocorticotropic hormoneCortisolThyroid-stimulating hormoneThyroxineTriiodothyronineGrowth hormoneGonadotrophinsSex hormonesInsulin-like growth factorSomatostatinProlactinEndorphinsPosterior Pituitary RegulationVasopressinOxytocinAutonomic SystemNorepinephrineEpinephrineAldosteroneRenin-Angiotensin SystemInsulinGlucagonEnkephalinsresponse or immediate clinical impact are highlighted here, including growth hormone (GH), macrophage inhibitory factor (MIF), aldosterone, and insulin.The Hypothalamic-Pituitary-Adrenal Axis. One of the main mechanisms by which the brain responds to injury-associated stress is through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Following injury, corticotrophin-releasing hormone (CRH) is secreted from the paraventricular nucleus (PVN) of the hypothalamus. This action is mediated in part by circulating cytokines produced as a result of the innate immune response to injury. These include tumor necrosis factor-α (TNF-α) IL-1β, IL-6, and the type I interferons (IFN-α/β). Cytokines that are produced as a result of the adaptive immune response (IL-2 and IFN-γ) are also capable of increasing cortisol release. Direct neu-ral input via afferent vagal fibers that interconnect with neurons projecting to the hypothalamus can also trigger CRH release. CRH acts on the anterior pituitary to stimulate the secretion of adrenocorticotropin hormone (ACTH) into the systemic circula-tion. Interestingly, the cytokines that act on the hypothalamus are also capable of stimulating ACTH release from the anterior pituitary so that marked elevations in ACTH and in cortisol can occur that are proportional in magnitude to the injury severity. Additionally, pain, anxiety, vasopressin, angiotensin II, chole-cystokinin, vasoactive intestinal peptide, and catecholamines all contribute to ACTH release in the injured patient.Brunicardi_Ch02_p0027-p0082.indd 3501/03/19 6:49 PM 36BASIC CONSIDERATIONSPART IACTH acts on the zona fasciculate of the adrenal glands to synthesize and secrete glucocorticoids (Fig. 2-3). Cortisol is the major glucocorticoid in humans and is essential for survival during significant physiologic stress. The resulting increase in cortisol levels following trauma have several important anti-inflammatory actions.Cortisol elicits its many actions through a cytosolic recep-tor, the glucocorticoid receptor (GR). Because it is lipid soluble, cortisol can diffuse through the plasma membrane to interact with its receptor, which is sequestered in the cytoplasm in a com-plex with heat shock proteins (Fig. 2-4). Upon ligand binding, the GR is activated and can employ a number of mechanisms to modulate proinflammatory gene transcription and signaling events, with a “net” anti-inflammatory effect.79 For example, the activated GR complex can interact with transcription factors to sequester them in the cytoplasm, promote their degradation, or inhibit them through other mechanisms. Affected target genes include proinflammatory cytokines, growth factors, adhesion molecules, and nitric oxide. In addition, glucocorticoids can negatively affect the access of the transcription factor, nuclear factor-κB (NF-κB), to the promoter regions of its target genes via a mechanism that involves histone deacetylase 2. In this way, glucocorticoids can inhibit a major mechanism by which TLR ligation induces proinflammatory gene expression.80 The GR complex can also bind to specific nucleotide sequences (termed glucocorticoid response elements) to promote the 17-˜-OH-progesterone11-DeoxycortisolCortisolCholesterolACTHPregnenolone17-˜-OH-PregnenoloneDehydroepiandrosteroneAndrostenedioneTestosteroneEstradiolSex steroidsGlucocorticoid11-DeoxycorticosteroneCorticosteroneAldosteroneMineralocorticoidProgesteroneFigure 2-3. Steroid synthesis from cholesterol. Adrenocorticotropic hormone (ACTH) is a principal regulator of steroid synthesis. The end products are mineralocorticoids, glucocorticoids, and sex steroids.HSPRProtein synthesisCytoplasmic membraneDNAmRNASRSSSSSSHSPRSNucleusFigure 2-4. Simplified schematic of steroid transport into the nucleus. Steroid molecules (S) diffuse readily across cytoplasmic membranes. Intracellularly, the receptors (R) are rendered inactive by being coupled to heat shock protein (HSP). When S and R bind, HSP dissoci-ates, and the S-R complex enters the nucleus, where the S-R complex induces DNA transcription, resulting in protein synthesis. mRNA = messenger RNA.Brunicardi_Ch02_p0027-p0082.indd 3601/03/19 6:49 PM 37SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2transcription of genes, which have anti-inflammatory functions. These include interleukin-10 and interleukin-1-receptor antago-nists. Further, GR complex activation can indirectly influence TLR activity via an interaction with signaling pathways such as the mitogen-activated protein kinase and transforming growth factor–activated kinase-1 (TAK1) pathways. Finally, a recent report demonstrated that GCs target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate TLR-induced signaling events.81Adrenal insufficiency represents a clinical syndrome high-lighted largely by inadequate amounts of circulating cortisol and aldosterone. Classically, adrenal insufficiency is described in patients with atrophic adrenal glands caused by exogenous steroid administration who undergo a stressor such as surgery. These patients subsequently manifest signs and symptoms such as tachycardia, hypotension, weakness, nausea, vomiting, and fever. However, it is now apparent that severe traumatic injury associated with an extended proinflammatory response can increase the risk of critical illness–related corticosteroid insuf-ficiency, or CIRCI.In the postinjury setting, CIRCI describes a phenomenon in which an exaggerated proinflammatory response is associated with a blunted adrenocortical response.82 Factors that have been linked to CIRCI include dysregulation of the HPA axis with altered adrenal synthesis of cortisol, altered cortisol metabo-lism, and tissue resistance to corticosteroids with inadequate glucocorticoid receptor activity. As a consequence, cortisol levels prove insufficient for the severity of stress. Investigators have determined that CIRCI in trauma patients occurs more fre-quently than previously thought.83 In one recent study, CIRCI occurred in 38 of 70 patients with multiple injuries. In most cases, the diagnosis was made within the first 48 hours follow-ing injury.84 Laboratory findings in adrenal insufficiency include hypoglycemia from decreased gluconeogenesis, hyponatremia from impaired renal tubular sodium resorption, and hyperka-lemia from diminished kaliuresis. Recommended guidelines to diagnose CIRCI include measuring delta cortisol (change in baseline cortisol at 60 min of <9 µg/dL) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dL. Treatment strategies remain controversial in the set-ting of trauma.85,86Macrophage Migration Inhibitory Factor Modulates Cortisol Function. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed by a variety of cells and tissues, including the anterior pituitary, macrophages and T lymphocytes. MIF is also classified as an atypical chemo-kine that binds to the CXC4 receptor.87 Several important func-tions of MIF in innate and adaptive immune responses and in inflammation have been described supporting the idea that MIF may function to counteract the anti-inflammatory activity of glucocorticoids.88 For example, MIF has been reported to play a central role in the exacerbation of inflammation associated with acute lung injury, where it has been detected in the affected lungs and in alveolar macrophages. MIF has also been reported to upregulate the expression of Toll-like receptor 4 (TLR4) in macrophages,89 and an early increase in plasma MIF has been detected in severely injured patients and was found to corre-late with NF-κB translocation and respiratory burst in PMNs derived from severely injured patients. Further, nonsurvivors were shown to have higher serum MIF concentrations early after injury than survivors.90 These data suggest that targeting MIF with available small molecule inhibitors may be a novel therapeutic strategy for preventing early PMN activation and subsequent organ failure in severely injured patients.Growth Hormone, Insulin-Like Growth Factor, and Ghrelin. Growth hormone (GH) is a neurohormone expressed primarily by the pituitary gland that has both metabolic and immunomodulatory effects. GH promotes both protein synthe-sis and insulin resistance while enhancing the mobilization of fat stores. GH secretion is upregulated by hypothalamic GH–releasing hormone and downregulated by somatostatin. GH pri-marily exerts its downstream effects through direct interaction with GH receptors and through the enhanced hepatic synthesis of insulin-like growth factor-1 (IGF-1), an anabolic growth fac-tor that is known to improve the metabolic rate, gut mucosal function, and protein loss after traumatic injury. Less than 5% of IGF-1 circulates free in the plasma, with the remainder bound principally to one of six IGF-binding proteins (IGFBPs), the majority to IGFBP-3. In the liver, IGF-1 stimulates protein syn-thesis and glycogenesis; in adipose tissue, it increases glucose uptake and lipid utilization; and in skeletal muscles, it mediates glucose uptake and protein synthesis. In addition to its effects on cellular metabolism, GH enhances phagocytic activity of immu-nocytes through increased lysosomal superoxide production. It also increases the proliferation of T-cell populations.91The catabolic state that follows severe injury has been linked to the suppression of the growth hormone-IGF-IGFBP axis, as critical illness is associated with decreased circulat-ing IGF-1 levels. Not surprising, the administration of exog-enous recombinant human GH (rhGH) has been studied in a prospective, randomized trial of critically ill patients where it was associated with increased mortality, prolonged ventilator dependence, and increased susceptibility to infection.92 More recently, circulating GH levels were examined on admission in 103 consecutive critically ill adult patients. In this study, cir-culating GH levels were increased by about sevenfold in the 24 nonsurvivors when compared with survivors, and they were an independent predictor of mortality, along with APACHE II/SAPS II scores. In distinct contrast, the effect of rhGH adminis-tration in severely burned children, both acutely and following prolonged treatment, has been proven to be beneficial. Pediatric burn patients receiving rhGH demonstrated markedly improved growth and lean body mass, while hypermetabolism was signifi-cantly attenuated.93 This finding was associated with significant increases in serum GH, IGF-I, and IGFBP-3.Ghrelin, a natural ligand for the GH-secretagogue receptor 1a (GHS-R1a), is an appetite stimulant that is secreted by the stomach. GHS-R1a is expressed in a variety of tissues in differ-ent concentrations including the immune cells, Band T-cells, and neutrophils. Ghrelin seems to play a role in promoting GH secretion, and in glucose homeostasis, lipid metabolism, and immune function. In a rodent gut ischemia/reperfusion model, ghrelin administration inhibits proinflammatory cytokine release, reduces neutrophil infiltration, ameliorates intestinal barrier dysfunction, attenuates organ injury, and improves sur-vival. It is interesting that this effect was dependent on an intact vagus nerve, and that intracerebroventricular injection of ghre-lin was also protective.94 These data suggest that the effect of ghrelin is mediated via the central nervous system, most likely through the “cholinergic anti-inflammatory pathway.” High ghrelin levels were demonstrated in critically ill patients as compared to healthy controls, independent of the presence of Brunicardi_Ch02_p0027-p0082.indd 3701/03/19 6:49 PM 38BASIC CONSIDERATIONSPART Iinflammatory markers. Moreover, the high ghrelin levels were a positive predictor of ICU-survival in septic patients, match-ing previous results from animal models. Based on these data, ghrelin seems to exert anti-inflammatory effects that are medi-ated by diverse pathways. Recent work has linked ghrelin to a novel pathway mediated by upregulation of uncoupling protein 2 (UCP2) particularly in the setting of traumatic brain injury.95The Role of Catecholamines in Postinjury Inflammation.  Injury-induced activation of the sympathetic nervous system results in secretion of acetylcholine from the preganglionic sympathetic fibers innervating the adrenal medulla. The adre-nal medulla is a special case of autonomic innervation and is considered a modified postganglionic neuron. Thus, acetyl-choline signaling to the resident chromaffin cells ensures that a surge of epinephrine (EPI) and norepinephrine (NE) release into the circulation takes place in a ratio that is tightly regulated by both central and peripheral mechanisms. Circulating levels of EPI and NE are threeto fourfold elevated, an effect that per-sists for an extended time. The release of EPI can be modulated by transcriptional regulation of phenylethanolamine N-methyl-transferase (PNMT), which catalyzes the last step of the cat-echolamine biosynthesis pathway methylating NE to form EPI. PNMT transcription, a key step in the regulation of epinephrine production, is activated in response to stress and tissue hypoxia by hypoxia-inducible factor 1α (HIF1A).Catecholamine release almost immediately prepares the body for the “fight or flight” response with well-described effects on the cardiovascular and pulmonary systems, and on metabolism. These include increased heart rate, myocardial contractility, conduction velocity, and blood pressure; the redi-rection of blood flow to skeletal muscle; increased cellular metabolism throughout the body; and mobilization of glucose from the liver via glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. To compound the resulting hyperglycemia, insulin release is decreased mainly through the stimulation of α-adrenergic pancreatic receptors. Hyperglycemia, as will be discussed, contributes to the proinflammatory response and to further mitochondrial dysfunction.The goal of this well-orchestrated catecholamine response is to reestablish and maintain the systems’ homeostasis, includ-ing the innate immune system. Circulating catecholamines can directly influence inflammatory cytokine production.96 Data indicate that basal EPI levels condition the activity and respon-siveness of cytokine-secreting cells, which may explain large inter-individual variability in innate cytokine profiles observed following injury. Epinephrine infusion at higher doses has been found to inhibit production of tumor necrosis factor (TNF)-alpha in vivo and to enhance the production of the anti-inflammatory cytokine interleukin IL-10.97 Additionally, in vitro studies indi-cate that stress levels of glucocorticoids and epinephrine, acting in concert, can inhibit production of IL-12, a potent stimulator of Th1 responses. Further, they have been shown in vitro to decrease Th1 cytokine production and increase Th2 cytokine production to a significantly greater degree compared to either adrenal hormone alone. Thus, catecholamines secreted from the adrenal, specifically epinephrine, play a role in both innate proinflammatory cytokine regulation, as well as adaptive Th responses, and may act in concert with cortisol during the injury response to modulate cytokine activity.98How are these effects explained? It is well established that a variety of human immune cells (e.g., mononuclear cells, macrophages, and granulocytes) express adrenergic receptors that are members of the family of G-protein coupled recep-tors that act through the activation of intracellular second mes-sengers such as cAMP and calcium ions influx (discussed in more detail in the following section). These second messengers can regulate a variety of immune cell functions, including the release of inflammatory cytokines and chemokines.The sympathetic nervous system also has direct immune-modulatory properties via its innervation of lymphoid tissues that contain resting and activated immune cells. The close prox-imity of sympathetic nerve terminals to immune cells responding to antigens (e.g., in the spleen) allows for a high concentration of norepinephrine to be localized within the microenvironment of antigen-activated immune cells. Norepinephrine can then interact with b2-adrenergic receptors expressed by CD4+ T and B lymphocytes, many of which also express α2-adrenergic receptors. Additionally, endogenous catecholamine expression has been detected in these cells (both CD4+ CD25+ T cells and phagocytes) as has the machinery for catecholamine synthesis. For example, monocytes contain inducible mRNA for the catecholamine-generating enzymes, tyrosine-hydroxylase, and dopamine-b-hydroxylase, and there is data to suggest that cells can regulate their own catecholamine synthesis in response to extracellular cues. Immune cell release of NE provides a way in which cells may exert additional regulation of inflammatory cell activation. For example, mature dendritic cells express both functional αand b-adrenergic receptor (AR) types, as do monocytes and monocyte-derived macrophages, whereas B cells and Th1 cells express b2-AR exclusively.99 Exposure of PBMCs to NE triggers a distinct genetic profile that indicates a modulation of Th cell function. Thus, stimulation of AR results in varied signaling events to regulate both immune cell pheno-type as well as mature cell function.100Aldosterone. Aldosterone is a mineralocorticoid released by the zona glomerulosa of the adrenal cortex. It binds to the mineralocorticoid receptor (MR) of principal cells in the col-lecting duct of the kidney where it can stimulate expression of genes involved in sodium reabsorption and potassium excretion to regulate extracellular volume and blood pressure. Mineralo-corticoid receptors (MR) have also been shown to have effects on cell metabolism and immunity. For example, recent studies show aldosterone interferes with insulin signaling pathways and reduces expression of the insulin-sensitizing factors, adiponec-tin and peroxisome proliferator activated receptor−γ (PPAR-γ), which contribute to insulin resistance. In the immune system, monocytes, lymphocytes, dendritic cells, and neutrophils have all been shown to possess a MR that binds aldosterone with high specificity, regulating sodium and potassium flux, as well as plasminogen activator inhibitor-1 and p22 phox expression in these cells.101 In dendritic cells, MR activation by aldoste-rone induces the secretion of proinflammatory cytokines. Fur-ther, aldosterone inhibits cytokine-mediated NF-κB activation in neutrophils, which also possess a functional MR.Insulin. Hyperglycemia and insulin resistance are hallmarks of injury and critical illness due to the catabolic effects of circu-lating mediators, including catecholamines, cortisol, glucagon, and growth hormone. The increase in these circulating progly-cemic factors, particularly epinephrine, induces glycogenoly-sis, lipolysis, and increased lactate production independent of available oxygen in a process that is termed “aerobic glycoly-sis.” Although there is an increase in insulin production at the Brunicardi_Ch02_p0027-p0082.indd 3801/03/19 6:49 PM 39SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2same time, severe stress is frequently associated with insulin resistance, leading to decreased glucose uptake in the liver and the periphery contributing to acute hyperglycemia. Insulin is a hormone secreted by the pancreas, which mediates an overall host anabolic state through hepatic glycogenesis and glycolysis, peripheral glucose uptake, lipogenesis, and protein synthesis.102The insulin receptor (IR) is widely expressed and con-sists of two isoforms, which can form homoor hetero-dimers with insulin binding. Dimerization leads to receptor autophos-phorylation and activation of intrinsic tyrosine kinase activity. Downstream signaling events are dependent on the recruitment of the adaptor proteins, insulin receptor substrate (IRS-1), and Shc to the IR. Systemic insulin resistance likely results from proinflammatory signals, which modulate the phosphorylation of IRS-1 to affect its function.Hyperglycemia during critical illness is predictive of increased mortality in critically ill trauma patients.103 It can modulate the inflammatory response by altering leukocyte func-tions and the resulting decreases in phagocytosis, chemotaxis, adhesion, and respiratory burst activities are associated with an increased risk for infection. In addition, glucose administration results in a rapid increase in NF-κB activation and proinflamma-tory cytokine production. Insulin therapy to manage hypergly-cemia has grown in favor and has been shown to be associated with both decreased mortality and a reduction in infectious complications in select patient populations. However, the trend towards tight glycemic control in the intensive care unit failed to show benefit when examined in several reviews.104 Thus, the ideal blood glucose range within which to maintain critically ill patients and to avoid hypoglycemia has yet to be determined.THE CELLULAR STRESS RESPONSESReactive Oxygen Species and the Oxidative Stress ResponseReactive oxygen and nitrogen species (ROS, RNS, respectively) are small molecules that are highly reactive due to the presence of unpaired outer orbit electrons. They can cause cellular injury to host cells and invading pathogens through the oxidation of cell membrane substrates, cellular proteins, and DNA. ROS has also been shown to have important roles as signaling messengers, particularly in the immune system.105,106Oxygen radicals (superoxide anion, hydroxyl radical, hydrogen peroxide) are produced as a by-product of oxygen metabolism. The main areas of ROS production are oxida-tive processes involving the mitochondrial electron transport chain as well as those mediated by NADPH oxidases (NOX), a large class of ROS producing enzymes. Additional metabolic enzymes such as lipoxygenases, cytochrome P-450 and b5, and cyclooxygenases also produce ROS as by-products of their reactions.107 The synthesis of ROS is regulated at several check-points and via complex signaling mechanisms, including Ca2+ signaling, phosphorylation, and small G protein activation, which influence both the recruitment of the molecules required for NOX function and the synthesis of ROS in the mitochondria. Not surprisingly, NOX activation is triggered by a number of inflammatory mediators (e.g., TNF, chemokines, lysophospho-lipids, complement, and leukotrienes).Host cells are protected from the damaging effects of ROS through a number of mechanisms. The best described of these is via the upregulation and/or activation of endogenous antioxidant enzymes such as superoxide dismutases, catalases, and glutaredoxins. Pyruvate kinase also provides negative feed-back for ROS synthesis as do molecules that react nonenzy-matically with ROS. Under normal physiologic conditions, ROS production is balanced effectively by these antioxidative strate-gies. As a consequence, ROS can act as signaling molecules through their ability to modulate cysteine residues by oxidation, and thus influence the functionality of target proteins.108 ROS can also contribute to transcriptional activity both indirectly through its effects on transcription factor lifespan, and directly through the oxidation of DNA.The role for ROS has been well described in phagocytes, which utilize these small molecules for pathogen killing. A sec-ond important role for ROS is in the regulation of the inflamma-some. As discussed previously, the inflammasome mediates the activation of inflammatory capsases leading to the production and secretion of mature cytokines in macrophages.109 Impor-tantly, the best described inflammasome, NLRP3, is redox sen-sitive. Increased intracellular ROS enables the assembly of the protein complex.110 ROS also appears to be involved in adap-tive immunity by influencing immune cell response.106 ROS can alter thiol group oxidative states on the cell surface and, in turn, affect cell signaling. Moreover, intracellular ROS can inhibit DNA transcription. ROS has been described as a prime source of phosphatase activation in both B and T lymphocytes, which can regulate the function of key receptors and intracellu-lar signaling molecules in these cells by affecting phosphoryla-tion events. Finally, large amounts of ROS cannot only suppress cell function, but also can result in cell death.111The Unfolded Protein ResponseSecreted, membrane-bound, and organelle-specific proteins fold in the lumen of the endoplasmic reticulum (ER) where they also receive their posttranslational modifications. Cellular stress dis-rupts the quality control required for this process leading to the accumulation of misfolded or unfolded proteins. These occur-rences are sensed by a highly conserved array of signaling pro-teins in the ER that try to reestablish appropriate folding, while at the same time decreasing protein synthesis.112 The important proteins involved in this process include inositol requiring enzyme 1 (IRE1), protein kinase RNA (PKR)–like ER kinase (PERK), and activating transcription factor 6 (ATF6). Together, these proteins form a complex that generates the unfolded pro-tein response (UPR). The UPR is a mechanism by which ER distress signals are sent to the nucleus to modulate transcription in an attempt to restore homeostasis. While obviously important to secretory epithelial cells, the UPR is also important to cells of the immune system.113Significant protein misfolding results in an alarm signal that, if not addressed, can result in cell death. Genes activated in the UPR result not only in the inhibition of translation, but also other potentially immunomodulatory events including induction of the acute phase response, activation of NF-κB, and the generation of antibody-producing B cells.114 Activation of the UPR is also an alternative mechanism for activation of the inflammasome115 and can increase proinflammatory cytokine production.116Markers of ER stress during critical illness have been demonstrated conclusively in burn patients,114,117 and in animal models they have been detected following hemorrhagic shock, correlating with the degree of organ dysfunction. Burn injury in particular leads to the marked reduction in ER calcium levels 4Brunicardi_Ch02_p0027-p0082.indd 3901/03/19 6:49 PM 40BASIC CONSIDERATIONSPART Iand activation of UPR sensing proteins. Moreover, recent data in a series of burn patients strongly links the UPR to insulin resistance and hyperglycemia in these patients.117 Thus, a better understanding of the UPR, which is triggered by severe inflam-mation, may allow the identification of novel therapeutic targets for injury-associated insulin resistance.118Fibroblast growth factor-21 (FGF21), a recently identi-fied hormone that regulates systemic metabolic homeostasis, is upregulated following mitochondrial damage and may be part of an integrated stress response that includes ER stress and the UPR.119 In animal models, induction of ER stress with chemical ER stressors results in increased FGF21 expression. A recent study examining FGF21 in critically ill patients demonstrated that serum FGF21 concentrations were eight-fold higher in the critically ill patients as compared with the matched controls, regardless of the presence of sepsis. While FGF21 concentrations gradually decreased over time, they remained highly elevated at all studied time points and cor-related with patient mortality.120 These data support the idea that the UPR may play an important role in the response to severe injury.AutophagyUnder normal circumstances, cells need to have a way of dis-posing of damaged organelles and debris aggregates that are too large to be managed by proteosomal degradation. In order to accomplish this housekeeping task, cells utilize a process referred to as “macroautophagy” (autophagy), which is thought to have originated as a stress response.121 The steps of autoph-agy include the engulfment of cytoplasm/organelle by an “isola-tion membrane,” which is also called a phagophore. The edges of the phagophore then fuse to form the autophagosome, a dou-ble-membraned vesicle that sequesters the cytoplasmic material and is a characteristic feature of autophagy. The autophagosome then fuses with a lysosome to form an autolysosome, where the contents, together with the inner membrane, are degraded. This process is controlled by numerous autophagy-specific genes and by the specific kinase, mammalian target of rapamycin (mTOR).As noted previously, autophagy is a normal cellular pro-cess that occurs in quiescent cells for cellular maintenance. However, under conditions of hypoxia and low cellular energy, autophagy is induced in an attempt to provide additional nutri-ents for energy production. The induction of autophagy pro-motes a shift from aerobic respiration to glycolysis and allows cellular components of the autophagosome to be hydrolyzed to energy substrates. Increased levels of autophagy are typical in activated immune cells and are a mechanism for the disposal of ROS and phagocytosed debris.Recent data support the idea that autophagy plays an important role in the immune response.122 Autophagy is stimu-lated by Th1 cytokines and with activation of TLR in macro-phages but is inhibited by Th2 cytokines. It is also recognized as an important regulator of cytokine secretion, particularly those cytokines of the IL-1 family that are dependent on inflamma-some processing for activation. For example, autophagosomes can sequester and degrade pro-IL-1β and inflammasome com-ponents. In animal models of sepsis, inhibition of autophagy results in increased proinflammatory cytokine levels that corre-late with increased mortality.123 These data suggest that autoph-agy is a protective mechanism whereby the cell can regulate the levels of cytokine production.ApoptosisApoptosis (regulated cell death) is an energy-dependent, orga-nized mechanism for clearing senescent or dysfunctional cells, including macrophages, neutrophils, and lymphocytes, without promoting an inflammatory response. This contrasts with cel-lular necrosis, which results in a disorganized sequence of intra-cellular molecular releases with subsequent immune activation and inflammatory response. Systemic inflammation modulates apoptotic signaling in active immunocytes, which subsequently influences the inflammatory response through the loss of effec-tor cells.Apoptosis proceeds primarily through two pathways: the extrinsic pathway and the intrinsic pathway. The extrinsic path-way is activated through the binding of death receptors (e.g., Fas, TNFR), which leads to the recruitment of Fas-associated death domain protein and subsequent activation of caspase 3 (Fig. 2-5). On activation, caspases are the effectors of apoptotic signaling because they mediate the organized breakdown of nuclear DNA. The intrinsic pathway proceeds through protein mediators (e.g., Bcl-2, Bcl-2-associated death promoter, Bcl-2–associated X protein, Bim) that influence mitochondrial mem-brane permeability. Increased membrane permeability leads to the release of mitochondrial cytochrome C, which ultimately activates caspase 3 and thus induces apoptosis. These pathways do not function in a completely autonomous manner because there is significant interaction and crosstalk between mediators of both extrinsic and intrinsic pathways. Apoptosis is modulated by several regulatory factors, including inhibitor of apoptosis proteins and regulatory caspases (e.g., caspases 1, 8, 10).Apoptosis during sepsis may influence the ultimate com-petency of the acquired immune response. In a murine model of peritoneal sepsis, increased lymphocyte apoptosis was associ-ated with mortality, which may be due to a resultant decrease in IFN-γ release. In postmortem analysis of patients who expired from overwhelming sepsis, there was an increase in lymphocyte apoptosis, whereas macrophage apoptosis did not appear to be affected. Clinical trials have observed an association between the degree of lymphopenia and disease severity in sepsis. In addition, after the phagocytosis of apoptotic cells by macro-phages, anti-inflammatory mediators such as IL-10 are released that may exacerbate immune suppression during sepsis. Neutro-phil apoptosis is inhibited by inflammatory products, including TNF, IL-1, IL-3, IL-6, GM-CSF, and IFN-γ. This retardation in regulated cell death may prolong and exacerbate secondary injury through neutrophil free radical release as the clearance of senescent cells is delayed.124NecroptosisCellular necrosis refers to the premature uncontrolled death of cells in living tissue typically caused by accidental exposure to external factors, such as ischemia, inflammation or trauma, which result in extreme cellular stress. Necrosis is character-ized by the loss of plasma membrane integrity and cellular col-lapse with extrusion of cytoplasmic contents, but the cell nuclei typically remain intact. Recent data have defined a process by which necrosis occurs through a series of well-described steps that are dependent on a signaling pathway that involves the receptor-interacting protein kinase (RIPK) complex. Termed “necroptosis,” it occurs in response to specific stimuli, such as TNFand TLR-mediated signals.125 For example, ligation of the tumor necrosis factor receptor 1 (TNFR1) under conditions in which caspase-8 is inactivated (e.g., by pharmacological Brunicardi_Ch02_p0027-p0082.indd 4001/03/19 6:49 PM 41SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2agents) results in the over-generation of ROS and a metabolic collapse. The net result is programmed necrosis (necroptosis). The effect of cell death by necroptosis on the immune response is not yet known. However, it is likely that the “DAMP” sig-nature that occurs in response to necroptotic cell death is an important contributor to the systemic inflammatory response. Evidence to support this concept was provided by investiga-tors who examined the role of necroptosis in murine model of sepsis. They demonstrated that Ripk3−/− mice were capable of recovering body temperature better, exhibited lower circu-lating DAMP levels, and survived at higher rates than their WT littermates.126 These data suggest that the cellular damage that occurs with programmed necrosis exacerbates the sepsis-associated systemic inflammatory response.PyroptosisPyroptosis is a form of regulated cell death that is dependent on the activity of the proinflammatory caspase enzymes associ-ated with the inflammasome and is thus an inflammatory form of cell death.127 Pyropotosis shares some features with apopo-tosis, including DNA fragmentation and positive annexin V staining, among others. However, it is associated with the acti-vation of caspase-1 and the formation of caspase-1–dependent pores that allow early permeabilization of the cell membrane, electrolyte movement into the cells, and, finally, osmotic lysis of the cell.128 As a form of cell death, pyroptosis seems to be largely observed in macrophages, dendritic cells, and neutro-phils, although it has been documented in other cells as well, especially if they express high levels of caspase-1. As noted, pyroptosis is linked to activation of the inflammasome, which can occur in response to diverse cell alarm signals, including DAMPs. Not surprising, the mechanism of cell death leads to the release of additional intracellular DAMPs, including HMGB1 and S100 proteins.A recent study examined pyroptosis in peripheral blood mononuclear cells in a cohort of 60 trauma patients.129 The investigators found that the percentages of pyroptotic PBMCs were significantly higher in trauma patients than those in healthy CD95TNFR-1(p55)TNFR-2(p75)FADDDDDDDDDEDDDDEDDDDEDDEDFADDCaspase 8Caspase 2CaspaseCascadeApoptosisNIKI-˜B/NF-˜BNF-˜BMEKK1JNKc-JunRIPRAIDDTRAF2IAPTRADDDDDDDDTRADDDEDDDDDFADDRecruitedTRAF1TRAF2IAPFigure 2-5. Signaling pathway for tumor necrosis factor receptor 1 (TNFR-1) (55 kDa) and TNFR-2 (75 kDa) occurs by the recruitment of several adapter proteins to the intracellular receptor complex. Optimal signaling activity requires receptor trimerization. TNFR-1 initially recruits TNFR-associated death domain (TRADD) and induces apoptosis through the actions of proteolytic enzymes known as caspases, a pathway shared by another receptor known as CD95 (Fas). CD95 and TNFR-1 possess similar intracellular sequences known as death domains (DDs), and both recruit the same adapter proteins known as Fas-associated death domains (FADDs) before activating caspase 8. TNFR-1 also induces apoptosis by activating caspase 2 through the recruitment of receptor-interacting protein (RIP). RIP also has a func-tional component that can initiate nuclear factor-κB (NF-κB) and c-Jun activation, both favoring cell survival and proinflammatory functions. TNFR-2 lacks a DD component but recruits adapter proteins known as TNFR-associated factors 1 and 2 (TRAF1, TRAF2) that interact with RIP to mediate NF-κB and c-Jun activation. TRAF2 also recruits additional proteins that are antiapoptotic, known as inhibitor of apoptosis proteins (IAPs). DED = death effector domain; I-κB = inhibitor of κB; I-κB/NF-κB = inactive complex of NF-κB that becomes activated when the I-κB portion is cleaved; JNK = c-Jun N-terminal kinase; MEKK1 = mitogen-activated protein/extracellular regulatory protein kinase kinase kinase-1; NIK = NF-κB–inducing kinase; RAIDD = RIP-associated interleukin-1b-converting enzyme and ced-homologue-1–like protein with death domain, which activates proapoptotic caspases. (Adapted with permission from Vincent JL: Marshall JC, Cohen J: Update in Intensive Care and Emergency Medicine: Vol. 31: Immune Response in Critical Illness. Berlin: Springer-Verlag; 2002.)Brunicardi_Ch02_p0027-p0082.indd 4101/03/19 6:49 PM 42BASIC CONSIDERATIONSPART Icontrols and correlated with injury severity. Moreover, increase in pyroptotic PBMCs significantly correlated with elevated cytokine levels (IL-10, IL-18, and MCP-1) and was a strong predictor for the development of sepsis.MEDIATORS OF INFLAMMATIONCytokinesCytokines are a class of protein signaling compounds that are essential for both innate and adaptive immune responses. Cytokines mediate a broad sequence of cellular responses, including cell migration, DNA replication, cell turnover, and immunocyte proliferation (Table 2-5). When function-ing locally at the site of injury and infection, cytokines mediate the eradication of invading microorganisms and also promote wound healing. However, an exaggerated proinflammatory cyto-kine response to inflammatory stimuli may result in hemody-namic instability (i.e., septic shock) and metabolic derangements (i.e., muscle wasting). Anti-inflammatory cytokines also are released, at least in part, as an opposing influence on the proin-flammatory cascade. These anti-inflammatory mediators may also result in immunocyte dysfunction and host immunosuppres-sion. Cytokine signaling after an inflammatory stimulus can best be represented as a finely tuned balance of opposing influences and should not be oversimplified as a “black and white” proin-flammatory/anti-inflammatory response. A brief discussion of the important cytokine molecules is included below.Tumor Necrosis Factor-α. Tumor necrosis factor-α (TNF-α) is a potent inflammatory mediator that is rapidly mobilized in response to stressors such as injury and infection. It is primar-ily synthesized by immune cells, such as macrophages, den-dritic cells, and T lymphocytes, and is generated in a precursor form that is expressed as a trimer on the surface of activated cells. After being processed by the metalloproteinase, TNF-α-converting enzyme (TACE, also known as ADAMS 17), a smaller, soluble form of TNF is released, which mediates its bio-logical activities through types 1 and 2 TNF receptors (TNFR-1; TNFR-2).130 Transmembrane TNF-α also binds to TNFR-1 and -2, but its biological activities are likely mediated through TNFR-2. While the two receptors share homology in their ligand-binding regions, there are distinct differences that regu-late their biologic function. For example, TNFR-1 is expressed by a wide variety of cells, but it is typically sequestered in the Golgi. Following appropriate cell signaling, TNFR-1 is mobi-lized to the cell surface, where it sensitizes cells to TNF or it can be cleaved from the surface in the form of a soluble recep-tor that can neutralize TNF.131 In contrast, TNFR-2 expression is confined principally to immune cells where it resides in the plasma membrane. Both TNF receptors are capable of binding intracellular adaptor proteins that lead to activation of complex signaling processes and mediate the effects of TNF.Although the circulating half-life of soluble TNF is brief, it acts upon almost every differentiated cell type, eliciting a wide range of important cellular responses. Moreover, it is one of the first cytokines to be released following trauma. In particular, TNF elicits many metabolic and immunomodulatory activities. It stimulates muscle breakdown and cachexia through increased catabolism, insulin resistance, and redistribution of amino acids to hepatic circulation as fuel substrates. TNF also mediates coagulation activation, cell migration, and macrophage phago-cytosis and enhances the expression of adhesion molecules, prostaglandin E2, platelet-activating factor, glucocorticoids, and eicosanoids. TNF-α increases endothelial cell permeability and activates macrophages, NK cells and lymphocytes to induce the secretion of various cytokines. While TNF is clearly play-ing a role in injury-induced inflammation, reports are conflict-ing whether postinjury TNF concentrations correlated with the development of multiple organ dysfunction syndrome.132Interleukin-1 Family. The IL-1 family of proteins contains 11 members. The best-studied of these are IL-1α and IL-1β and IL-1 receptor antagonist (IL-1Ra), but member cytokines also include IL-18, IL-33, IL-36, IL-3,7 and IL-38. IL-1α and IL-1β, which are encoded by two distinct IL-1 genes, share similar bio-logic functions despite limited sequence homology. They uti-lize the same cell surface receptor, termed IL-1 receptor type 1 (IL-1RI), which is present on nearly all cells. Once bound to its receptor, IL-1 initiates signaling events that result in the synthe-sis and release of a variety of inflammatory mediators. Members of the IL-1 family are expressed as proforms (pIL-1) that are matured through enzymatic cleavage. The IL-1α precursor is constitutively expressed and stored in a variety of healthy cells, including epithelium and endothelium, and its expression can be increased in response to proinflammatory or stress-associated stimuli.133Both the precursor and mature forms of IL-α have nearly identical biologic activities as measured by their ability to trig-ger IL-6 and TNF release. With appropriate signals, IL-1α can move both to the cell membrane, where it can act on adjacent cells bearing the IL-1R and to the nucleus where it can stim-ulate gene transcription. Pro-IL-1α can also be released pas-sively from damaged injured cells in its active form. In this way, IL-1α is believed to function as a DAMP, which promotes the synthesis of inflammatory mediators, such as chemokines and eicosanoids. These mediators attract neutrophils to the injured site, facilitate their exit from the vasculature, and promote their activation. Once they have reached their target, neutrophil lifes-pan is extended by the presence of IL-1α.8,134IL-1β is a multifunctional proinflammatory cytokine whose expression and synthesis is tightly regulated and con-fined to activated cells, such as monocytes, tissue macrophages, and dendritic cells.134 In contrast to IL-1α, IL-1β is synthesized as an inactive precursor, pro-IL-1β, which is processed by the inflammasome in response to various stimuli, including cyto-kines and foreign pathogens, via pattern recognition receptors such as TLR4 as well as ROS. Mature IL-1β is then released from the cell via an unconventional secretory pathway.135 IL-1β has a spectrum of proinflammatory effects that are largely simi-lar to those induced by TNF, and injection of IL-1β alone is sufficient to induce an acute inflammatory response. High doses of either IL-1β or TNF are associated with profound hemody-namic compromise. Interestingly, low doses of both IL-1β and TNF administered together elicit hemodynamic events similar to those elicited by high doses of either mediator, which sug-gests a synergistic effect.There are two primary receptor types for IL-1: IL-1R1 and IL-1R2. IL-1R1 is widely expressed and mediates inflammatory signaling on ligand binding. IL-1R2 is proteolytically cleaved from the membrane surface to soluble form on activation and thus serves as another mechanism for competition and regula-tion of IL-1 activity. IL-1α or IL-1β bind first to the IL-1R1, which is considered the ligand-binding chain. This is followed by recruitment of a transmembrane co-receptor, termed the 5Brunicardi_Ch02_p0027-p0082.indd 4201/03/19 6:49 PM 43SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Table 2-5Cytokines and their sourcesCYTOKINESOURCECOMMENTTNFMacrophages/monocytesKupffer cellsNeutrophilsNK cellsAstrocytesEndothelial cellsT lymphocytesAdrenal cortical cellsAdipocytesKeratinocytesOsteoblastsMast cellsDendritic cellsAmong earliest responders after injury; half-life <20 min; activates TNF receptors 1 and 2; induces significant shock and catabolismIL-1Macrophages/monocytesB and T lymphocytesNK cellsEndothelial cellsEpithelial cellsKeratinocytesFibroblastsOsteoblastsDendritic cellsAstrocytesAdrenal cortical cellsMegakaryocytesPlateletsNeutrophilsNeuronal cellsTwo forms (IL-1 α and IL-1 β); similar physiologic effects as TNF; induces fevers through prostaglandin activity in anterior hypothalamus; promotes β-endorphin release from pituitary; half-life <6 minIL-2T lymphocytesPromotes lymphocyte proliferation, immunoglobulin production, gut barrier integrity; half-life <10 min; attenuated production after major blood loss leads to immunocompromise; regulates lymphocyte apoptosisIL-3T lymphocytesMacrophagesEosinophilsMast cellsIL-4T lymphocytesMast cellsBasophilsMacrophagesB lymphocytesEosinophilsStromal cellsInduces B-lymphocyte production of IgG4 and IgE, mediators of allergic and anthelmintic response; downregulates TNF, IL-1, IL-6, IL-8IL-5T lymphocytesEosinophilsMast cellsBasophilsPromotes eosinophil proliferation and airway inflammationIL-6MacrophagesB lymphocytesNeutrophilsBasophilsMast cellsFibroblastsEndothelial cellsElicited by virtually all immunogenic cells; long half-life; circulating levels proportional to injury severity; prolongs activated neutrophil survival(Continued)Brunicardi_Ch02_p0027-p0082.indd 4301/03/19 6:49 PM 44BASIC CONSIDERATIONSPART ITable 2-5Cytokines and their sourcesCYTOKINESOURCECOMMENTAstrocytesSynovial cellsAdipocytesOsteoblastsMegakaryocytesChromaffin cellsKeratinocytesIL-8Macrophages/monocytesT lymphocytesBasophilsMast cellsEpithelial cellsPlateletsChemoattractant for neutrophils, basophils, eosinophils, lymphocytesIL-10T lymphocytesB lymphocytesMacrophagesBasophilsMast cellsKeratinocytesProminent anti-inflammatory cytokine; reduces mortality in animal sepsis and ARDS modelsIL-12Macrophages/monocytesNeutrophilsKeratinocytesDendritic cellsB lymphocytesPromotes Th1 differentiation; synergistic activity with IL-2IL-13T lymphocytesPromotes B-lymphocyte function; structurally similar to IL-4; inhibits nitric oxide and endothelial activationIL-15Macrophages/monocytesEpithelial cellsAnti-inflammatory effect; promotes lymphocyte activation; promotes neutrophil phagocytosis in fungal infectionsIL-18MacrophagesKupffer cellsKeratinocytesAdrenal cortical cellsOsteoblastsSimilar to IL-12 in function; levels elevated in sepsis, particularly gram-positive infections; high levels found in cardiac deathsIFN-γT lymphocytesNK cellsMacrophagesMediates IL-12 and IL-18 function; half-life of days; found in wounds 5–7 d after injury; promotes ARDSGM-CSFT lymphocytesFibroblastsEndothelial cellsStromal cellsPromotes wound healing and inflammation through activation of leukocytesIL-21T lymphocytesPreferentially secreted by Th2 cells; structurally similar to IL-2 and IL-15; activates NK cells, B and T lymphocytes; influences adaptive immunityHMGB1Monocytes/lymphocytesHigh mobility group box chromosomal protein; DNA transcription factor; late (downstream) mediator of inflammation (ARDS, gut barrier disruption); induces “sickness behavior”ARDS = acute respiratory distress syndrome; GM-CSF = granulocyte-macrophage colony-stimulating factor; IFN = interferon; Ig = immunoglobulin; IL = interleukin; NK = natural killer; Th1 = helper T cell subtype 1; Th2 = helper T cell subtype 2; TNF = tumor necrosis factor.(Continued)accessory protein (IL-1RAcP). A complex is formed of IL-1RI plus IL-1 plus the coreceptor. The signal is initiated with recruit-ment of the adaptor protein MyD88 to the Toll-IL-1 receptor (TIR) domains of the receptor complex and signal transduction via intermediates, which are homologous to the signal cascade initiated by TLRs. These events culminate in the activation of NF-kB and its nuclear translocation.136Recent animal studies have implicated postinjury IL-1β in the exacerbation of traumatic brain injury.137 In a mouse model of polytrauma, which included both cortical brain injury and tibial fracture, mice that received both injuries demonstrated increased neuroinflammation, brain damage, and behavioral deficits compared to mice given an isolated-TBI. These changes correlated with increased IL-1β levels in the brain. Treatment Brunicardi_Ch02_p0027-p0082.indd 4401/03/19 6:49 PM 45SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2with IL-1R antagonist post injury reduced volume loss in the injured cortex as well as markers of axonal injury, resulting in improved outcome in these animals.IL-18 is also a member of the IL-1 superfamily of cytokines.138 First noted as an IFN-γ-inducing factor produced by LPS-stim-ulated macrophages, IL-18 expression is found both in immune cells and nonimmune cells at low to intermediate levels. How-ever, activated macrophages and Kupffer cells produce large amounts of mature IL-18. Similar to IL-1β, IL-18 is synthe-sized and stored as an inactive precursor form (pro-IL-18), and activation requires activation of the inflammasome resulting the processing of pro-IL-18 by caspase-1.139 It then exits the cell through a nontraditional secretory pathway. The IL-18 receptor (IL-18R) is composed of two subunits, IL-18Rα and IL-18Rβ, and is a member of the IL-1R superfamily that is structurally similar in their cytoplasmic domains to the TLR. One unique biological property of IL-18 is the potential, in conjunction with IL-12, to promote the Th1 response.IL-18 induces IFNγ production by CD4+ T cells. IFNγ, in turn, activates macrophages to produce inflammatory cytokines. Independent of its ability to induce interferon, IL-18 can act similarly to other proinflammatory cytokines by acting directly to increase in cell adhesion molecule expression, nitric oxide synthesis, and chemokine production by macrophages.140In a cohort of critically ill patients with acute lung injury and ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. Moreover, plasma IL-18 were also elevated and served as a marker of mor-tality risk.141 Recent studies suggest that IL-18 therapy may hold promise as effective therapy in promoting immune recovery after severe surgical stress.142IL-33, a second important IL-1 family member, is mainly expressed in surface epithelium and endothelium, where it is normally bound via an N-terminal chromatin-binding motif.143 Nuclear localization is important for its function and perhaps its regulation. Expression in mice of an IL-33 that lacks the nuclear localization sequence, results lethal inflammation, suggesting that nuclear localization acts to prevent unregulated extracel-lular release.144 Similar to HMGB1 and other IL-1 family mem-bers, IL-33 lacks a signal sequence for active secretion so that its release is injury-dependent. Once released from damaged cells, full length IL-33 is biologically active, but it can be further pro-cessed by inflammatory proteases to a mature form that exhibits tento thirtyfold higher activity. Il-33 can binds to a member of the IL-1R family, ST2, leading to activation of NF-kB-mediated transcriptional events. ST2+ cells include macrophages, mast cells, Th2 cells, and tissue regulatory T cells (Tregs) which are important controllers of immune homeostasis.Interleukin-2 Family. Interleukin-2 (IL-2) is a multifunc-tional cytokine produced primarily by CD4+ T cells after antigen activation, which plays pivotal roles in the immune response. Other cellular sources for IL-2 include CD8+ and NK T cells, mast cells, and activated dendritic cells. Discovered as a T cell growth factor, IL-2 also promotes CD8+ T cell and natural killer cell cytolytic activity and modulates T cell differentiation pro-grams in response to antigen. Thus, IL-2 promotes naive CD4+ T cell differentiation into T helper 1 (Th1) and T helper 2 (Th2) cells while inhibiting T helper 17 (Th17) and T follicular helper (Tfh) cell differentiation. Moreover, IL-2 is essential for the development and maintenance of T regulatory (Treg) cells and for activation-induced cell death, thereby mediating tolerance and limiting inappropriate immune reactions. The upregulation of IL-2 requires calcium as well as protein kinase C signaling, which leads to the activation of transcription factors such as nuclear factor of activated T cells (NFAT) and NF-κB. MicroRNAs also play a role in the regulation of IL-2 expression.145IL-2 binds to IL-2 receptors (IL-2R), which are expressed on leukocytes. IL-2Rs are formed from various combinations of three receptor subunits: IL-2Rα, IL-2Rβ, and IL-2Rγ. These subunits form in low, medium, and high affinity forms of the receptor depending on the subunit combination. IL-2Rγ has been renamed the common cytokine receptor γ chain (γc), which is now known to be shared by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Constitutive IL-2 receptor expression is low and is inducible by T cell receptor ligation and cytokine stimulation. Importantly, the transcription of each receptor subunit is indi-vidually regulated via a complex process to effect tight control of surface expression. Once the receptor is ligated, the major IL-2 signaling pathways that are engaged include Janus Kinase (JAK)-signal transducer and activator of transcription (STAT), Shc-Ras-MAPK, and phosphoinositol-3-kinase (PI3-K)-AKT. Partly due to its short half-life of <10 minutes, IL-2 is not read-ily detectable after acute injury. IL-2 receptor blockade induces immunosuppressive effects and can be pharmacologically used for organ transplantation. Attenuated IL-2 expression observed during major injury or blood transfusion may contribute to the relatively immunosuppressed state of the surgical patient.146Interleukin-6 Family. Following burn or traumatic injury, damage-associated molecular patterns (DAMPs) from dam-aged or dying cells stimulate TLRs to produce IL-6, a proin-flammatory cytokine that plays a central role in host defense. IL-6 levels in the circulation are detectable by 60 minutes post injury, peak between 4 and 6 hours, and can persist for as long as 10 days. Further, plasma levels of IL-6 are proportional to the degree of injury. In the liver, IL-6 strongly induces a broad spec-trum of acute-phase proteins such as C-reactive protein (CRP) and fibrinogen, among others, while it reduces expression of albumin, cytochrome P 450, and transferrin. In lymphocytes, IL-6 induces B cell maturation into immunoglobulin-producing cells and regulates Th17/Treg balance. IL-6 modulates T cell behavior by inducing the development of Th17 cells and inhib-iting Treg cell differentiation in conjunction with transforming growth factor-β. IL-6 also promotes angiogenesis and increased vascular permeability, which are associated with local inflam-matory responses. To date, ten IL-6 family cytokines have been identified, including IL-6, oncostatin M, neuropoietin, IL-11, IL-27, and IL-31.147The interleukin-6 receptor (IL-6R, gp80) is expressed on hepatocytes, monocytes, B cells, and neutrophils in humans. However, many other cells respond to IL-6 through a process known as trans-signaling.148 In this case, soluble IL-6Rs (sIL-6R) exist in the serum and bind to IL-6, forming an IL-6/sIL-6R complex. The soluble receptor is produced by proteo-lytic cleavage from the surface of neutrophils in a process that is stimulated by C-reactive protein, complement factors, and leu-kotrienes. The IL6/sIL6R complex can then bind to the gp130 receptor, which is expressed ubiquitously on cells. Upon IL-6 stimulation, gp130 transduces two major signaling pathways: the JAK-STAT3 pathway and the SHP2-Gab-Ras-Erk-MAPK pathway, which is regulated by cytoplasmic suppressor of cytokine signaling (SOCS3). These signaling events can lead to increased expression of adhesion molecules as well as proinflammatory chemokines and cytokines. High plasma IL-6 levels have been associated with mortality during Brunicardi_Ch02_p0027-p0082.indd 4501/03/19 6:49 PM 46BASIC CONSIDERATIONSPART Iintra-abdominal sepsis.149 Moreover, prolonged (more than 3 days) elevation of IL-6 concentrations has been reported to correlate with the occurrence of complications and mortality following severe traumatic injury. More recently, a meta-analy-sis analyzed the predictive value of IL-6 for the development of complications and mortality after trauma and found that the con-centration of IL-6 in the first 24 hours after trauma was predic-tive for the development of multiple organ failure and death.150Interleukin-10 Family. We have talked almost exclusively about the factors that initiate the proinflammatory response fol-lowing cellular stress or injury. The reestablishment of immune homeostasis following these events requires the resolution of inflammation and the initiation of tissue repair processes. Interleukin-10 (IL-10) plays a central role in this anti-inflammatory response by regulating the duration and magnitude of inflamma-tion in the host.151The IL-10 family currently has six members, includ-ing IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. IL-10 is produced by a variety of immune cells of both myeloid and lymphoid origin. Its synthesis is up-regulated during times of stress and systemic inflammation; however, each cell type that produces IL-10 does so in response to different stimuli, allow-ing for tight control of its expression. IL-10 exerts effects by binding to the IL-10 receptor (IL-10R), which is a tetramer formed from two distinct subunits, IL-10R1 and IL-10R2. Specifically, IL-10 binds first to the IL10R1 subunit, which then recruits IL-10R2, allowing the receptor complex to form. While IL-10R2 is widely expressed, IL-10R1 expression is confined to leukocytes so that the effects of IL-10 are confined to the immune system. Once receptor ligation occurs, signaling proceeds by the activation of JAK1 and STAT3. In particular, STAT3 in conjunction with IL-10 is absolutely required for the transcription of genes responsible for the anti-inflammatory response (AIR). IL-10 inhibits the secretion of proinflamma-tory cytokines, including TNF and IL-1, partly through the downregulation of NF-κB and thereby functions as a nega-tive feedback regulator of the inflammatory cascade.151 In macrophages, IL-10 suppresses the transcription of 20% of all LPS-induced genes. Further, experimental models of inflam-mation have shown that neutralization of IL-10 increases TNF production and mortality, whereas restitution of circulating IL-10 reduces TNF levels and subsequent deleterious effects. Increased plasma levels of IL-10 also have been associated with mortality and disease severity after traumatic injury.Interleukin-12 Family. Interleukin-12 (IL-12) is unique among the cytokines in being the only heterodimeric cytokine. This family, which includes IL-12, IL-23, IL-27, and IL-35, consists of an α-chain that is structurally similar to the IL-6 cytokine and a β-chain that is similar to the class I receptor for cytokines. The individual IL-12 family members are formed from various combinations of the α and β subunits. Despite the sharing of individual subunits, and the similarities of their receptors, the IL-12 cytokines have different biological func-tions. IL-12 and IL-23 are considered proinflammatory, stimu-latory cytokines with key roles in the development of Th1 and Th17 subsets of helper T cells. In contrast, both IL-27 and IL-35 appear to have immunoregulatory functions that are associated with cytokine inhibition in specific Treg cell populations, par-ticularly the Th17 cells.152 The effects of these cytokines require specific receptor chains that are also shared among the cyto-kines. The complexity of signaling is evidenced by the fact that these receptor chains can function both as dimers and as mono-mers. Ligation of the IL-12 receptors initiate signaling events via the JAK-STAT pathway.IL-12 synthesis and release is increased during endotox-emia and sepsis.153 Together with IL-18, it stimulates lympho-cytes to increase secretion of IFN-γ. IL-12 also stimulates NK cell cytotoxicity and helper T cell differentiation in this setting. IL-12 release is inhibited by IL-10, and its deficiency inhibits phagocytosis in neutrophils. In experimental models of inflam-matory stress, IL-12 neutralization conferred a mortality benefit in mice during endotoxemia.IL-23, an important IL-12 family member, is a heterodi-meric cytokine comprised of a unique p19 subunit linked to a p40 subunit that is common with IL-12. IL-23 appears to be an important survival signal for a specific subset of T helper (Th) cells, Th-17 cells, where it provides a secondary stimu-lus for Th-17 differentiation.152 The Th-17 population of cells has recently been demonstrated to expand following traumatic injury and may mark an early phenotypic shift in cell population that has prognostic significance.154,155Interleukin-17 Family. IL-17A (also called IL-17) is the major effector cytokine predominantly produced by a subset of helper T cells, the T helper (Th)-17 cells.156 It is the founding member of the IL-17 family of cytokines, which includes IL-17A through F. The original described activity for IL-17A was to promote the differentiation of bone marrow progenitor cells along the granulopoietic lineage. Subsequent studies have confirmed that IL-17A is required for increasing circulating neutrophil numbers following stress. In the setting of infection, it is now known that IL-17 acts in conjunction with IL-23 to upregulate granulocyte-colony stimulating factor to promote granulopoi-esis. IL-17A has also been shown to regulate the production of specific chemokines in both gut and lung epithelial cells and thus can modulate both the emigration of neutrophils into these tissues and their activation at the site. IL-17 also induces the expression of matrix metalloproteinases, which can make the extracellular matrix more accessible for immune cell recruitment.156IL-17 has the ability to induce the expression of impor-tant proinflammatory cytokines, including IL-1β, IL-6, and TNF from macrophages and other cells, and in this way, cre-ates a self-sustaining loop that enhances its own production and strengthens its overall effects.157 Recent data supports a pivotal role for IL-17 in the posttrauma immune response and has iden-tified associations between increased IL-17 expression associ-ated with Th17immune response outcomes following blunt trauma.154Interferons. Interferons were first recognized as soluble mediators that inhibited viral replication through the activa-tion of specific antiviral genes in infected cells. Interferons are categorized into three types based on receptor specificity and sequence homology. The two major types, type I and type II are discussed in the following section.Type I interferon family is composed of twenty distinct proteins. These include IFN-α, IFN-β, and IFN-ω, which are structurally related and bind to a common receptor.158 They are likely produced by most cell types and tissues after the detec-tion of PAMPs/ DAMPs by cytosolic or membrane receptors, including TLR in macrophages and dendritic cells. Type 1 IFNs bind to a heterodimeric transmembrane receptor interferon (α and β) receptor 1, resulting in STAT activation and nuclear trans-location. In the nucleus, dimeric STATs recruit an additional Brunicardi_Ch02_p0027-p0082.indd 4601/03/19 6:49 PM 47SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2transcriptional factor to form a complex capable of binding to interferon-stimulated response elements, inducing hundreds of IFN-stimulated genes.Type I interferons influence adaptive immune responses by inducing the maturation of dendritic cells and by stimulat-ing class I MHC expression. IFN-α and IFN-β also enhance immune responses by increasing the cytotoxicity of natural killer cells both in culture and in vivo. Further, they have been implicated in the enhancement of chemokine synthesis, particu-larly those that recruit myeloid cells and lymphoid cells. Thus, IFN/STAT signaling has important effects on the mobilization, tissue recruitment, and activation of immune cells that compose the inflammatory infiltrate. In contrast, type I IFNs appear to inhibit inflammasome activity, possibly via IL-10.159The single type II interferon, IFN-γ is secreted by various T cells, NK cells, and antigen-presenting cells in response to bacterial antigens and cytokines. It functions as a key regula-tor of macrophage activation toward the “M1” proinflammatory phenotype.160 In response to IFN-γ, macrophages produce high levels of proinflammatory cytokines such as Il-1β, IL-12, IL-23, and TNF-α as well as reactive nitrogen and oxygen species. As a consequence, macrophages demonstrate enhanced phagocyto-sis and killing. In addition, IFN-γ signaling generates additional cytokines and inflammatory factors to sustain inflammation and help to maintain Th1 responses.IFN-γ regulation of macrophage activity may contribute to acute lung injury after major surgery or trauma. A dimin-ished IFN-γ level, as seen in knockout mice, is associated with increased susceptibility to both viral and bacterial pathogens. In addition, IFN-γ promotes differentiation of T cells to the helper T cell subtype 1 and also enhances B-cell isotype switching to immunoglobulin G.158Receptors of all IFN subtypes belong to the class II of cytokine receptors and utilize JAK-STAT signaling pathway for nuclear signaling, although different STAT activation (e.g., STAT1 and STAT2) is favored by individual receptors.Granulocyte-Macrophage Colony-Stimulating Fac-tor/Interleukin-3/Interleukin-5 Family. Granulocytemacrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5 compose a small family of cytokines that regulates the growth and activation of immune cells. They are largely the products of activated T cells, which when released, stimulate the behavior of myeloid cells by inducing cytokine expression and antigen presentation. In this way, GM-CSF, IL-3, and IL-5 are able to link the innate and acquired immune responses. With the exception of eosinophils, GM-CSF/IL-3/IL-5 are not essential for constitutive hematopoietic cell function. Rather, they play an important role when the host is stressed by serving to increase the numbers of activated and sensitized cells required to bol-ster host defense.161 Currently, GM-CSF is in clinical trials for administration to children with an injury severity score >10 fol-lowing blunt or penetrating trauma. The goal of the study is to provide evidence of the effectiveness of GM-CSF as an agent that can ameliorate posttraumatic immune suppression.Receptors for the GM–CSF/IL-3/IL-5 family of cytokines are expressed at very low level on hematopoietic cells. Similar to the other cytokine receptors discussed, they are heterodimers composed of a cytokine-specific α subunit and a common β sub-unit (βc), which is shared by all three receptors and is required for high affinity signal transduction. The binding of cytokine to its receptor activates JAK2-STAT, MAPK, and PI3-K—mediated signaling events to regulate a variety of important cell behaviors, including effector function in mature cells.EicosanoidsOmega-6 Polyunsaturated Fat Metabolites: Arachidonic Acid. Eicosanoids are derived primarily by oxidation of the membrane phospholipid, arachidonic acid (AA), which is relatively abundant in the membrane lipids of inflammatory cells. The major precursor of arachidonic acid is the omega-6 (n-6) polyunsaturated fatty acid (PUFA) linolenic acid, a major source of which is soybean oil. Not surprising, an excess of linolenic acid is thought to promote inflammation via increased availability of AA, and in turn, eicosanoids.Eicosanoids generated from AA include prostaglandins, thromboxanes, and leukotrienes. When a cell senses the proper stimulus, AA is released from phospholipids or diacylglycerols by the enzymatic activation of phospholipase A2 (Fig. 2-6A). Prostanoids, which include all of the prostaglandins (PG) and the thromboxanes, result from the sequential action of the cyclooxy-genase (COX) enzyme and terminal synthetases on arachidonic acid. In contrast, arachidonic acid may be oxidized along the lipoxygenase pathway via the central enzyme 5-lipoxygenase, to produce several classes of leukotrienes and lipoxins, which have anti-inflammatory functions. In general, the effects of eico-sanoids are mediated via specific receptors, which are members of a superfamily of G protein-coupled receptors.Eicosanoids are not stored within cells but are instead generated rapidly in response to many proinflammatory stimuli, including hypoxic injury, direct tissue injury, endotoxin (lipo-polysaccharide), norepinephrine, vasopressin, angiotensin II, bradykinin, serotonin, acetylcholine, cytokines, and histamine. They have a broad range of physiologic roles, including neuro-transmission, and vasomotor regulation. Eicosanoids are also involved in immune cell regulation (Table 2-6), by modulating the intensity and duration of inflammatory responses.Glucocorticoids, NSAIDs, and leukotriene inhibitors can successfully block the end products of eicosanoid pathways to modulated inflammation.The production of eicosanoids is celland stimulus-specific. Therefore, the signaling events that are initiated will depend on the concentrations and types of eicosanoids gener-ated, as well as the unique complement of receptors expressed by their target cells. For example, prostaglandin E2 (PGE2) suppresses the effector function of macrophages (i.e., phago-cytosis and intracellular pathogen killing) via a mechanism that is dependent on increased cAMP levels. PGE2 also modulates chemokine production and enhances local accumulation of reg-ulatory T cells and myeloid-derived suppressor cells. Prostacy-clin (PGI2) has an inhibitory effect on Th1 and Th2-mediated immune responses, while enhancing Th17 differentiation and cytokine production. Leukotrienes are potent mediators of capil-lary leakage as well as leukocyte adherence, neutrophil activa-tion, bronchoconstriction, and vasoconstriction. Leukotriene B4 is synthesized from arachidonic acid in response to acute Ca2+ signaling induced by inflammatory mediators.162 High affinity leukotriene receptors (BLT1) are expressed primarily in leu-kocytes, including granulocytes, eosinophils, macrophages, and differentiated T cells, whereas the low affinity receptor is expressed in many cell types. Leukotrienes, most notably leu-kotriene B4 (LTB4), has been implicated in the development of both acute lung injury and acute kidney injury following hemor-rhagic shock in animal models.163,164Brunicardi_Ch02_p0027-p0082.indd 4701/03/19 6:49 PM 48BASIC CONSIDERATIONSPART IPhospholipidPhospholipase A2CorticosteroidsCyclooxygenaseLipoxygenaseProstaglandinsPGD2PGE2PGF2˜PGI2ThromboxaneTXA2Hydroxyeicosatetraenoic acid(HETE)LeukotrienesLTA4LTB4LTC4LTD4LTE4Hydroperoxyeicosatetraenoic acid(HPETE)Cyclic endoperoxides(PGG2,PGH2)Arachidonic acidAFree eicosapentaenoic acidCyclooxygenaseLipoxygenase3-seriesprostaglandins5-seriesleukotrienesPGG3LTA5LTC5LTB5PGH35-HPEPEAnti-inflammatory andinflammation resolvingE-seriesresolvinsBFigure 2-6. Schematic diagram of (A) arachidonic acid and (B) eicosapentaenoic acid metabolism. LT = leukotriene; PG = prostaglandin; TXA2 = thromboxane A2; HPEPE = hydroperoxyeicosapentaenoic acid.Omega-3 Polyunsaturated Fat Metabolites: All-cis-5, 8, 11, 14, 17-Eicosapentaenoic Acid. The second major family of PUFAs is the omega-3 fatty acid, α-linolenic acid, which is found primarily in cold water fish. α-Linolenic acid is the metabolic precursor of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 PUFAs are also sub-strates for the cyclooxygenase and lipoxygenase enzymes that produce eicosanoids, but the mediators produced have a differ-ent structure from the AA-derived mediators, and this influences their actions (Fig. 2-6B). For example, omega-3 fatty acids are reported to have specific anti-inflammatory effects, including inhibition of NF-κB activity, TNF release from hepatic Kupffer cells, and leukocyte adhesion and migration. Key derivatives of omega-3 PUFAs have also been identified and synthesized. These include resolvins, protectins, and maresins. In a vari-ety of model systems, resolvins have been shown to attenuate the inflammatory phenotypes of a number of immune cells by decreasing neutrophil recruitment, reducing synthesis of pro-inflammatory cytokines and regulating transcription factor activation.165,166The ratio of dietary omega-6 to omega-3 PUFA is reflected in the membrane composition of various cells, including cells of the immune system, which has potential implications for the inflammatory response. For example, a diet that is rich in omega-6 PUFA will result in cells whose membranes are “omega-6 PUFA rich.” When omega-6 PUFAs are the main plasma membrane lipid available for phospho-lipase activity, more proinflammatory PUFAs (i.e., 2-series prostaglandins) are generated. Many lipid preparations are soy-based and thus primarily composed of omega-6 fatty acids. These are thought to be “inflammation-enhancing.” Nutritional supplementation with omega-3 fatty acid has the potential to dampen inflammation by shifting the cell mem-brane composition in factor of omega 3-PUFAs. In a study of surgical patients, preoperative supplementation with omega-3 fatty acid was associated with reduced need for mechanical ventilation, decreased hospital length of stay, and decreased mortality with a good safety profile.167Plasma Contact SystemComplement. Following traumatic injury, there is almost immediate activation of the complement system, which is a major effector mechanism of the innate immune system. The complement system was thought to act initially as the required “first line of defense” for the host against pathogens, by bind-ing and clearing them from the circulation. Recent data indicate Brunicardi_Ch02_p0027-p0082.indd 4801/03/19 6:49 PM 49SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2depicted as a linear process in which parallel pathways are activated, it actually functions more like a central node that is tightly networked with other systems. Then, depending on the activating signal, several initiation and regulatory events act in concert to heighten immune surveillance.Complement activation proceeds via distinct pathways. Pathway initiation occurs by the binding and activation of a specific recognition unit to its designated ligand. The classical pathway, which is often referred to as “antibody-dependent” is initiated by direct binding of C1q to its common ligands, which include IgM/IgG aggregates. Alternately, C1q can activate complement by binding to soluble pattern recognition molecules such as pentraxins (e.g., C-reactive protein [CRP]). In a series of subsequent activation and amplification steps, the pathway ulti-mately leads to the generation of C3a and C5a, which are potent anaphylotoxins, in addition to C3b, which acts as an opsonin. An additional product, C5b, initiates the formation of the mem-brane attack complex, which becomes inserted into cell mem-brane to form a lytic pore. The subsequent effect of complement signaling is neutrophil activation leading to ROS production, as well as protease and vasoactive mediator secretion.168 The complement cascade also results in the release of proinflamma-tory cytokines synergistically with TLR-signaling, which con-tributes to systemic inflammation and generalized capillary leak following severe injury.An additional means of complement activation via the lectin pathway is initiated by mannose-binding lectins (MBL) or ficolins, which bind specific carbohydrate structures. This pathway has been speculated to be a major mechanism for complement activation post injury by interactions with matrix fragments and mitochondrial DAMPs. In addition, both low pH and serine proteases of the coagulation cascade may contribute to complement activation. As a consequence, high levels of acti-vated complement components may help to continue to drive systemic inflammation post injury.169Kallikrein-Kinin System. The kallikrein-kinin system, also referred to as the “contact” system, is a group of proteins that contribute to both coagulation and inflammation. Prekalli-krein circulates in the plasma bound to high molecular weight kininogen (HK). A variety of stimuli lead to the binding of prekallikrein-HK complex to Hageman factor (factor XII) to initiate the intrinsic clotting cascade. This results in formation of the serine protease kallikrein, which is both proinflamma-tory and procoagulant. HK is cleaved by kallikrein to form bradykinin (BK).The kinins (e.g., BK) mediate several physiologic pro-cesses, including vasodilation, increased capillary perme-ability, tissue edema, and neutrophil chemotaxis.170 They also increase renal vasodilation and consequently reduce renal per-fusion pressure. Kinin receptors are members of the rhodopsin family of G-protein-coupled receptors and are located on vas-cular endothelium and smooth muscle cells. Kinin receptors are rapidly upregulated following TLR4 and cytokine signal-ing and appear to have important effects on both immune cell behavior and on immune mediators.171 For example, activation of the kinin receptor, B1, results in increased neutrophil che-motaxis, while increased B2 receptor expression causes activa-tion of arachidonic-prostaglandin pathways. Bradykinin and kallikrein levels are increased following hemorrhagic shock and tissue injury. The degree of elevation in the levels of these mediators has been associated with the magnitude of injury and mortality.Table 2-6Systemic stimulatory and inhibitory actions of eicosanoidsORGAN/FUNCTIONSTIMULATORINHIBITORPancreas Glucose-stimulated  insulin secretion Glucagon secretion12-HPETEPGD2, PGE2PGE2Liver Glucagon-stimulated  glucose production PGE2Fat Hormone-stimulated  lipolysis PGE2Bone ResorptionPGE2, PGE-m, 6-K-PGE1, PGF1α, PGI2 Pituitary Prolactin Luteinizing hormone Thyroid-stimulating  hormone Growth hormonePGE1PGE1, PGE2, 5-HETEPGA1, PGB1, PGE1, PGE1PGE1 Parathyroid   Parathyroid hormonePGE2PGF2Lung BronchoconstrictionPGF2α TXA2, LTC4, LTD4, LTE4PGE2Kidney Stimulation of renin  secretionPGE2, PGI2 Gastrointestinal system Cytoprotective effectPGE2 Immune response Suppression of  lymphocyte activityPGE2 Hematologic system Platelet aggregationTXA2PGI25-HETE = 5-hydroxyeicosatetraenoic acid; 12-HPETE = 12-hydroxyperoxyeicosatetraenoic acid; 6-K-PGE1 = 6-keto-prostaglandin E1; LT = leukotriene; PG = prostaglandin; PGE-m = 13,14-dihydro-15-keto-PGE2 (major urine metabolite of PGE2); TXA2 = thromboxane A2.that complement is also participates in the elimination of immune complexes as well as damaged and dead cells. In addi-tion, complement is recognized as contributing to mobiliza-tion of hematopoietic stem/progenitor cells (HSPC) and lipid metabolism.168 Although complement activation is typically Brunicardi_Ch02_p0027-p0082.indd 4901/03/19 6:49 PM 50BASIC CONSIDERATIONSPART ISerotoninSerotonin is a monoamine neurotransmitter (5-hydroxytrypta-mine; 5-HT) derived from tryptophan. Serotonin is synthesized by neurons in the CNS as well as by intestinal enterochromaf-fin cells, which are the major source of plasma 5-HT. Once in the plasma, 5-HT is taken up rapidly into platelets via the serotonin transporter (SERT), where it is either stored in the dense granules in millimolar concentrations or targeted for deg-radation. It is interesting that the surface expression of SERT on platelets is sensitive to plasma 5-HT levels, which in turn modulates platelet 5-HT content. Receptors for serotonin are widely distributed in the periphery and are found in the GI tract, cardiovascular system, and some immune cells.172 Serotonin is a potent vasoconstrictor and also modulates cardiac inotropy and chronotropy through nonadrenergic cyclic adenosine mono-phosphate (cAMP) pathways. Serotonin is released at sites of injury, primarily by platelets. Recent work has demonstrated an important role for platelet 5-HT in the local inflammatory response to injury. Using mice that lack the nonneuronal iso-form of tryptophan hydroxylase (Tph1), the rate-limiting step for 5-HT synthesis in the periphery, investigators demonstrated fewer neutrophils rolling on mesenteric venules.173 Tph1-/mice, in response to an inflammatory stimulus, also showed decreased neutrophil extravasation. Together, these data indicate an impor-tant role for nonneuronal 5-HT in neutrophil recruitment to sites of inflammation and injury.HistamineHistamine is a short-acting endogenous amine that is widely distributed throughout the body. It is synthesized by histidine decarboxylase (HDC), which decarboxylates the amino acid his-tidine. Histamine is either rapidly released or stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets and plasma levels are increased with hemorrhagic shock, trauma, thermal injury, and sepsis.174 Not surprisingly, circulating cyto-kines can increase immune cell expression of HDC to further contribute to histamine synthesis. There are four histamine receptor (HR) subtypes with varying physiologic roles, but they are all members of the rhodopsin family of G-protein coupled receptors. H1R binding mediates vasodilation, bronchocon-striction, intestinal motility, and myocardial contractility. H1R knockout mice demonstrate significant immunologic defects, including impaired B and T cell responses.H2R binding is best described for its stimulation of gastric parietal cell acid secretion. However, H2R can also modulate a range of immune system activities, such as mast cell degranula-tion, antibody synthesis, Th1 cytokine production, and T-cell proliferation. H3R was initially classified as a presynaptic auto-receptor in the peripheral and central nervous system (CNS). However, data using H3R knockout mice demonstrates that it also participates in inflammation in the CNS. H3R knockout mice display increased severity of neuroinflammatory diseases, which correlates with dysregulation of blood-brain barrier per-meability and increased expression of macrophage inflammatory protein 2, IFN-inducible protein 10, and CXCR3 by peripheral T cells. H4R is expressed primarily in bone marrow, but it has also been detected in leukocytes, including neutrophils, eosino-phils, mast cells, dendritic cells, T cells, and basophils. H4R is emerging as an important modulator of chemoattraction and cytokine production in these cells. Thus, it is clear that cells of both the innate and adaptive immune response can be regulated by histamine, which is up-regulated following injury.175CELLULAR RESPONSE TO INJURYCytokine Receptor Families and Their Signaling PathwaysCytokines act on their target cells by binding to specific membrane receptors. These receptor families have been organized by struc-tural motifs and include type 1 cytokine receptors, type II cytokine receptors, chemokine receptors, tumor necrosis factor receptors (TNFR), and transforming growth factor receptors (TGFR). In addition, there are cytokine receptors that belong to the immuno-globulin receptor superfamilies. Several of these receptors have characteristic signaling pathways that are associated with them. These will be briefly reviewed in the following section.JAK-STAT SignalingA major subgroup of cytokines, comprising roughly 60 factors, bind to receptors termed type I/II cytokine receptors. Cytokines that bind these receptors include type I IFNs, IFN-γ, many inter-leukins (e.g., IL-6, IL-10, IL-12, and IL-13), and hematopoietic growth factors. These cytokines play essential rolls in the initia-tion, maintenance, and modulation of innate and adaptive immu-nity for host defense. All type I/II cytokine receptors selectively associate with the Janus kinases (JAK1, JAK2, JAK3, TYK2), which represent a family of tyrosine kinases that mediate the signal transduction for these receptors. As such, the JAK-STAT signaling pathway is considered a central communication hub for the immune system.176JAKs are constitutively bound to the cytokine receptors, and on ligand binding and receptor dimerization, activated JAKs phosphorylate the receptor to recruit signal transducer and acti-vator of transcription (STAT) molecules (Fig. 2-7). Activated STAT proteins further dimerize and translocate into the nucleus where they modulate the transcription of target genes. Rather than being a strictly linear pathway, it is likely that individual cytokines activate more than one JAK-STAT combination. The molecular implications for this in terms of cytokine signaling are still being unraveled, but the development of JAK-specific inhibitors (jakinibs) is moving the field forward quickly.177 Inter-estingly, STAT-DNA binding can be observed within minutes of cytokine binding. STATs have also been shown to modulate gene transcription via epigenetic mechanisms. Thus, JAKs and STATs are central players in the regulation of key immune cell function, by providing a signaling platform for proinflamma-tory cytokines (IL-6 via JAK1 and STAT3); anti-inflammatory cytokines (IL-10 via STAT3) and integrating signals required for helper and regulatory T cell development and differentiation. The JAK/STAT pathway is inhibited by the action of phospha-tase, the export of STATs from the nucleus, as well the interac-tion of antagonistic proteins.178 JAK/STAT signaling has also been implicated in the secondary muscle wasting that occurs with chronic, persistent inflammation.179Suppressors of Cytokine SignalingSuppressor of cytokine signaling (SOCS) molecules are a fam-ily of proteins that function as a negative feedback loop for types I and II cytokine receptors by terminating JAK/STAT signaling. There are currently eight family members (SOCS1-7 and CIS [cytokine-inducible SH2-containing protein]) that are associated with cytokine receptor signaling. Pattern recognition receptors, including both TLR and C-type lectin receptors, also activate SOCS.180 Interestingly, induction of SOCS proteins is also achieved through activators of JAK/STAT signaling, creating an inhibitory feedback loop through which cytokines Brunicardi_Ch02_p0027-p0082.indd 5001/03/19 6:49 PM 51SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2JAKJAKPPJAKJAKPSTATSTATPPPSTATPSTATSTATSTATSOCSPSTATNuclear translocationNucleusReceptordimerizationFigure 2-7. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway also requires dimer-ization of monomeric units. STAT molecules possess “docking” sites that allow for STAT dimerization. The STAT complexes translocate into the nucleus and serve as gene transcription fac-tors. JAK/STAT activation occurs in response to cytokines (e.g., interleukin-6) and cell stressors, and has been found to induce cell proliferation and inflammatory function. Intracellular molecules that inhibit STAT function, known as suppressors of cytokine sig-naling (SOCSs), have been identified. P = phosphate.can effectively self-regulate by extinguishing their own signal. SOCS molecules can positively and negatively influence the activation of macrophages and dendritic cells and are crucial for T-cell development and differentiation.181 All SOCS proteins are able to regulate receptor signaling through the recruitment of proteasomal degradation components to their target proteins, whether the target is a specific receptor or an associated adaptor molecule. Once associated with the SOCS complex, target pro-teins are readily ubiquinated and targeted for proteasomal deg-radation. SOCS1 and SOCS3 can also exert an inhibitory effect on JAK-STAT signaling via their N-terminal kinase inhibitory region (KIR) domain, which acts as a pseudo-substrate for JAK.SOCS3 has been shown to be a positive regulator of TLR4 responses in macrophages via inhibition of IL-6 receptor-medi-ated STAT3 activation.181,182 A deficiency of SOCS activity may render a cell hypersensitive to certain stimuli, such as inflamma-tory cytokines and growth hormones. Interestingly, in a murine model, SOCS knockout resulted in a lethal phenotype in part because of unregulated interferon signaling.Chemokine Receptors Are Members of the G-ProteinCoupled Receptor Family All chemokine receptors are mem-bers of the G-protein-coupled seven transmembrane family of receptors (GPCR), which is one of the largest and most diverse of the membrane protein families. GPCRs function by detect-ing a wide spectrum of extracellular signals, including photons, ions, small organic molecules, and entire proteins. After ligand binding, GPCRs undergo conformational changes, causing the recruitment of heterotrimeric G proteins to the cytoplasmic sur-face (Fig. 2-8). Heterotrimeric G proteins are composed of three subunits, Gα, Gβ, and Gγ, each of which have numerous mem-bers, adding to the complexity of the signaling. When signaling, however, G proteins perform functionally as dimers because the signal is communicated either by the Gα subunit or the Gβγ complex. The GPCR family includes the receptors for catechol-amines, bradykinins, and leukotrienes, in addition to a variety of other ligands important to the inflammatory response.183 In gen-eral, GPCRs can be classified according to their pharmacological properties into four main families: class A rhodopsin-like, class B secretin-like, class C metabotropic glutamate/pheromone, and frizzled receptors. As noted above, GPCR activation by ligand binding results in an extracellular domain shift, which is then transmitted to cytoplasmic portion of the receptor to facilitate coupling to its principle effector molecules, the heterotrimeric G proteins. Although there are more than 20 known Gα subunits, they have been divided into four families based on sequence similarity, which has served to define both receptor and effec-tor coupling. These include Gαs and Gαi, which signal through the activation (Gαs) or inhibition (Gαi) of adenylate cyclase to increase or decrease cyclic adenosine monophosphate (cAMP) levels, respectively. Increased intracellular cAMP can activate gene transcription through the activity of intracellular signal transducers such as protein kinase A. The Ga subunits also include the Gq pathway, which stimulates phospholipase C-β to produce the intracellular messengers inositol triphosphate and diacylglycerol. Inositol triphosphate triggers the release of calcium from intracellular stores, while diacylglycerol recruits protein kinase C to the plasma membrane for activation. Finally, Gα12/13 appears to act through Rho and Ras-mediated signaling.Tumor Necrosis Factor SuperfamilySignaling pathway for tumor necrosis factor receptor 1 (TNFR-1) (55 kDa) and TNFR-2 (75 kDa) occurs by the recruitment of sev-eral adapter proteins to the intracellular receptor complex. Opti-mal signaling activity requires receptor trimerization. TNFR-1 initially recruits TNFR-associated death domain (TRADD) and induces apoptosis through the actions of proteolytic enzymes known as caspases, a pathway shared by another receptor, CD95 (Fas). CD95 and TNFR-1 possess similar intracellular sequences known as death domains (DDs), and both recruit the same adapter proteins (Fas-associated death domains [FADDs]) before activating caspase 8. TNFR-1 also induces apoptosis by activating caspase 2 through the recruitment of receptor-inter-acting protein (RIP). RIP also has a functional component that can initiate nuclear factor kB (NF-kB) and c-Jun activation, both favoring cell survival and proinflammatory functions. TNFR-2 lacks a DD component but recruits adapter proteins known as TNFR-associated factors 1 and 2 (TRAF1, TRAF2) that inter-act with RIP to mediate NF-kB and c-Jun activation. TRAF2 also recruits additional proteins that are antiapoptotic, known as inhibitors of apoptosis proteins (IAPs).Transforming Growth Factor-a Family of ReceptorsTransforming growth factor-β1 (TGF-β1) is a pleiotropic cyto-kine expressed by immune cells that has potent immunoregula-tory activities. Specifically, recent data indicate that TGF-β is Brunicardi_Ch02_p0027-p0082.indd 5101/03/19 6:49 PM 52BASIC CONSIDERATIONSPART Iessential for T cell homeostasis, as mice deficient in TGF-β1 develop a multiorgan autoimmune inflammatory disease and die a few weeks after birth, an effect that is dependent upon the presence of mature T cells. The receptors for TGF-β ligands are the TGF-β superfamily of receptors, which are type I transmem-brane proteins that contain intrinsic serine/threonine kinase activ-ity. These receptors comprise two subfamilies, the type I and the type II receptors that are distinguished by the presence of a glycine/serine-rich membrane domain found in the type I receptors. Each TGF-β ligand binds a characteristic combination of type I and type II receptors, both of which are required for signaling. Whether the type I or the type II receptor binds first is ligand-dependent, and the second type I or type II receptor is then recruited to form a het-eromeric signaling complex. When TGF-β binds to the TGF-βR, heterodimerization activates the receptor which then directly recruits and activates a receptor-associated Smad (Smad 2 or 3) through phosphorylation. An additional “common” Smad is then recruited. The activated Smad-complex translocates into the nucleus and, with other nuclear cofactors, regulates the transcrip-tion of target genes. TGF-β can also induce the rapid activation of the Ras-extracellular signal-regulated kinase (ERK) signaling pathway in addition to other MAPK pathways (JNK, p38MAPK). How does TGF-β inhibit immune responses? One of the most important effects is the suppression of interleukin-2 production by T cells. It also inhibits T cell proliferation.184 More recently, it was noted that TGF-β can regulate the maturation of differenti-ated dendritic cells and dendritic cell-mediated T-cell responses. Importantly, TGF-β can induce “alternative activation” macro-phages, designated M2 macrophages, which express a wide array of anti-inflammatory molecules, including IL-10 and arginase1.TRANSCRIPTIONAL AND TRANSLATIONAL REGULATION OF THE INJURY RESPONSETranscriptional Events Following Blunt TraumaInvestigators have examined the transcriptional response in cir-culating leukocytes in a large series of patients who suffered severe blunt trauma. This work identified an overwhelming 5GRELigandProtein kinase CactivationCA2+ releaseRGESecond messengers(cAMP, IP3)LigandERCell membraneCytoplasmG-protein receptors(vasoactive polypeptides, mitogens, phospholipids, neurotransmitters, prostaglandins)Figure 2-8. G-protein–coupled receptors are transmembrane pro-teins. The G-protein receptors respond to ligands such as adrenaline and serotonin. On ligand binding to the receptor (R), the G protein (G) undergoes a conformational change through guanosine triphosphate–guanosine diphosphate conversion and in turn activates the effector (E) component. The E component subse-quently activates second messengers. The role of inositol triphosphate (IP3) is to induce release of calcium from the endoplasmic reticulum (ER). cAMP = cyclic adenosine triphosphate.shift in the leukocyte transcriptome, with more than 80% of the cellular functions and pathways demonstrating some altera-tion in gene expression. In particular, changes in gene expres-sion for pathways involved in the systemic inflammatory, innate immune, compensatory anti-inflammatory, and adaptive immune responses were simultaneous and marked. Moreover, they occurred rapidly (within 4–12 hours), and were prolonged for days and weeks. When different injuries (i.e., blunt trauma, burn injury, human model of endotoxemia) were compared, the patterns of gene expression were surprisingly similar, sug-gesting that the stress response to both injury and inflammation is highly conserved and may follow a universal pathway that includes common denominators. Finally, delayed clinical recov-ery and organ injury were not associated with a distinct pattern of transcriptional response elements.3 These data describe a new paradigm based on the observation of a rapid and coordinated transcriptional response to severe traumatic injury that involves both the innate and adaptive immune systems. Further, the data support the idea that individuals who are destined to die from their injuries are characterized primarily by the degree and dura-tion of their dysregulated inflammatory response rather than a “unique signature” indicative of a “second hit.”Transcriptional Regulation of Gene ExpressionMany genes are regulated at the point of DNA transcription and thus influence whether messenger RNA (mRNA) and its subse-quent product are expressed (Fig. 2-9). Gene expression relies on the coordinated action of transcription factors and coactiva-tors (i.e., regulatory proteins), which are complexes that bind to highly specific DNA sequences upstream of the target gene known as the promoter region. Enhancer sequences of DNA mediate gene expression, whereas repressor sequences are non-coding regions that bind proteins to inhibit gene expression. For example, nuclear factor κB (NF-κB), one of the best-described transcription factors, has a central role in regulating the gene products expressed after inflammatory stimuli (Fig. 2-10). The NF-κB family of transcription factors is composed of five mem-bers that share a common domain. They form numerous homo or heterodimers that are normally retained in the cytosol through Brunicardi_Ch02_p0027-p0082.indd 5201/03/19 6:49 PM 53SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2TranscriptionDNAmRNAmRNAProteinInactivemRNAInactiveproteinCytoplasmCell membraneNucleusFigure 2-9. Gene expression and protein synthesis can occur within a 24-hour period. The process can be regulated at various stages: transcription, messenger RNA (mRNA) processing, or pro-tein packaging. At each stage, it is possible to inactivate the mRNA or protein, rendering these molecules nonfunctional.Ligand(e.g.: TNF, IL-1)PI-˜B kinaseDegradation of I-˜BUbiquitinizationI-˜Bp65p50I-˜Bp65p50I-˜Bp65p50Pp65p50Nuclear translocationNucleusNF-˜B activationFigure 2-10. Inhibitor of κB (I-κB) binding to the p50-p65 subunits of nuclear factor κB (NF-κB) inactivates the molecule. Ligand binding to the receptor activates a series of downstream signaling molecules, of which I-κB kinase is one. The phosphorylated NF-κB complex further undergoes ubiquitinization and proteosome degradation of I-κB, activating NF-κB, which translocates into the nucleus. Rapid resynthesis of I-κB is one method of inactivating the p50-p65 complex. IL-1 = interleukin-1; P = phosphate; TNF = tumor necrosis factor.the inhibitory binding of inhibitor of κB (I-κB). In response to an inflammatory stimulus (e.g., TNF, IL-1, or DAMP) a sequence of intracellular mediator phosphorylation reactions leads to the degradation of I-κB and subsequent release of NF-κB to allow nuclear translocation and the initiation of transcription.Epigenetic Regulation of TranscriptionThe DNA access of protein machineries involved in transcription processes is tightly regulated by histones, which are a family of basic proteins that associate with DNA in the nucleus. Histone proteins help to condense the DNA into tightly packed nucleo-somes that limit transcription. Emerging evidence indicates that transcriptional activation of many proinflammatory genes requires nucleosome remodeling, a process that is regulated by the histone modifying enzymes.185 There are at least seven identified chromatin modifications, including acetylation, meth-ylation, phosphorylation, ubiquitinylation, sumoylation, ADP ribosylation, deimination, and proline isomerization. Alteration of chromatin packing in this way makes the DNA more or less accessible for transcription. Recently, the development of chro-matin immunoprecipitation (ChIP) coupled to massively parallel DNA sequencing technology (ChIP-Seq) has enabled the map-ping of histone modifications in living cells. In this way, it has allowed the identification of the large number of posttranslational histone modifications that are “written” and “erased” by histone-modifying enzymes. The role of histone modifications in the reg-ulation of gene expression is referred to as “epigenetic” control.The addition of an acetyl group to lysine residues on his-tones is an epigenetic mark associated with gene activation. These acetyl groups are reversibly maintained by histone acet-yltransferases (HATs) and histone deacetylases (HDACs).186 Hemorrhagic shock has been shown to alter the acetylation of histone proteins via an imbalance of HDAC/HAT activity in the heart, lung, and liver in a tissue-specific pattern. In animal mod-els, postshock administration of the HDAC inhibitor valproic acid improved overall survival.187 Valproic acid is currently in Phase 2 clinical trials for the treatment of hemorrhaghic shock.188Translation Regulation of Inflammatory Gene ExpressionOnce mRNA transcripts are generated, they can also be regu-lated by a variety of mechanisms, including (a) splicing, which can cleave mRNA and remove noncoding regions; (b) capping, which modifies the 5’ ends of the mRNA sequence to inhibit breakdown by exonucleases; (c) and the addition of a polyad-enylated tail, which adds a noncoding sequence to the mRNA, to regulated the half-life of the transcript. Recent data has identified microRNAs (miRNAs) as important translational regulators of gene expression via their binding to partially complementary sequences in the 3’-untranslated region (3’-UTR) of target mRNA transcripts.189 Binding of miRNA to the Brunicardi_Ch02_p0027-p0082.indd 5301/03/19 6:49 PM 54BASIC CONSIDERATIONSPART ImRNA usually results in gene silencing. MicroRNAs are endog-enous, single-stranded RNAs of approximately 22 nucleotides in length that are highly conserved in eukaryotes. MicroRNAs are encoded either singly or can be transcribed in a “polycis-tronic” clusters and produced by an elaborate expression and processing mechanism. After a primary miRNA transcript is generated by RNA polymerase II or III, it is processed in the nucleus to produce a short hairpin precursor miRNA transcript. The precursor is then transported into the cytoplasm where the final mature miRNA is generated by a protein termed Dicer. The mature double-stranded miRNA is then incorporated into the RNA-induced silencing complex (RISC) in the cytoplasm. Once programmed with a small RNA, RISC can silence targeted genes by one of several distinct mechanisms, working at (a) the level of protein synthesis through translation inhibition, (b) the transcript level through mRNA degradation, or (c) the level of the genome itself through the formation of heterochromatin or by DNA elimination. MiRNAs are involved in TLR signaling in the innate immune system by targeting multiple molecules in the TLR signaling pathways.190 Traumatic brain injury alters serum miRNA profiles that may be useful both as biomarkers for severe TBI and as therapeutic targets.189CELL-MEDIATED INFLAMMATORY RESPONSENeutrophilsNeutrophils (PMNs) are among the first responders to sites of infection and injury and as such are potent mediators of acute inflammation.191 Mobilization of PMNs from the bone mar-row is facilitated by reduction in bone-marrow expression of stromal cell-derived factor-1 (SDF1, also CXCL12) and subse-quent expression of both SDF1 and its receptor CXCR4 in target tissues.192 This and other chemotactic mediators induce PMN adherence to the vascular endothelium and promote eventual cell migration into the injured tissue. Early signals for PMN recruitment include endogenous “self” molecules released from damaged tissues, like the DAMPs described previously and also include histone proteins as well as adenosine triphos-phate. DAMP molecules can also induce secretion of powerful chemokines such as IL-8 (CXCL8), which can bind to tissue glycosaminoglycans, creating a gradient for PMN migration. PMNs generally have short half-lives (4 to 10 hours). However, inflammatory signals may promote their longevity in target tis-sues, which can contribute to their potential detrimental effects and subsequent bystander injury. In addition, following sterile trauma, large numbers of immature PMNs are recruited from the bone marrow into the circulation.193Once primed and activated by inflammatory stimuli, includ-ing TNF, IL-1, and microbial pathogens, PMNs are capable of amplifying the inflammatory response as well as releasing toxic effectors such as ROS and proteolytic enzymes into the extracel-lular space.193 Neutrophils can also dump their granule contents into the extracellular space, and many of these proteins also have important effects on the innate and adaptive immune responses. When highly activated, neutrophils can extrude a meshwork of chromatin fibers, composed of DNA and histones that are deco-rated with granule contents. Termed neutrophils extracellular traps or NETs, they were first described as effective mechanism whereby neutrophils can immobilize bacteria to facilitate their killing. In the setting of tissue injury, NETS may allow continued presentation of auto-antigens to the host immune system, which can contribute to further tissue injury.194 NETS may also serve to prime T cells, making their threshold for activation lower.Neutrophils do facilitate the recruitment of monocytes into inflamed tissues. These recruited cells are capable of phagocy-tosing apoptotic neutrophils to contribute to resolution of the inflammatory response and to promote tissue repair.195 How-ever, at least some portion of the neutrophil population from the injury site is capable of reentering the blood stream and return-ing to the bone marrow in a process regulated by chemokine CXC receptor 4.196 Whether reverse migration of neutrophils is beneficial to the host or likely to cause distant organ injury needs further investigation.Monocyte/MacrophagesMonocytes and macrophages are mononuclear phagocytes that play a critical role in inflammation and the injury response.197 Monocytes are leukocytes derived from bone marrow pro-genitors that circulate in the bloodstream and given the right stimuli, exit the vasculature, and differentiate into monocyte-derived macrophages (e.g., alveolar macrophages or Kupffer cells) upon migrating into appropriate tissues. Macrophages represent the large number of phagocytes that are resident in tissues under resting conditions. Distinct from monocytes, they are derived from embryonic precursors and can repopulate their numbers either by self-renewal or from monocytes derived from the bone marrow.198 Together, monocytes/macrophages are the main effector cells that sense and respond to “danger signals,” primarily through mechanisms that include phagocytosis of cel-lular debris, release of inflammatory mediators, and recruitment of additional immune cells to injury sites. Moreover, these cells fulfill homeostatic roles beyond host defense by performing important functions in the remodeling of tissues, both during development and in the adult animal. SDF1 has also been impli-cated in the recruitment of monocytes to sites of tissue injury.199 Importantly, SDF1 forms a complex with HMGB1, a DAMP molecule, which potently increases its chemotactic function. In conjunction with CXCR4, the SDF1-HMGB1 complex induces early monocyte migration into injured tissues, where they play an important role coordinating between innate and adaptive immunity.In tissues, mononuclear phagocytes are quiescent. How-ever, they respond to external cues (e.g., PAMPs, DAMPs, acti-vated lymphocytes) by changing their phenotype.200 In response to various signals, macrophages may undergo classical M1 acti-vation (stimulated by TLR ligands and IFN-γ) or alternative M2 activation (stimulated by type II cytokines IL-4/IL-13); these states mirror the Th1–Th2 polarization of T cells described in the following section. The M1 phenotype is characterized by the expression of high levels of proinflammatory cytokines, like TNF-α, IL-1 and IL-6, in addition to the synthesis of ROS and RNS. Activated macrophages can also secrete HMGB1 and in this way, can recruit additional macrophages to form a self-activating loop.In contrast, M2 macrophages are considered to be involved in the promotion of wound repair and the restoration of immune homeostasis through their expression of arginase-1 and IL-10, in addition to a variety of PRR (e.g., scavenging molecules).201 In truth, this classification system is overly simplistic. In fact, macrophages are highly heterogeneous and possess specialized properties that are precisely adapted to individual tissues. Thus, they are likely to also possess individualized response to local tissue damage.197Brunicardi_Ch02_p0027-p0082.indd 5401/03/19 6:49 PM 55SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2TH1Injury Severity:IL-12, IL-18, IFN-, TNF, IL-1, IL-21, TGF-˜IL-4, IL-5, IL-6, IL-10, (Glucocorticoids)IL-2IL-3IL-6IL-12IFN-TNF-°GM-CSFTNF-˜IL-3IL-4IL-5IL-6IL-9IL-10IL-13TNF-°GM-CSFCell-mediatedImmunityAntibody-mediatedImmunityless severemore severeTH2Figure 2-11. Specific immunity mediated by helper T lympho-cytes subtype 1 (TH1) and subtype 2 (TH2) after injury. A TH1 response is favored in lesser injuries, with intact cell-mediated and opsonizing antibody immunity against microbial infections. This cell-mediated immunity includes activation of monocytes, B lym-phocytes, and cytotoxic T lymphocytes. A shift toward the TH2 response from naive helper T cells is associated with injuries of greater magnitude and is not as effective against microbial infec-tions. A TH2 response includes the activation of eosinophils, mast cells, and B-lymphocyte immunoglobulin 4 and immunoglobulin E production. (Primary stimulants and principal cytokine prod-ucts of such responses are in bold characters.) Interleukin-4 (IL-4) and IL-10 are known inhibitors of the TH1 response. Interferon-γ (IFN-γ) is a known inhibitor of the TH2 response. Although not cytokines, glucocorticoids are potent stimulants of a TH2 response, which may partly contribute to the immunosuppressive effects of cortisol. GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; TGF = transforming growth factor; TNF = tumor necrosis factor. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery, Surgery 2000 Feb;127(2):117-126.)In a mouse model of hemorrhagic shock/reperfusion, mac-rophages play a key role in the recruitment of hematopoietic stem cells from the bone marrow by secreting granulocyte-monocyte stimulating factor (GM-CSF) in response to circu-lating HMGB1.202 In the lung, alveolar macrophages sense DAMPs and extracellular matrix fragments via pattern recog-nition receptors. In response, they upregulate their expression of TLR4, which primes the cell for response against potential infection.203 At the same time, they release proinflammatory cytokines and ROS, which contribute injury to the alveolar epithelial cells. More recently, data indicate that an imbalance of M1/M2 macrophage populations in the lung contribute to acute lung injury following hemorrhagic shock (HS).204 In this study, investigators demonstrated that HS/resuscitation resulted in a significant decrease in M2 phenotype macrophages, with a delayed increase in M1. Augmenting the M2 population prior to injury lessened the degree of lung injury as assessed histologically.Lymphocytes and T-Cell ImmunityThe expression of genes associated with the adaptive immune response is rapidly altered following severe blunt trauma.3 In fact, significant injury is associated with adaptive immune sup-pression that is characterized by altered cell–mediated immu-nity. This correlates with both a decrease in the overall number of lymphocytes as well as the balance between the NK and T cell populations.205CD4+ T cells (helper) play central roles in the function of the immune system through their effects on B cell anti-body production, their enhancement of specific TReg cell func-tions, and their assistance with macrophage activation. CD4+ Th cells are functionally divided into subsets, which include Th1, Th2, and Th17 cells. Each of these groups produces spe-cific effector cytokines that are under unique transcriptional control. The specific functions of these cells include the rec-ognition and killing of intracellular pathogens (cellular immu-nity, Th1 cells); regulation of antibody production (humoral immunity, TH2 cells); and maintenance of mucosal immu-nity and barrier integrity (Th17 cells). Historically, activi-ties have been characterized as proinflammatory (Th1) and anti-inflammatory (Th2) respectively, as determined by their distinct cytokine signatures (Fig. 2-11). Given the proinflam-matory action of IL-17A produced by Th17 cells, they could also be placed in this category. However, it is clear that the Th17 differentiation is more complex and may involve the two distinct phenotypes, a pathogenic phenotype characterized by increased IL-17 production and a more regulatory phenotype in which IL-10 expression is increased.206Recent evidence suggests that the population of Th17 cells is altered following severe traumatic injury. Mass cytometry by time-of-flight (CyTOF) was used to collect single cell phenotyp-ing data on circulating peripheral blood mononuclear cells from a cohort of severely injured trauma patients.155 The investigators identified an expansion of Th17 cells at all time points follow-ing injury and was associated with an increase in the cytokine profile associated with a Th17 phenotype. This supports prior work also demonstrating a robust type 17 immune response early (within the first 24 hours) among nonsurvivors, which also identified a Th17 profile more consistent with “pathogenic” Th17 cells.154Successful recovery from injury also depends upon a bal-anced Th1/Th2 response. Following injury, however, there is a reduction in Th1 cell differentiation and cytokine production in favor of an increased population of Th2 lymphocytes and their signaling products. As a consequence, both macrophage activation and proinflammatory cytokine synthesis are inhib-ited. This imbalance, which may be associated with decreased IL-12 production by activated monocytes/macrophages, has been associated with increased risk of infectious complications following surgery and trauma. What are the systemic mecha-nisms responsible for this shift? Several events have been impli-cated, including the direct effect of glucocorticoids on monocyte IL-12 production and T cell IL-12 receptor expression. In addi-tion, sympathoadrenal catecholamine production has also been demonstrated to reduce IL-12 production and proinflammatory cytokine synthesis. Finally, more recent work has implicated circulating immature myeloid cells, termed myeloid-derived suppressor cells, that have immune suppressive activity par-ticularly through their increased expression of arginase.208 These cells have the potential to deplete the microenvironment of argi-nine, leading to further T cell dysfunction.Dendritic CellsRecent studies have focused on the cellular components of the immune system in the context of polytrauma. While the Brunicardi_Ch02_p0027-p0082.indd 5501/03/19 6:49 PM 56BASIC CONSIDERATIONSPART Iactivation of granulocytes and monocyte/macrophages follow-ing trauma has been well described, more recent work has dem-onstrated that dendritic cells (DC) are also activated in response to damage signals, to stimulate both the innate and the adaptive immune responses.Dendritic cells are the most important antigen-presenting cells (APCs) for initiating T-cell responses against protein antigens. Primary “danger signals” that are recognized and activated by DC include debris from damaged or dying cells (e.g., HMGB1, nucleic acids including single nucleotides, and degradation products of the extracellular matrix). DC are fre-quently referred to as “professional APCs” since their principal function is to capture, process, and present both endogenous and exogenous antigens, which, along with their co-stimulatory molecules, are capable of inducing a primary immune response in resting naive T lymphocytes. In addition, they have the capac-ity to further regulate the immune response, both positively and negatively, through the upregulation and release of immuno-modulatory molecules such as the chemokine CCL5 (RANTES) and the CXC chemokine CXCL5. Finally, they have been impli-cated both in the induction and maintenance of immune toler-ance as well as in the acquisition of immune memory.209 There are distinct classes and subsets of DC, which are functionally heterogeneous. Different levels of damage-sensing receptors (e.g., TLR) that dictate a preferential response to DAMPs at that site. While relatively small in number relative to the total leukocyte population, the diverse distribution of DC in virtually all body tissues underlines their potential for a collaborative role in the initiation of the trauma-induced sterile systemic inflam-matory response. Data support a phenotypic alteration in these cells following traumatic injury.210PlateletsPlatelets are small (2 µm), circulating fragments of a larger cell precursor, the megakaryocyte that is located chiefly within the bone marrow. Although platelets lack a nucleus, they contain both mRNA and a large number of cytoplasmic and surface pro-teins that equip them for diverse functionality. While their role in hemostasis is well described, more recent work suggest that platelets play a role in both local and systemic inflammatory responses, particularly following ischemia reperfusion. Plate-lets express functional scavenger and Toll-like receptors (TLR) that are important detectors of both pathogens and “damage”-associated molecules.211 At the site of tissue injury, complex interactions between platelets, endothelial cells, and circulating leukocytes facilitate cellular activation by the numerous local alarmins and immune mediators. For example, platelet-specific TLR4 activation can cause thrombocytes to bind to and activate neutrophils to extrude their DNA to form neutrophil extracel-lular traps or NETs, an action that facilitates the capacity of the innate immune system to trap bacteria but also leads to local endothelial cell damage.212Once activated, platelets adopt an initial proinflamma-tory phenotype by expressing and releasing a variety of adhe-sion molecules, cytokines, and other immune modulators, including high mobility group 1 protein (HMGB1), interleukin (IL)-1β, and CD40 ligand (CD40L, CD154). However, acti-vated platelets also express large amounts of the immunosup-pressive factor, transforming growth factor-β (TGFβ), that has been implicated in Treg cell homeostasis. Recently, in a large animal model of hemorrhage, TGF-b levels were shown to be significantly increased 2 hours post injury, suggesting a pos-sible mechanism for injury-related immune dysfunction.213 And, while soluble CD154 was not increased following hemorrhage and traumatic brain injury in that study, in a murine model of mesenteric ischemia-reperfusion injury, platelet expression of CD40 and CD154 was linked to remote organ damage.Mast CellsMast cells are important in the primary response to injury because they are located in tissues. TNF release from mast cells has been found to be crucial for neutrophil recruitment and pathogen clearance. Mast cells are also known to play an impor-tant role in the anaphylactic response to allergens. On activation from stimuli including allergen binding, infection, and trauma, mast cells produce histamine, cytokines, eicosanoids, proteases, and chemokines, which leads to vasodilatation, capillary leak-age, and immunocyte recruitment. Mast cells are thought to be important cosignaling effector cells of the immune system via the release of IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, and IL-14, as well as macrophage migration–inhibiting factor.214ENDOTHELIUM-MEDIATED INJURYVascular EndotheliumUnder physiologic conditions, the vascular endothelium has important anticoagulant properties and forms a critical barrier to regulate the tissue migration of circulating cells. Following injury, endothelial cells are differentially modulated, resulting in a procoagulant shift that may lead to microthrombosis and organ injury. Recent work has associated postinjury vascular dysfunc-tion (traumatic endotheliopathy) with circulating levels of syn-decan-1, a surrogate marker for disruption of the endothelial cell glycocalyx.215 In a cohort of over 400 severely injured patients, higher syndecan-1 measurements correlated with ISS and plasma catecholamine levels and, ultimately, with mortality in this group. The authors’ hypothesize that the increased disruption of the endothelial glycocalyx results in endothelial cell injury and an altered phenotype resulting in a prothrombotic state that leads to microvascular thrombosis and ensuing organ dysfunction.Neutrophil-Endothelium InteractionThe regulated inflammatory response to infection facilitates neutrophil and other immunocyte migration to compromised regions through the actions of increased vascular permeabil-ity, chemoattractants, and increased endothelial adhesion fac-tors referred to as selectins that are elaborated on cell surfaces (Table 2-7). In response to inflammatory stimuli released from sentinel leukocytes in the tissues, including chemokines, throm-bin, leukotrienes, histamine, and TNF, vascular endothelium are activated and their surface protein expression is altered. Within 10 to 20 minutes, prestored reservoirs of the adhesion molecule P-selectin are mobilized to the cell surface where it can mediate neutrophil recruitment (Fig. 2-12). After 2 hours, endothelial cell transcriptional processes provide additional surface expression of E-selectin. E-selectin and P-selectin bind P-selectin glycoprotein ligand-1 (PSGL-1) on the neutrophils to orchestrate the capture and rolling of these leukocytes and allow targeted immunocyte extravasation. Immobilized chemo-kines on the endothelial surface create a chemotactic gradient to further enhance immune cell recruitment.216 Also important are secondary leukocyte-leukocyte interactions in which PGSL-1 and L-selectin binding facilitates further leukocyte tethering. Brunicardi_Ch02_p0027-p0082.indd 5601/03/19 6:49 PM 57SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Table 2-7Molecules that mediate leukocyte-endothelial adhesion, categorized by familyADHESION MOLECULEACTIONORIGININDUCERS OF EXPRESSIONTARGET CELLSSelectins L-selectin P-selectin E-selectinFast rollingSlow rollingVery slow rollingLeukocytesPlatelets and endotheliumEndotheliumNativeThrombin, histamineCytokinesEndothelium, platelets, eosinophilsNeutrophils, monocytesNeutrophils, monocytes, lymphocytesImmunoglobulins ICAM-1 ICAM-2 VCAM-1 PECAM-1Firm adhesion/transmigrationFirm adhesionFirm adhesion/transmigrationAdhesion/ transmigrationEndothelium, leukocytes, fibroblasts, epitheliumEndothelium, plateletsEndotheliumEndothelium, platelets, leukocytesCytokinesNativeCytokinesNativeLeukocytesLeukocytesMonocytes, lymphocytesEndothelium, platelets, leukocytesβ2-(CD18) Integrins CD18/11a CD18/11b (Mac-1) CD18/11cFirm adhesion/transmigrationFirm adhesion/transmigrationAdhesionLeukocytesNeutrophils, monocytes, natural killer cellsNeutrophils, monocytes, natural killer cellsLeukocyte activationLeukocyte activationLeukocyte activationEndotheliumEndotheliumEndotheliumβ1-(CD29) Integrins VLA-4Firm adhesion/transmigrationLymphocytes, monocytesLeukocyte activationMonocytes, endothelium, epitheliumICAM-1 = intercellular adhesion molecule-1; ICAM-2 = intercellular adhesion molecule-2; Mac-1 = macrophage antigen 1; PECAM-1 = platelet-endothelial cell adhesion molecule-1; VCAM-1 = vascular cell adhesion molecule-1; VLA-4 = very late antigen-4.Although there are distinguishable properties among individ-ual selectins in leukocyte rolling, effective rolling most likely involves a significant degree of functional overlap.217ChemokinesChemokines are a family of small proteins (8–13 kDa) that were first identified through their chemotactic and activating effects on inflammatory cells. They are produced at high levels follow-ing nearly all forms of injury in all tissues, where they are key attractants for immune cell extravasation. There are more than 50 different chemokines and 20 chemokine receptors that have been identified. Chemokines are released from endothelial cells, mast cells, platelets, macrophages, and lymphocytes. They are soluble proteins, which when secreted, bind to glycosamino-glycans on the cell surface or in the extracellular matrix. In this way, the chemokines can form a fixed chemical gradient that promotes immune cell exit to target areas. Supporting the idea of their importance in leukocyte recruitment post injury, a sub-set of chemokines are elevated early following traumatic injury in both survivors and nonsurvivors.218Chemokines are distinguished (in general) from cyto-kines by virtue of their receptors, which are members of the G-protein–coupled receptor superfamily. Most chemokine receptors recognize more than one chemokine ligand leading to redundancy in chemokine signaling.The chemokines are subdivided into families based on their amino acid sequences at their N-terminus. For example, CC chemokines contain two N-terminus cysteine residues that are immediately adjacent (hence the “C-C” designation) while the N-terminal cysteines in CXC chemokines are separated by a single amino acid. The CXC chemokines are particularly impor-tant for neutrophil (PMN) proinflammatory function. Members of the CXC chemokine family, which include IL-8 (CXCL8), induce neutrophil migration and secretion of cytotoxic granu-lar contents and metabolites. Additional chemokine families include the Cand CX3C-chemokines.216Recent studies support the idea that a subset of chemo-kines, monokine induced by γ-interferon (MIG), monocyte chemotactic protein 1 (MCP-1), and interferon γ-induced pro-teins 10 (IP-10) may work in concert to regulate the inflam-matory response post injury and may serve as biomarkers for clinical outcome in trauma patients.218,219 These investigators propose that MIG, MCP-1, and IP-10 function as a “chemo-kine switch” in which the relative levels of each chemokine may promote its own expression, which suppresses the expres-sion of the other two according to the severity and type of injury.220 In this way, the authors propose that the balance between these three chemokines, by regulating inflammatory mediator production (e.g., IL-6) may help to correlate with long-term outcomes.Brunicardi_Ch02_p0027-p0082.indd 5701/03/19 6:49 PM 58BASIC CONSIDERATIONSPART ICaptureFastrollingSlowrollingArrest50–150 µm/sec20–50 µm/sec10–20 µm/sec0–10 µm/secVelocity:LeukocyteSeconds0Velocity (µm/second)1501000501234EndotheliumFigure 2-12. Simplified sequence of selectin-mediated neutrophil-endothelium interaction after an inflammatory stimulus. CAPTURE (tethering), predominantly mediated by cell L-selectin with contri-bution from endothelial P-selectin, describes the initial recognition between leukocyte and endothelium, in which circulating leuko-cytes marginate toward the endothelial surface. FAST ROLLING (20 to 50 μm/s) is a consequence of rapid L-selectin shedding from cell surfaces and formation of new downstream L-selectin to endo-thelium bonds, which occur in tandem. SLOW ROLLING (10 to 20 μm/s) is predominantly mediated by P-selectins. The slowest rolling (3 to 10 μm/s) before arrest is predominantly mediated by E-selec-tins, with contribution from P-selectins. ARREST (firm adhesion) leading to transmigration is mediated by β-integrins and the immu-noglobulin family of adhesion molecules. In addition to interact-ing with the endothelium, activated leukocytes also recruit other leukocytes to the inflammatory site by direct interactions, which are mediated in part by selectins. (Adapted with permission from Lin E, Calvano SE, Lowry SF. Selectin neutralization: does it make biological sense? Crit Care Med. 1999 Sep;27(9):2050-2053.)Nitric OxideNitric oxide (NO) was initially known as endothelium-derived relaxing factor due to its effect on vascular smooth muscle. Normal vascular smooth muscle cell relaxation is maintained by a constant output of NO that is regulated in the endothe-lium by both flowand receptor-mediated events. NO can also reduce microthrombosis by reducing platelet adhesion and aggregation (Fig. 2-13) and interfering with leukocyte adhe-sion to the endothelium. NO easily traverses cell membranes and has a short half-life of a few seconds. Endogenous NO formation is derived largely from the action of NO synthase (NOS), which is constitutively expressed in endothelial cells (NOS3, eNOS). Nitric oxide synthase generates NO by cata-lyzing the degradation of L-arginine to L-citrulline and NO, in the presence of oxygen and NADPH. There are two addi-tional isoforms of NOS: neuronal NOS (NOS1, nNOS) and inducible NOS (iNOS/NOS2), which is expressed in response to cytokines and bacterial products. The vasodilatory effects of NO are mediated by guanylyl cyclase, an enzyme that is found in vascular smooth muscle cells and most other cells of the body. When NO is formed by endothelium, it rapidly diffuses into adjacent cells where it binds to and activates gua-nylyl cyclase. This enzyme catalyzes the dephosphorylation of GTP to cGMP, which serves as a second messenger for many important cellular functions, particularly for signaling smooth muscle relaxation.NO synthesis is increased due to the upregulation of iNOS expression in response to proinflammatory media-tors such as TNF-α, and IL-1β, as well as microbial products.221,222 In fact, studies in both animal models and humans have shown that severe systemic injury and asso-ciated hemorrhage produce an early upregulation of iNOS in the liver, lung, spleen, and vascular system. In these cir-cumstances, NO is reported to function as an immunoregu-lator, which is capable of modulating cytokine production and immune cell development.223 In particular, recent data supports a role for iNOS/eNOS in the regulation of T-cell dysfunction in the setting of trauma as evidenced by sup-pressed proliferative and TH1 cytokine release. In particular, the formation of S-nitrosothiols, which can serve as a molec-ular switch to regulate protein functions, may explain many signaling effects of both iNOSand eNOS-derived NO in the immune system with regard to T-cell activation and signaling through the T cell receptor. In T cells, NO effects have been implicated in the regulation of the immune synapse as well as the regulation of mitochondrial bioenergetics indicating that NO may play an important role as a link between innate and adaptive immunity.224Inhibition of NO production seemed initially to be a promising strategy in patients with severe sepsis. However, a randomized clinical trial in patients with septic shock determined that treatment with a nonselective NOS inhibitor was associated with an increase in mortality compared with placebo.225 More recent data utilizing an ovine model of perito-nitis demonstrated that selective iNOS inhibition reduced pul-monary artery hypertension and gas exchange impairment and promoted higher visceral organ blood flow, coinciding with lower plasma cytokine concentrations.226 These data suggest that specific targeting of iNOS in the setting of sepsis may remain a viable therapeutic option.Recent work using an animal model of traumatic brain injury (TBI) showed that acute TBI results in endothelial dys-function in a remote vascular bed.227 The investigators linked the effect of TBI with impaired nitric oxide (NO) production and also with an increase in arterial arginase activity, implicat-ing the depletion of L-arginine by arginase with the decreased NO production.ProstacyclinThe immune effects of prostacyclin (PGI2) have been discussed previously. The best-described effects of PGI2 are in the car-diovascular system, however, where it is produced by vascular endothelial cells. Prostacyclin is a potent vasodilator that also inhibits platelet aggregation. In the pulmonary system, PGI2 reduces pulmonary blood pressure as well as bronchial hyper-responsiveness. In the kidneys, PGI2 modulates renal blood flow and glomerular filtration rate. Prostacyclin acts through its receptor (a G-protein–coupled receptor of the rhodopsin family) to stimulate the enzyme, adenylate cyclase, allowing the syn-thesis of cyclic adenosine monophosphate (cAMP) from ATP. Brunicardi_Ch02_p0027-p0082.indd 5801/03/19 6:49 PM 59SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2cAMPcAMPcGMPcGMPNONOPGI2AAPlateletETETPGI2Big ETL-arginineEndotheliumSmooth muscleRelaxationFigure 2-13. Endothelial interac-tion with smooth muscle cells and with intraluminal platelets. Prosta-cyclin (prostaglandin I2, or PGI2) is derived from arachidonic acid (AA), and nitric oxide (NO) is derived from L-arginine. The increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine mono-phosphate (cGMP) results in smooth muscle relaxation and inhibition of platelet thrombus formation. Endo-thelins (ETs) are derived from “big ET,” and they counter the effects of prostacyclin and NO.This leads to a cAMP-mediated decrease in intracellular cal-cium and subsequent smooth muscle relaxation.During systemic inflammation, endothelial prostacyclin expression is impaired, and thus the endothelium favors a more procoagulant profile. Exogenous prostacyclin analogues, both intravenous and inhaled, have been utilized to improve oxygen-ation in patients with acute lung injury. Early clinical studies with prostacyclin have delivered some encouraging results.228 However, a recent study examining the administration of epo-prostenol in the setting of severe injury and TBI demonstrated and attenuation of the inflammatory response as measured by serologic markers had no effect on long-term outcome.229EndothelinsEndothelins (ETs) are potent mediators of vasoconstriction ET-1, synthesized primarily by endothelial cells, is the most potent endogenous vasoconstrictor, and is estimated to be 10 times more potent than angiotensin II. ET release is upregu-lated in response to hypotension, LPS, injury, thrombin, TGF-b, IL-1, angiotensin II, vasopressin, catecholamines, and anoxia. ETs release is transcriptionally regulated and occurs at the ablu-minal side of endothelial cells. Very little is stored in cells; thus, a plasma increase in ET is associated with a marked increase in production. Three endothelin receptors have been identified and function via the G-protein–coupled receptor mechanism. ETB receptors are associated with increased NO and prostacyclin production, which may serve as a feedback mechanism. Atrial ETA receptor activation has been associated with increased inotropy and chronotropy. ET-1 infusion is associated with increased pulmonary vascular resistance and pulmonary edema and may contribute to pulmonary abnormalities during sepsis. At low levels, in conjunction with NO, ETs regulate vascular tone. However, at increased concentrations, ETs can disrupt the normal blood flow and distribution and may compromise oxy-gen delivery to the tissue. Recent data links endothelin expres-sion in pulmonary vasculature with persistent inflammation associated with the development of pulmonary hypertension.230 Endothelin expression is linked to posttranslational and tran-scriptional initiation of the unfolded protein response in the affected cells, which results in the production of inflammatory cytokines.231 Persistent endothelin-1 stimulation may play a role in decreased vascular reactivity that is evident following hemor-rhagic shock.232Platelet Activating FactorPhosphotidylcholine is a major lipid constituent of the plasma membrane. Its enzymatic processing by cytosolic phospho-lipase A2 (cPLA2) or calcium-independent phospholipase A2 (iPLA2) generates powerful small lipid molecules, which func-tion as intracellular second messengers. One of these is arachi-donic acid, the precursor molecule for eicosanoids. Another is platelet-activating factor (PAF). During acute inflammation, PAF is released by immune cells following the activation of PLA2. The receptor for PAF (PAFR), which is constitutively expressed by platelets, leukocytes, and endothelial cells, is a G-protein–coupled receptor of the rhodopsin family. Ligand binding to the PAFR promotes the activation and aggregation of platelets and leukocytes, leukocyte adherence, motility, chemotaxis, and invasion, as well as ROS generation.233 Addi-tionally, PAF activation of human PMNs induces extrusion of neutrophil extracellular traps (NETs), while platelet activa-tion induces IL-1 via a novel posttranscriptional mechanism. Finally, PAFR ligation results not only in the upregulation of numerous proinflammatory genes, including COX-2, iNOS, and IL-6, but also in the generation of lipid intermediates such as arachidonic acid and lysophospholipids through the Brunicardi_Ch02_p0027-p0082.indd 5901/03/19 6:49 PM 60BASIC CONSIDERATIONSPART IBrainRBCWBCNerveKidneyMuscleHeartKidneyMuscleAminoacidsGlycerol16gFattyacid160g40gFatty acid120gKetone60gGlucose180g36g144g36gLactate + PyruvateLIVERGlycogen75gGluconeogenesisOxidationFuel utilization in short-term fasting man (70 kg)Muscleprotein75gFat storestriglycerides160gFigure 2-14. Fuel utilization in a 70-kg man during short-term fasting with an approximate basal energy expenditure of 1800 kcal. During starvation, muscle proteins and fat stores provide fuel for the host, with the latter being most abundant. RBC = red blood cell; WBC = white blood cell. activation of Phospholipase A2. Antagonists to PAF recep-tors have been experimentally shown to mitigate the effects of ischemia and reperfusion injury. Of note, human sepsis is associated with a reduction in the levels of PAF-acetylhydro-lase, which inactivates PAF by removing an acetyl group. Indeed, PAF-acetylhydrolase administration in patients with severe sepsis has yielded some reduction in multiple organ dysfunction and mortality234; however, larger phase III clinical trials failed to show benefit.Natriuretic PeptidesThe natriuretic peptides, atrial natriuretic factor (ANP) and brain natriuretic peptide (BNP), are a family of peptides that are released primarily by atrial and ventricular tissue respectively, but are also synthesized by the gut, kidney, brain, adrenal glands, and endothelium. The functionally active forms of the peptides are C-terminal fragments of a larger pro-hormone, and both Nand C-terminal fragments are detectable in the blood (referred to a N-terminal pro-BNP and pro-ANF, respectively). ANF and BNP share most biological properties, including diuretic, natri-uretic, vasorelaxant, and cardiac remodeling properties that are affected by signaling through a common receptor: the guanylyl cyclase(GC-) A receptor. They are both increased in the setting of cardiac disorders; however, evidence indicates some distinctions in the setting of inflammation. For example, elevated proBNP has been detected in septic patients in the absence of myocardial dysfunction and appears to have prognostic significance.235 More recently, investigators examined changes in N-terminal pro-BNP (NT-proBNP) in a cohort of severely injured patients and deter-mined that persistently high level of NT-proBNP in major trauma patients is indicative of poor outcome.236SURGICAL METABOLISMThe initial hours after surgical or traumatic injury are metaboli-cally associated with a reduced total body energy expenditure and urinary nitrogen wasting. With adequate resuscitation and stabilization of the injured patient, a reprioritization of substrate use ensues to preserve vital organ function and to support repair of injured tissue. This phase of recovery also is characterized by functions that participate in the restoration of homeostasis, such as augmented metabolic rates and oxygen consumption, enzymatic preference for readily oxidizable substrates such as glucose, and stimulation of the immune system. Understanding of the collective alterations in amino acid (protein), carbohy-drate, and lipid metabolism characteristic of the surgical patient lays the foundation upon which metabolic and nutritional sup-port can be implemented.Metabolism During FastingFuel metabolism during unstressed fasting states has historically served as the standard to which metabolic alterations after acute injury and critical illness are compared (Fig. 2-14). To maintain basal metabolic needs (i.e., at rest and fasting), a normal healthy adult requires approximately 22 to 25 kcal/kg per day drawn from carbohydrate, lipid, and protein sources. This requirement can substantially increase during severe stress states, such as those seen in patients with burn injuries.In the healthy adult, principal sources of fuel during short-term fasting (<5 days) are derived from muscle protein and body fat, with fat being the most abundant source of energy (Table 2-8). The normal adult body contains 300 to 400 g of carbohydrates in the form of glycogen, of which 75 to 100 g are stored in the liver. Approximately 200 to 250 g of glycogen are stored within skeletal, cardiac, and smooth muscle cells. The greater glycogen stores within the muscle are not read-ily available for systemic use due to a deficiency in glucose-6-phosphatase but are available for the energy needs of muscle cells. Therefore, in the fasting state, hepatic glycogen stores are rapidly and preferentially depleted, which results in a fall of serum glucose concentration within hours (<16 hours).During fasting, a healthy 70-kg adult will utilize 180 g of glucose per day to support the metabolism of obligate glycolytic cells such as neurons, leukocytes, erythrocytes, and the renal medullae. Other tissues that use glucose for fuel are skeletal muscle, intestinal mucosa, fetal tissues, and solid tumors.Brunicardi_Ch02_p0027-p0082.indd 6001/03/19 6:49 PM 61SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2RBCWBCNerveKidneyMuscleMuscleProteinpyruvateKetoneLactate + PyruvateFattyacidGlucoseKetoneGlucoseAlanineGlucose-alanine cycleCori cycleLIVERGluconeogenesisFigure 2-15. The recycling of peripheral lactate and pyruvate for hepatic gluconeogenesis is accomplished by the Cori cycle. Alanine within skeletal muscles can also be used as a precursor for hepatic gluconeogenesis. During starvation, such fatty acid provides fuel sources for basal hepatic enzymatic function. RBC = red blood cell; WBC = white blood cell.Glucagon, norepinephrine, vasopressin, and angiotensin II can promote the utilization of glycogen stores (glycogenolysis) during fasting. Although glucagon, epinephrine, and cortisol directly promote gluconeogenesis, epinephrine and cortisol also promote pyruvate shuttling to the liver for gluconeogen-esis. Precursors for hepatic gluconeogenesis include lactate, glycerol, and amino acids such as alanine and glutamine. Lac-tate is released by glycolysis within skeletal muscles, as well as by erythrocytes and leukocytes. The recycling of lactate and pyruvate for gluconeogenesis is commonly referred to as the Cori cycle, which can provide up to 40% of plasma glucose during starvation (Fig. 2-15).Lactate production from skeletal muscle is insufficient to maintain systemic glucose needs during short-term fasting (simple starvation). Therefore, significant amounts of protein must be degraded daily (75 g/d for a 70-kg adult) to provide the amino acid substrate for hepatic gluconeogenesis. Proteolysis during starvation, which results primarily from decreased insu-lin and increased cortisol release, is associated with elevated urinary nitrogen excretion from the normal 7 to 10 g/d up to 30 g or more per day.237 Although proteolysis during starvation occurs mainly within skeletal muscles, protein degradation in solid organs also occurs.In prolonged starvation, systemic proteolysis is reduced to approximately 20 g/d and urinary nitrogen excretion stabilizes at 2 to 5 g/d (Fig. 2-16). This reduction in proteolysis reflects the adaptation by vital organs (e.g., myocardium, brain, renal cortex, and skeletal muscle) to using ketone bodies as their prin-cipal fuel source. In extended fasting, ketone bodies become an important fuel source for the brain after 2 days and gradually become the principal fuel source by 24 days.Enhanced deamination of amino acids for gluconeogen-esis during starvation consequently increases renal excretion of ammonium ions. The kidneys also participate in gluconeo-genesis by the use of glutamine and glutamate and can become the primary source of gluconeogenesis during prolonged star-vation, accounting for up to one-half of systemic glucose production.Table 2-8A. Body fuel reserves in a 70-kg man and B. Energy equivalent of substrate oxidationA. COMPONENTMASS (kg)ENERGY (kcal)DAYS AVAILABLEWater and minerals4900Protein6.024,00013.0Glycogen0.28000.4Fat15.0140,00078.0Total70.2164,80091.4B. SUBSTRATEO2 CONSUMED (L/g)CO2 PRODUCED (L/g)RESPIRATORY QUOTIENTkcal/gRECOMMENDED DAILY REQUIREMENTGlucose0.750.751.04.07.2 g/kg per dayDextrose———3.4—Lipid2.01.40.79.01.0 g/kg per dayProtein1.00.80.84.00.8 g/kg per dayBrunicardi_Ch02_p0027-p0082.indd 6101/03/19 6:50 PM 62BASIC CONSIDERATIONSPART IWOUNDRBCWBCNerveKidneyMuscleHeartKidneyMuscleAminoacidsGlycerol17gFattyacid170g40gFatty acid130gKetone60gGlucose360g180g180gLactate+PyruvateKIDNEYGluconeogenesisGluconeogenesisLIVEROxidationFuel utilization following traumaMuscleProtein250gFat storesTriglycerides170gFigure 2-17. Acute injury is associated with significant alterations in substrate utilization. There is enhanced nitrogen loss, indicative of catabolism. Fat remains the primary fuel source under these circumstances. RBC = red blood cell; WBC = white blood cell.Fuel utilization in long-term fasting man (70 kg)HeartKidneyMuscleAminoacidsGlycerol18gFattyacid180g45gFatty acid135gKetone68gGlucose80g44g36gLactate + PyruvateKIDNEYGluconeogenesis15g5g40g40g10g (100 mEq) in urine44g36g58gMuscleProtein20gFat storesTriglycerides180gBrainRBCWBCNerveKidneyMuscleLIVERGlycogenGluconeogenesisOxidationFigure 2-16. Fuel utilization in extended starvation. Liver glycogen stores are depleted, and there is adaptive reduction in proteolysis as a source of fuel. The brain uses ketones for fuel. The kidneys become important participants in gluconeogenesis. RBC = red blood cell; WBC = white blood cell. Lipid stores within adipose tissue provide 40% or more of caloric expenditure during starvation. Energy requirements for basal enzymatic and muscular functions (e.g., gluconeogenesis, neural transmission, and cardiac contraction) are met by the mobilization of triglycerides from adipose tissue. In a resting, fasting, 70-kg person, approximately 160 g of free fatty acids and glycerol can be mobilized from adipose tissue per day. Free fatty acid release is stimulated in part by a reduction in serum insulin levels and in part by the increase in circulating glucagon and catecholamine. Such free fatty acids, like ketone bodies, are used as fuel by tissues such as the heart, kidney (renal cortex), muscle, and liver. The mobilization of lipid stores for energy importantly decreases the rate of glycolysis, gluconeogenesis, and proteolysis, as well as the overall glucose requirement to sustain the host. Furthermore, ketone bodies spare glucose utili-zation by inhibiting the enzyme pyruvate dehydrogenase.Metabolism After InjuryInjuries or infections induce unique neuroendocrine and immu-nologic responses that differentiate injury metabolism from that of unstressed fasting (Fig. 2-17). The magnitude of metabolic expenditure over time appears to be directly proportional to the severity of insult, with thermal injuries and severe infections having the highest energy demands (Fig. 2-18). Of note, the first few days following both sepsis and trauma are not hyper-metabolic states, with the more severe insults associated with increased “metabolic hibernation.” However, by week 2, the total energy expenditure increases dramatically.238 The increase Brunicardi_Ch02_p0027-p0082.indd 6201/03/19 6:50 PM 63SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 201020304050% REE100752550125150175200225Days after injuryMajor burnsSepsis/peritonitisSkeletal traumaNormalrangeElective surgeryStarvationFigure 2-18. Influence of injury severity on resting metabolism (resting energy expenditure, or REE). The shaded area indicates normal REE. (Reproduced with permission from Long CL, Schaffel N, Geiger JW, et al: Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorim-etry and nitrogen balance, JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):452-456.)DietarytriglyceridesIntestinal lumenLymphatic ductPancreaticlipaseGutenterocyteMonoglyceridesTriglyceridesMonoglyceride + 2 Fatty acyI-CoAFatty acidsChylomicron+ ProteinFigure 2-19. Pancreatic lipase within the small intestinal brush borders hydrolyzes triglycerides into monoglycerides and fatty acids. These components readily diffuse into the gut enterocytes, where they are re-esterified into triglycerides. The resynthesized triglycerides bind car-rier proteins to form chylomicrons, which are transported by the lymphatic system. Shorter triglycerides (those with <10 carbon atoms) can bypass this process and directly enter the portal circulation for transport to the liver. CoA = coenzyme A.in energy expenditure is mediated in part by sympathetic acti-vation and catecholamine release, which has been replicated by the administration of catecholamines to healthy human sub-jects. Lipid metabolism after injury is intentionally discussed first because this macronutrient becomes the primary source of energy during stressed states.239Lipid Metabolism After InjuryLipids are not merely nonprotein, noncarbohydrate fuel sources that minimize protein catabolism in the injured patient. Lipid metabolism potentially influences the structural integrity of cell membranes as well as the immune response during systemic inflammation. Adipose stores within the body (triglycerides) are the predominant energy source (50% to 80%) during critical ill-ness and after injury. Fat mobilization (lipolysis) occurs mainly in response to catecholamine stimulus of the hormone-sensitive triglyceride lipase. Other hormonal influences that potentiate lipolysis include adrenocorticotropic hormone (ACTH), cat-echolamines, thyroid hormone, cortisol, glucagon, growth hor-mone release, and reduction in insulin levels.240Lipid Absorption. Although the process is poorly understood, adipose tissue provides fuel for the host in the form of free fatty acids and glycerol during critical illness and injury. Oxidation of 1 g of fat yields approximately 9 kcal of energy. Although the liver is capable of synthesizing triglycerides from carbohy-drates and amino acids, dietary and exogenous sources provide the major source of triglycerides. Dietary lipids are not readily absorbable in the gut but require pancreatic lipase and phospho-lipase within the duodenum to hydrolyze the triglycerides into free fatty acids and monoglycerides. The free fatty acids and monoglycerides are then readily absorbed by gut enterocytes, which resynthesize triglycerides by esterification of the mono-glycerides with fatty acyl coenzyme A (acyl-CoA) (Fig. 2-19). Long-chain triglycerides (LCTs), defined as those with 12 car-bons or more, generally undergo this process of esterification Brunicardi_Ch02_p0027-p0082.indd 6301/03/19 6:50 PM 64BASIC CONSIDERATIONSPART Iand enter the circulation through the lymphatic system as chy-lomicrons. Shorter fatty acid chains directly enter the portal circulation and are transported to the liver by albumin carriers. Hepatocytes use free fatty acids as a fuel source during stress states but also can synthesize phospholipids or triglycerides (i.e., very-low-density lipoproteins) during fed states. Systemic tissue (e.g., muscle and the heart) can use chylomicrons and triglycerides as fuel by hydrolysis with lipoprotein lipase at the luminal surface of capillary endothelium.241 Trauma or sepsis suppresses lipoprotein lipase activity in both adipose tissue and muscle, presumably mediated by TNF.Lipolysis and Fatty Acid Oxidation. Periods of energy demand are accompanied by free fatty acid mobilization from adipose stores. This is mediated by hormonal influences (e.g., catecholamines, ACTH, thyroid hormones, growth hormone, and glucagon) on triglyceride lipase through a cAMP pathway (Fig. 2-20). In adipose tissues, triglyceride lipase hydrolyzes triglycerides into free fatty acids and glycerol. Free fatty acids enter the capillary circulation and are transported by albumin to tissues requiring this fuel source (e.g., heart and skeletal mus-cle). Insulin inhibits lipolysis and favors triglyceride synthesis by augmenting lipoprotein lipase activity as well as intracellu-lar levels of glycerol-3-phosphate. The use of glycerol for fuel depends on the availability of tissue glycerokinase, which is abundant in the liver and kidneys.Free fatty acids absorbed by cells conjugate with acyl-CoA within the cytoplasm. The transport of fatty acyl-CoA from the outer mitochondrial membrane across the inner mito-chondrial membrane occurs via the carnitine shuttle (Fig. 2-21). Medium-chain triglycerides (MCTs), defined as those 6 to 12 carbons in length, bypass the carnitine shuttle and readily cross the mitochondrial membranes. This accounts in part for the fact that MCTs are more efficiently oxidized than LCTs. Ideally, the rapid oxidation of MCTs makes them less prone to fat deposition, particularly within immune cells and the reticu-loendothelial system—a common finding with lipid infusion in parenteral nutrition.242 However, exclusive use of MCTs as fuel in animal studies has been associated with higher metabolic demands and toxicity, as well as essential fatty acid deficiency.Within the mitochondria, fatty acyl-CoA undergoes b-oxidation, which produces acetyl-CoA with each pass through the cycle. Each acetyl-CoA molecule subsequently enters the tricarboxylic acid (TCA) cycle for further oxidation to yield 12 adenosine triphosphate (ATP) molecules, carbon dioxide, and water. Excess acetyl-CoA molecules serve as precursors for ketogenesis. Unlike glucose metabolism, oxidation of fatty acids requires proportionally less oxygen and produces less car-bon dioxide. This is frequently quantified as the ratio of carbon dioxide produced to oxygen consumed for the reaction and is known as the respiratory quotient (RQ). An RQ of 0.7 would imply greater fatty acid oxidation for fuel, whereas an RQ of 1 indicates greater carbohydrate oxidation (overfeeding). An RQ of 0.85 suggests the oxidation of equal amounts of fatty acids and glucose.KetogenesisCarbohydrate depletion slows the entry of acetyl-CoA into the TCA cycle secondary to depleted TCA intermediates and enzyme activity. Increased lipolysis and reduced systemic carbo-hydrate availability during starvation diverts excess acetyl-CoA Hormone-receptoractivationCapillaryAdiposecellFFAcAMPProtein kinaseTriglyceride lipaseTriglycerideDiglycerideMonoglycerideGlycerolFFAFFAFFAFigure 2-20. Fat mobilization in adipose tissue. Triglyceride lipase activation by hormonal stimulation of adipose cells occurs through the cyclic adenosine monophosphate (cAMP) pathway. Triglycerides are serially hydrolyzed with resultant free fatty acid (FFA) release at every step. The FFAs diffuse readily into the capillary bed for transport. Tissues with glycerokinase can use glycerol for fuel by forming glycerol-3-phosphate. Glycerol-3-phosphate can esterify with FFAs to form triglycerides or can be used as a precursor for renal and hepatic gluconeogenesis. Skeletal muscle and adipose cells have little glycerokinase and thus do not use glycerol for fuel.Brunicardi_Ch02_p0027-p0082.indd 6401/03/19 6:50 PM 65SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Carnitineacyltransferase ITransportproteinCytosolMitochondriaFFAAcetyl-CoABeta OxidationCarnitineCarnitineacyltransferase IICoACarnitineMitochondrialmembraneORCCarnitineORCCoAROCCoAORCCarnitineCoAFigure 2-21. Free fatty acids (FFAs) in the cells form fatty acyl-coenzyme A (CoA) with CoA. Fatty acyl-CoA cannot enter the inner mitochondrial membrane and requires carnitine as a carrier protein (carnitine shuttle). Once inside the mitochondria, carnitine dissociates, and fatty acyl-CoA is reformed. The carnitine molecule is transported back into the cytosol for reuse. The fatty acyl-CoA undergoes β-oxidation to form acetyl-CoA for entry into the tri-carboxylic acid cycle. “R” represents a part of the acyl group of acyl-CoA.toward hepatic ketogenesis. A number of extrahepatic tissues, but not the liver itself, are capable of using ketones for fuel. Ketosis represents a state in which hepatic ketone production exceeds extrahepatic ketone utilization.The rate of ketogenesis appears to be inversely related to the severity of injury. Major trauma, severe shock, and sepsis attenuate ketogenesis by increasing insulin levels and by caus-ing rapid tissue oxidation of free fatty acids. Minor injuries and infections are associated with modest elevations in plasma free fatty acid concentrations and ketogenesis. However, in minor stress states ketogenesis does not exceed that in nonstressed starvation.Carbohydrate MetabolismIngested and enteral carbohydrates are primarily digested in the small intestine, where pancreatic and intestinal enzymes reduce the complex carbohydrates to dimeric units. Disaccharidases (e.g., sucrase, lactase, and maltase) within intestinal brush bor-ders dismantle the complex carbohydrates into simple hexose units, which are transported into the intestinal mucosa. Glu-cose and galactose are primarily absorbed by energy-dependent active transport coupled to the sodium pump. Fructose absorp-tion, however, occurs by concentration-dependent facilitated diffusion. Neither fructose and galactose within the circulation nor exogenous mannitol (for neurologic injury) evokes an insu-lin response. Intravenous administration of low-dose fructose in fasting humans has been associated with nitrogen conservation, but the clinical utility of fructose administration in human injury remains to be demonstrated.Discussion of carbohydrate metabolism primarily refers to the utilization of glucose. The oxidation of 1 g of carbohy-drate yields 4 kcal, but sugar solutions such as those found in intravenous fluids or parenteral nutrition provide only 3.4 kcal/g of dextrose. In starvation, glucose production occurs at the expense of protein stores (i.e., skeletal muscle). Hence, the primary goal for maintenance glucose administration in surgical patients is to minimize muscle wasting. The exog-enous administration of small amounts of glucose (approxi-mately 50 g/d) facilitates fat entry into the TCA cycle and reduces ketosis. Unlike in starvation in healthy subjects, in septic and trauma patients provision of exogenous glucose never has been shown to fully suppress amino acid degrada-tion for gluconeogenesis. This suggests that during periods of stress, other hormonal and proinflammatory mediators have a profound influence on the rate of protein degradation and that some degree of muscle wasting is inevitable. The administra-tion of insulin, however, has been shown to reverse protein catabolism during severe stress by stimulating protein synthe-sis in skeletal muscles and by inhibiting hepatocyte protein degradation. Insulin also stimulates the incorporation of ele-mental precursors into nucleic acids in association with RNA synthesis in muscle cells.In cells, glucose is phosphorylated to form glucose-6-phosphate. Glucose-6-phosphate can be polymerized during glycogenesis or catabolized in glycogenolysis. Glucose catabolism occurs by cleavage to pyruvate or lactate (pyruvic acid pathway) or by decarboxylation to pentoses (pentose shunt) (Fig. 2-22).Excess glucose from overfeeding, as reflected by RQs >1.0, can result in conditions such as glucosuria, thermogenesis, and conversion to fat (lipogenesis). Excessive glucose adminis-tration results in elevated carbon dioxide production, which may be deleterious in patients with suboptimal pulmonary function, as well as hyperglycemia, which may contribute to infectious risk and immune suppression.Injury and severe infections acutely induce a state of peripheral glucose intolerance, despite ample insulin produc-tion at levels several-fold above baseline. This may occur in part due to reduced skeletal muscle pyruvate dehydrogenase activity after injury, which diminishes the conversion of pyru-vate to acetyl-CoA and subsequent entry into the TCA cycle. The three-carbon structures (e.g., pyruvate and lactate) that consequently accumulate are shunted to the liver as substrate for gluconeogenesis. Furthermore, regional tissue catheteriza-tion and isotope dilution studies have shown an increase in net splanchnic glucose production by 50% to 60% in septic patients and a 50% to 100% increase in burn patients.242 The increase in plasma glucose levels is proportional to the severity of injury, and this net hepatic gluconeogenic response is believed to be under the influence of glucagon. Unlike in the nonstressed sub-ject, in the hypermetabolic, critically ill patient the hepatic glu-coneogenic response to injury or sepsis cannot be suppressed by exogenous or excess glucose administration but rather persists. Hepatic gluconeogenesis, arising primarily from alanine and glutamine catabolism, provides a ready fuel source for tissues such as those of the nervous system, wounds, and erythrocytes, which do not require insulin for glucose transport. The elevated glucose concentrations also provide a necessary energy source for leukocytes in inflamed tissues and in sites of microbial invasions.Brunicardi_Ch02_p0027-p0082.indd 6501/03/19 6:50 PM 66BASIC CONSIDERATIONSPART IThe shunting of glucose away from nonessential organs such as skeletal muscle and adipose tissues is mediated by cat-echolamines. Experiments with infusing catecholamines and glucagon in animals have demonstrated elevated plasma glu-cose levels as a result of increased hepatic gluconeogenesis and peripheral insulin resistance. Interestingly, although glucocorti-coid infusion alone does not increase glucose levels, it does pro-long and augment the hyperglycemic effects of catecholamines and glucagon when glucocorticoid is administered concurrently with the latter.Glycogen stores within skeletal muscles can be mobilized by epinephrine activation of b-adrenergic receptors, GTP-binding proteins (G-proteins), which subsequently activates the second messenger, cAMP. The cAMP activates phosphorylase kinase, which in turn leads to conversion of glycogen to glucose-1-phosphate. Phosphorylase kinase also can be activated by the second messenger, calcium, through the breakdown of phos-phatidylinositol phosphate, which is the case in vasopressin-mediated hepatic glycogenolysis.243Protein and Amino Acid MetabolismThe average protein intake in healthy young adults ranges from 80 to 120 g/d, and every 6 g of protein yields approximately 1 g of nitrogen. The degradation of 1 g of protein yields approxi-mately 4 kcal of energy, similar to the yield in carbohydrate metabolism. After injury, the initial systemic proteolysis, medi-ated primarily by glucocorticoids, increases urinary nitrogen excretion to levels in excess of 30 g/d, which roughly corre-sponds to a loss in lean body mass of 1.5% per day. An injured individual who does not receive nutrition for 10 days can theo-retically lose 15% lean body mass. Therefore, amino acids can-not be considered a long-term fuel reserve, and indeed excessive protein depletion (i.e., 25% to 30% of lean body weight) is not compatible with sustaining life.244Protein catabolism after injury provides substrates for gluconeogenesis and for the synthesis of acute phase proteins. Radiolabeled amino acid incorporation studies and protein anal-yses confirm that skeletal muscles are preferentially depleted acutely after injury, whereas visceral tissues (e.g., the liver and kidney) remain relatively preserved. The accelerated urea excretion after injury also is associated with the excretion of intracellular elements such as sulfur, phosphorus, potassium, magnesium, and creatinine. Conversely, the rapid utilization of elements such as potassium and magnesium during recovery from major injury may indicate a period of tissue healing.The net changes in protein catabolism and synthesis corre-spond to the severity and duration of injury (Fig. 2-23). Elective operations and minor injuries result in lower protein synthesis and moderate protein breakdown. Severe trauma, burns, and sepsis are associated with increased protein catabolism. The rise in urinary nitrogen and negative nitrogen balance can be detected early after injury and peak by 7 days. This state of pro-tein catabolism may persist for as long as 3 to 7 weeks. The patient’s prior physical status and age appear to influence the degree of proteolysis after injury or sepsis. Activation of the ubiquitin-proteosome system in muscle cells is one of the major path-ways for protein degradation during acute injury. This response is accentuated by tissue hypoxia, acidosis, insulin resistance, and elevated glucocorticoid levels.NUTRITION IN THE SURGICAL PATIENTThe goal of nutritional support in the surgical patient is to prevent or reverse the catabolic effects of disease or injury. Although several important biologic parameters have been used to measure the efficacy of nutritional regimens, the ultimate validation for nutritional support in surgical patients should be improvement in clinical outcome and restoration of function.Estimation of Energy RequirementsAll patients admitted to the hospital should have their nutritional status assessed. Overall nutritional assessment is undertaken to 7GlycogenGlucoseGlucose-6-Phosphate6-PhosphogluconatePyruvicacidLacticacidPentosemonophosphateshuntTricarboxylic acidFigure 2-22. Simplified schema of glucose catabolism through the pen-tose monophosphate pathway or by breakdown into pyruvate. Glucose-6-phosphate becomes an important “crossroad” for glucose metabolism.Brunicardi_Ch02_p0027-p0082.indd 6601/03/19 6:50 PM 67SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2Nitrogen excretion (g/d)128041620242832DaysMajor burnsSevere sepsisSkeletal traumaInfection010203040Elective surgeryPartial starvationTotal starvationFigure 2-23. The effect of injury sever-ity on nitrogen wasting. (Reproduced with permission from Long CL, Schaffel N, Geiger JW, et al: Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance, JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):452-456.)determine the severity of nutrient deficiencies or excess and to aid in predicting nutritional requirements. Pertinent information is obtained by determining the presence of weight loss, chronic illnesses, or dietary habits that influence the quantity and quality of food intake. Social habits predisposing to malnutrition and the use of medications that may influence food intake or urina-tion should also be investigated. Physical examination seeks to assess loss of muscle and adipose tissues, organ dysfunction, and subtle changes in skin, hair, or neuromuscular function reflecting frank or impending nutritional deficiency. Anthropo-metric data (i.e., weight change, skinfold thickness, and arm cir-cumference muscle area) and biochemical determinations (i.e., creatinine excretion, albumin level, prealbumin level, total lym-phocyte count, and transferrin level) may be used to substantiate the patient’s history and physical findings. This information, in conjunction with nutritional risk assessment scoring, can iden-tify patients who may benefit from early nutritional support.For critically ill and injured patients, validated scoring systems such as the Nutritional Risk Screening (NRS)245 or the Nutrition Risk in the Critically Ill (NUTRIC)246 score should be employed to make this determination and should be performed in conjunction with assessment of GI tract function and risk of aspiration. Appreciation for the stresses and natural history of the disease process, in combination with nutritional assess-ment, remains the basis for identifying patients in acute or anticipated need of nutritional support. Currently, specialized enteral nutrition can be avoided in patients who are deemed to be a low nutritional risk with low disease severity for up to one week. However, their nutritional status should be reassessed regularly.247A fundamental goal of nutritional support is to meet the energy requirements for essential metabolic processes and tissue repair. Failure to provide adequate nonprotein energy sources will lead to consumption of lean tissue stores. The requirement for energy may be measured by indirect calorimetry, which is the gold standard in hospitalized patients and is recommended for the critically ill.243 However, the use of indirect calorimetry, particularly in the critically ill patient, may not be available or feasible in this setting. Moreover, it may lead to an overestima-tion of caloric requirements, which has been associated with increased risk of infectious complications.248In the absence of indirect calorimetry, resting energy expenditure may also be estimated using a published predictive equation. Adjusted for the type of surgical stress, such equations are suitable for estimating energy requirements in the major-ity of hospitalized patients. Alternately, a simple weight-based equation of 25 to 30 kcal/kg (using dry or usual body weight) per day is appropriate with a low risk of overfeeding and is con-sistent with current recommendations from ASPEN (American Society of Parenteral and Enteral Nutrition) in the ICU setting.247 After trauma or sepsis, energy substrate demands are increased during the recovery phase and may necessitate greater nonpro-tein calories beyond calculated energy expenditure (Table 2-9). These additional nonprotein calories provided after injury are usually 1.2 to 2.0 times greater than calculated resting energy expenditure, depending on the type of injury. It is seldom appro-priate to exceed this level of nonprotein energy intake during the height of the catabolic phase. Currently, standard enteral nutri-tion delivers 49% to 53% of calories as carbohydrate and 29% to 30% of calories as fat, which is consistent with current recom-mendations. For parenteral nutrition, dextrose-containing stock solutions are prepared and available in different concentrations. The percentage of calories that is contributed by dextrose should be determined on a per-patient basis according to the severity of injury/illness and the estimated caloric needs. Lipid emul-sions can be included in the total mixture or be administered separately in 10% or 20% solutions with 1.1 kcal/ml and 2 kcal/ml, respectively.The second objective of nutritional support is to meet the substrate requirements for protein synthesis. Protein nutritional support is especially important for maintaining immune func-tion and lean body mass and is more closely linked to positive outcomes than total caloric intake. Although the mean protein requirement of healthy individuals is defined as 0.8 g/kg per day by the Food and Nutrition Board of the U.S. National Research Council, current recommendations for protein dosing exceed this Brunicardi_Ch02_p0027-p0082.indd 6701/03/19 6:50 PM 68BASIC CONSIDERATIONSPART Iamount (1.2–2 gm protein/kg per day), especially for the critically ill and injured. Higher protein intake seems to support improved nitrogen balance and high-protein nutritional support is currently recommended for patients with body mass index >30.247Vitamins and MineralsThe requirements for vitamins and essential trace minerals usu-ally can be met easily in the average patient with an uncom-plicated postoperative course. Therefore, vitamins usually are not given in the absence of preoperative deficiencies. Patients maintained on elemental diets or parenteral hyperalimenta-tion require complete vitamin and mineral supplementation. Commercial enteral diets contain varying amounts of essential minerals and vitamins. It is necessary to ensure that adequate replacement is available in the diet or by supplementation. Numerous commercial vitamin preparations are available for intravenous or intramuscular use, although most do not contain vitamin K and some do not contain vitamin B12 or folic acid. Supplemental trace minerals may be given intravenously via commercial preparations. Essential fatty acid supplementation also may be necessary, especially in patients with depletion of adipose stores.OverfeedingOverfeeding usually results from overestimation of caloric needs, as occurs when actual body weight is used to calculate the BEE in patient populations such as the critically ill with sig-nificant fluid overload and the obese. Indirect calorimetry can be used to quantify energy requirements but frequently overes-timates BEE by 10% to 15% in stressed patients, particularly if they are receiving ventilatory support. In these instances, esti-mated dry weight should be obtained from preinjury records or family members. Adjusted lean body weight also can be cal-culated. Overfeeding may contribute to clinical deterioration via increased oxygen consumption, increased carbon dioxide production and prolonged need for ventilatory support, fatty liver, suppression of leukocyte function, hyperglycemia, and increased risk of infection.ENTERAL NUTRITIONRationale for Enteral NutritionEnteral nutrition (EN) is preferred over parenteral nutrition (PN) based on the lower cost of enteral feeding and the associ-ated risks of the intravenous route, including vascular access complications.249 Of further consideration are the consequences of gastrointestinal tract disuse, which include diminished solu-ble IgA production and cytokine production as well as bacterial overgrowth and altered mucosal barrier function and immune defenses. In support of this idea, recent meta-analysis demon-strated a significant reduction in infectious complications in criti-cally ill or injured patients receiving EN when compared to PN as well as ICU length of stay.250 However, no increase in overall survival was noted. While EN is recommended as the first choice for nutritional support in patients who can tolerate it, a recent large trial from Europe comparing early isocaloric EN vs. PN in adult critically ill patients with shock did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications including intestinal ischemia.251The benefits of enteral feeding in patients undergoing elective surgery appear to be linked to their preoperative nutri-tional status. Historical studies comparing postoperative enteral and parenteral nutrition in patients undergoing gastrointestinal surgery have demonstrated reduced infectious complications and acute phase protein production in those fed by the enteral route. Yet prospectively randomized studies of patients with adequate nutritional status (albumin ≥4 g/dL) undergoing gas-trointestinal surgery demonstrate no differences in outcome and complications between those administered enteral nutrition and those given maintenance intravenous fluids alone in the initial days after surgery.252Early vs. Late FeedingCurrent recommendations support early enteral nutrition (within 48 hours) in critically ill patients, but with a caveat.253 Early “full nutrition” is likely to be harmful and is associated with a higher infection rate. The aim therefore is a caloric target below the actual energy expenditure, with the goal of providing >80% of estimated total energy goals gradually by 3 to 4 days. Early EN may be protective of the enteral epithelial barrier func-tion and help to maintain the diversity of the microbiome. While early caloric limitation seems to benefit the critically ill patient when compared to overfeeding, the restriction likely creates a significant shortfall in protein provision considering the low protein-to-calorie ratio of most enteral products.254In this regard, it is important to distinguish “permissive underfeeding” in which the total calories provided average 1500 kcal/d with 40 gm/d of protein from hypocaloric nutri-tion which has the same total calories with 140 gm/d protein. Hypocaloric nutrition is currently recommended for critically ill obese patients, but some investigators argue that this nutritional strategy may also benefit nonobese patients especially during Table 2-9Caloric adjustments above basal energy expenditure (BEE) in hypermetabolic conditionsCONDITIONkcal/kg PER DAYADJUSTMENT ABOVE BEEGRAMS OF PROTEIN/ kg PER DAYNONPROTEIN CALORIES: NITROGENNormal/moderate malnutrition25–301.11.0150:1Mild stress25–301.21.2150:1Moderate stress301.41.5120:1Severe stress30–351.62.090–120:1Burns35–402.02.590–100:1Brunicardi_Ch02_p0027-p0082.indd 6801/03/19 6:50 PM 69SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2the early acute period of critical illness.255 This recommendation excludes those patients whose pre-ICU weight loss indicate that they are malnourished.As the patient enters the recovery period of their illness, total protein and caloric requirements are likely to significantly increase. Based on our understanding of starvation, increased extrinsic delivery of both calories and protein are likely to be required during this period.For patients undergoing elective surgery, healthy patients without malnutrition who are undergoing uncomplicated sur-gery can tolerate 10 days of partial starvation (i.e., maintenance intravenous fluids only) before any clinically significant protein catabolism occurs. Earlier intervention is likely indicated for patients in whom preoperative protein-calorie malnutrition has been identified. Other clinical scenarios for which the benefits of enteral nutritional support have been substantiated include permanent neurologic impairment, oropharyngeal dysfunction, short-bowel syndrome, and bone marrow transplantation.Initiation of enteral nutrition should occur as soon as fea-sible after adequate resuscitation, most readily determined by adequate urine output. The presence of bowel sounds and the passage of flatus or stool are not absolute prerequisites for ini-tiation of enteral nutrition, but in the setting of gastroparesis feedings should be administered distal to the pylorus. Gastric residuals of 200 mL or more in a 4to 6-hour period or abdomi-nal distention requires cessation of feeding and adjustment of the infusion rate. Concomitant gastric decompression with dis-tal small-bowel feedings may be appropriate in certain patients such as closed-head injury patients with gastroparesis. There is no evidence to support withholding enteric feedings for patients after bowel resection or for those with low-output enterocutane-ous fistulas of <500 mL/d. In fact, a recent systematic review of studies of early enteral feeding (within 24 hours of gastro-intestinal surgery) showed no effect on anastomotic leak and a reduction in mortality. Early enteral feeding is also associated in reduced incidence of fistula formation in patients with open abdomen. Enteral feeding should also be offered to patients with short-bowel syndrome or clinical malabsorption, but necessary calories, essential minerals, and vitamins should be supple-mented using parenteral modalities.Intermittent vs. Continuous Enteral FeedingEnteral nutrition can be administered either continuously or intermittently; however, the standard choice for critically injured adults is continuous enteral feeding (CEF) due to the lower complication rates.247 Data also suggest that CEF may promote protein anabolism by inhibiting protein breakdown.256Enteral FormulasFor most critically ill patients, the choice of enteral formula will be determined by a number of factors and will include a clinical judgment as to the “best fit” for the patients’ needs. In general, feeding formulas to consider are GI tolerance-promot-ing, anti-inflammatory, immune-modulating, organ support-ive, and standard enteral nutrition. In addition, guidelines from professional nutrition societies identify certain populations of patients who can benefit from formulations with specific pharmaconutrients.257 For many others, each physician must use his or her own clinical judgment about what formula will best meet the patient’s needs.The functional status of the gastrointestinal tract deter-mines the type of enteral solutions to be used. Patients with an intact gastrointestinal tract will tolerate complex solutions, but patients who have not been fed via the gastrointestinal tract for prolonged periods are less likely to tolerate complex carbohy-drates. In those patients who are having difficulty tolerating standard enteral formulas, peptideand medium-chain triglyc-eride-based formulas with prebiotics can lessen GI tolerance problems. Additionally, in patients with demonstrated malab-sorption issues, such as with inflammatory bowel diseases or short bowel syndrome, current guidelines endorse the provision of hydrolyzed protein formulas to improve absorption. Guide-lines have not yet been made with regard to the fiber content of enteral formulas. However, recent evidence indicates that supplementation of enteral formulas with soluble dietary fiber may be beneficial for improving stool consistency in patients suffering from diarrhea.Factors that influence the choice of enteral formula also include the extent of organ dysfunction (e.g., renal, pulmonary, hepatic, or gastrointestinal), the nutrients needed to restore optimal function and healing, and the cost of specific products. There are still no conclusive data to recommend one category of product over another, and nutritional support committees typically develop the most cost-efficient enteral formulary for the most commonly encountered disease categories within the institution.As discussed extensively in the first sections of this chap-ter, surgery and trauma result in a significant “sterile” inflamma-tory response that impacts for the innate and adaptive immune systems. The provision of immune-modulating nutrients, termed “immunonutrition,” is one mechanism by which the immune response can be supported and an attempt made to lower infec-tious risk. At present, the best studied of immune-nutrients are glutamine, arginine, and omega-3 PUFAs.“Immunonutrients.” As discussed extensively in the first sections of this chapter, surgery and trauma result in a sig-nificant “sterile” inflammatory response that impacts both the innate and adaptive immune systems. The provision of immune-modulating nutrients, termed “immunonutrition,” is one mecha-nism by which the immune response can be supported and an attempt made to lower infectious risk. Studies have shown that a variety of nutrients, including amino acids (glutamine and arginine); lipids (omega-3 PUFAs); and micronutrients (e.g., vitamin C and selenium) can provide support to the immune system. While current evidence does not support their use uni-versally, benefit may exist for individual patients.258 At present, the best studied of immune-nutrients are glutamine, arginine, and omega-3 PUFAs.Glutamine is the most abundant amino acid in the human body, comprising nearly two thirds of the free intracel-lular amino acid pool. Considered a nonessential amino acid, glutamine is a necessary substrate for nucleotide synthesis in most dividing cells and hence provides a major fuel source for enterocytes. It also serves as an important fuel source for immu-nocytes. During stress states, peripheral glutamine stores are rapidly depleted, and the amino acid is preferentially shunted as a fuel source toward the visceral organs and tumors, respectively.259 These situations create, at least experimentally, a glutamine-depleted environment with potential immune consequences, thus generating interest in both enteral and parenteral glutamine supplementation. However, recently reported data from two large randomized controlled clinical trials in which critically ill patients received glutamine supplementation demonstrated Brunicardi_Ch02_p0027-p0082.indd 6901/03/19 6:50 PM 70BASIC CONSIDERATIONSPART Iincreased 6-month mortality in the patients who received glutamine.260 Therefore, glutamine supplementation in the criti-cally ill patient is not currently recommended.247Arginine, also a nonessential amino acid in healthy sub-jects, first attracted attention for its immunoenhancing proper-ties, wound-healing benefits, and association with improved survival in animal models of sepsis and injury.261 However, arginine can be metabolized to nitric oxide, via nitric oxide synthase (NOS). If NOS is upregulated, with arginine as avail-able substrate, NO production can also increase, which can have a negative impact on the critically ill patient. As with glutamine, the benefits of experimental arginine supplementa-tion during stress states are diverse. In clinical studies involv-ing critically ill and injured patients and patients who have undergone surgery for certain malignancies, enteral adminis-tration of arginine has led to net nitrogen retention and pro-tein synthesis, whereas isonitrogenous diets have not. Some of these studies also provide in vitro evidence of enhanced immunocyte function. The clinical utility of arginine supple-mentation in improving overall patient outcome remains an area of investigation.262As previously discussed, omega-3 polyunsaturated fatty acids (PUFAs, canola oil, or fish oil) displaces omega-6 fatty acids in cell membranes, which theoretically reduces the pro-inflammatory response from prostaglandin production. Hence, there has been significant interest in reducing the ratio of omega-6 to omega-3. The data regarding supplementation of enteral feedings with fish oil as a source for omega-3 PUFAs has been mixed, however, with no demonstrated improvement in respiratory complications in severe trauma patients and pos-sible benefits in patients with mild sepsis.166Standard Polymeric Formulas. Most polymeric formulas provide a caloric density from 1 to 2 kcal/mL, and approxi-mately 1500 to 1800 mL are required to meet daily require-ments. These compositions provide baseline carbohydrates, protein, electrolytes, water, fat, and fat-soluble vitamins (some do not have vitamin K). These contain no fiber bulk and there-fore leave minimum residue. These solutions usually are consid-ered to be the standard or first-line formulas for stable patients with an intact gastrointestinal tract. Normal digestive function is required for this formula.Fiber-Containing Formulas. Isotonic formulas with fiber contain soluble and insoluble fiber, which is most often soy based. Physiologically, fiber-based solutions delay intestinal transit time and may reduce the incidence of diarrhea compared with nonfiber solutions. It is most beneficial in this regard in patients who have a high number of loose stools.263 Fiber stimu-lates pancreatic lipase activity and is degraded by gut bacteria into short-chain fatty acids (SCFA), an important fuel for colo-nocytes. Recent data have also demonstrated the expression of SCFA receptors on leukocytes, suggesting that fiber fermenta-tion by the colonic microbiome may indirectly regulate immune cell function. Another potential plus of fiber-containing formu-las is the inclusion of prebiotic fibers with the goal of positively impacting bacterial targets in the gut as well as gut barrier func-tion. While there has been limited research in this area to deter-mine the possible impact on clinical outcomes, addition of these fermentable soluble fiber additives is something that should be considered in the ICU patient as a measure that can aid in the maintenance or restoration of a healthy balance of commensal gut bacteria.Immune-Enhancing Formulas. Immune-enhancing formulas are fortified with special nutrients that are purported to enhance various aspects of immune or solid organ function as previously discussed. Such additives include glutamine, arginine, omega-3 fatty acids, and nucleotides.264 Although several trials have pro-posed that one or more of these additives reduce surgical com-plications and improve outcome, these results have not been uniformly corroborated by other trials. The Canadian Clinical Practice Guidelines currently do not recommend the addition of arginine supplements for critically ill patients due to the poten-tial for harm when used in septic patients.265 Omega-3 PUFAs results from the EDEN-Omega study demonstrated that twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.266 Glutamine supplemen-tation should be strictly guided by the individual patient condi-tion for the reasons discussed previously.Calorie-Dense Formulas. The primary distinction of calorie-dense formulas is a greater caloric value for the same volume. Most commercial products of this variety provide 1.5 to 2 kcal/mL and therefore are suitable for patients requiring fluid restriction or those unable to tolerate large-volume infusions. As expected, these solutions have higher osmolality than standard formulas and are suitable for intragastric feedings.High-Protein Formulas/Bariatric Formulas. High-protein formulas are available in isotonic and nonisotonic mixtures and are proposed for critically ill or trauma patients with high protein requirements. These formulas have nonprotein-calorie to nitrogen ratios between 80:1 and 120:1. While some obser-vational studies show improved outcomes with higher protein intakes in critically ill patients, there is limited data from ran-domized trials that prevents making strong conclusions about the dose of protein in critically ill patients.As discussed previously, there has been support for high-protein, hypocaloric feeding in obese patients. As such, enteral formulas termed “bariatric formulas” have been developed. As an example, one product has 1 kcal/mL of formula, with 37% of the calories coming from protein. As the evidence for high-protein, hypocaloric feeding is low grade, it is unclear whether clinical outcomes with respect to survival and infectious com-plications is improved, and more data is required for definitive recommendation.267Elemental Formulas. Elemental formulas contain predigested nutrients and provide proteins in the form of small peptides. Complex carbohydrates are limited, and fat content, in the form of MCTs and LCTs, is minimal. The primary advantage of such a formula is ease of absorption, but the inherent scarcity of fat, associated vitamins, and trace elements limits its long-term use as a primary source of nutrients. Due to its high osmolarity, dilution, or slow infusion rates usually are necessary, particu-larly in critically ill patients. These formulas have been used frequently in patients with malabsorption, gut impairment, and pancreatitis, but their cost is significantly higher than that of standard formulas. To date, there has been no evidence of their benefit in routine use.Renal-Failure Formulas. The primary benefits of renal for-mulas are the lower fluid volume and concentrations of potas-sium, phosphorus, and magnesium needed to meet daily calorie requirements. This type of formulation almost exclusively Brunicardi_Ch02_p0027-p0082.indd 7001/03/19 6:50 PM 71SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2contains essential amino acids and has a high nonprotein-calorie to nitrogen ratio; however, it does not contain trace elements or vitamins. Current guidelines suggest that patients with chronic kidney disease (CKD) who require enteral feeding should be placed on “standard enteral formulations.” Moreover, standard recommendations for both protein and calories support are also recommended.263Hepatic-Failure Formulas. Close to 50% of the proteins in hepatic-failure formulas are branched-chain amino acids (e.g., leucine, isoleucine, and valine). The goal of such a formula is to reduce aromatic amino acid levels and increase the levels of branched-chain amino acids, which can potentially reverse encephalopathy in patients with hepatic failure.268 The use of these formulas is controversial, however, because no clear bene-fits have been proven by clinical trials. Protein restriction should be avoided in patients with end-stage liver disease because such patients have significant protein energy malnutrition that pre-disposes them to additional morbidity and mortality.269 Similar to patients with CKD, standard formulations are recommended initially unless the patient develops hepatic encephalopathy that is refractory to standard treatment. With regard to protein sup-plementation, data indicate that providing 1.5 gm protein/kg per day improves clinical outcomes in these patients.270Access for Enteral Nutritional SupportThe available techniques and repertoire for enteral access have provided multiple options for feeding the gut. Presently used methods and preferred indications are summarized in Table 2-10.271Nasoenteric Tubes. Nasogastric feeding should be reserved for those with intact mentation and protective laryngeal reflexes to minimize risks of aspiration. Even in intubated patients, naso-gastric feedings often can be recovered from tracheal suction. Nasojejunal feedings are associated with fewer pulmonary complications including risk of pneumonia, but access past the pylorus requires greater effort to accomplish. Therefore, routine use of small bowel feedings is preferred in units where small bowel access is readily feasible. Where there may be difficul-ties obtaining access, small bowel feedings may be considered a priority for those patients at high risk for intolerance to enteral nutrition (e.g., high gastric residuals).Blind insertion of nasogastric feeding tubes is fraught with misplacement, and air instillation with auscultation is inaccurate for ascertaining proper positioning. Radiographic confirmation is usually required to verify the position of the nasogastric feed-ing tube.Several methods have been recommended for the passage of nasoenteric feeding tubes into the small bowel, including use of prokinetic agents, right lateral decubitus positioning, gastric insufflation, tube angulation, and application of clock-wise torque. However, the successful placement of feeding tubes by these methods is highly variable and operator depen-dent. Furthermore, it is time consuming, and success rates for intubation past the duodenum into the jejunum by these methods are <20%. Fluoroscopy-guided intubation past the pylorus has a >90% success rate, and more than half of these intubations result in jejunal placement. Similarly, endoscopy-guided placement past the pylorus has high success rates, but attempts to advance the tube beyond the second portion of the duodenum using a standard gastroduodenoscope is unlikely to be successful.Table 2-10Options for enteral feeding accessACCESS OPTIONCOMMENTSNasogastric tubeShort-term use only; aspiration risks; nasopharyngeal trauma; frequent dislodgmentNasoduodenal/nasojejunal tubeShort-term use; lower aspiration risks in jejunum; placement challenges (radiographic assistance often necessary)Percutaneous endoscopic gastrostomy (PEG)Endoscopy skills required; may be used for gastric decompression or bolus feeds; aspiration risks; can last 12–24 mo; slightly higher complication rates with placement and site leaksSurgical gastrostomyRequires general anesthesia and small laparotomy; procedure may allow placement of extended duodenal/jejunal feeding ports; laparoscopic placement possibleFluoroscopic gastrostomyBlind placement using needle and T-prongs to anchor to stomach; can thread smaller catheter through gastrostomy into duodenum/jejunum under fluoroscopyPEG-jejunal tubeJejunal placement with regular endoscope is operator dependent; jejunal tube often dislodges retrograde; two-stage procedure with PEG placement, followed by fluoroscopic conversion with jejunal feeding tube through PEGDirect percutaneous endoscopic jejunostomy (DPEJ)Direct endoscopic tube placement with enteroscope; placement challenges; greater injury risksSurgical jejunostomyCommonly carried out during laparotomy; general anesthesia; laparoscopic placement usually requires assistant to thread catheter; laparoscopy offers direct visualization of catheter placementFluoroscopic jejunostomyDifficult approach with injury risks; not commonly doneSmall-bowel feeding is more reliable for delivering nutri-tion than nasogastric feeding. Furthermore, the risks of aspi-ration pneumonia can be reduced by 25% with small-bowel feeding compared with nasogastric feeding. The disadvantages of the use of nasoenteric feeding tubes are clogging, kinking, and inadvertent displacement or removal of the tube as well as nasopharyngeal complications. If nasoenteric feeding will be required for longer than 30 days, access should be converted to a percutaneous one.272Brunicardi_Ch02_p0027-p0082.indd 7101/03/19 6:50 PM 72BASIC CONSIDERATIONSPART IPercutaneous Endoscopic Gastrostomy. The most common indications for percutaneous endoscopic gastrostomy (PEG) include impaired swallowing mechanisms, oropharyngeal or esophageal obstruction, and major facial trauma. It is frequently used for debilitated patients requiring caloric supplementation, hydration, or frequent medication dosing. It is also appropriate for patients requiring passive gastric decompression. Relative contraindications for PEG placement include ascites, coagu-lopathy, gastric varices, gastric neoplasm, and lack of a suitable abdominal site. Most tubes are 18F to 28F in size and may be used for 12 to 24 months.Identification of the PEG site requires endoscopic transil-lumination of the anterior stomach against the abdominal wall. A 14-gauge angiocatheter is passed through the abdominal wall into the fully insufflated stomach. A guidewire is threaded through the angiocatheter, grasped by snares or forceps, and pulled out through the mouth. The tapered end of the PEG tube is secured to the guidewire and is pulled into position out of the abdominal wall. The PEG tube is secured without tension against the abdominal wall, and many have reported using the tube within hours of placement. It has been the practice of some to connect the PEG tube to a drainage bag for passive decom-pression for 24 hours before use, allowing more time for the stomach to seal against the peritoneum.If endoscopy is not available or technical obstacles pre-clude PEG placement, the interventional radiologist can attempt the procedure percutaneously under fluoroscopic guidance by first insufflating the stomach against the abdominal wall with a nasogastric tube. If this also is unsuccessful, surgical gas-trostomy tube placement can be considered, particularly with minimally invasive methods. When surgery is contemplated, it may be wise to consider directly accessing the small bowel for nutrition delivery.Although PEG tubes enhance nutritional delivery, facili-tate nursing care, and are superior to nasogastric tubes, serious complications occur in approximately 3% of patients. These complications include wound infection, necrotizing fasciitis, peritonitis, aspiration, leaks, dislodgment, bowel perforation, enteric fistulas, bleeding, and aspiration pneumonia.273 For patients with significant gastroparesis or gastric outlet obstruc-tion, feedings through PEG tubes are hazardous. In such cases, the PEG tube can be used for decompression and allow access for converting the PEG tube to a transpyloric feeding tube.Percutaneous Endoscopic Gastrostomy-Jejunostomy and Direct Percutaneous Endoscopic Jejunostomy. Although gastric bolus feedings are more physiologic, patients who can-not tolerate gastric feedings or who have significant aspiration risks should be fed directly past the pylorus. In the percutane-ous endoscopic gastrostomy-jejunostomy (PEG-J) method, a 9F to 12F tube is passed through an existing PEG tube, past the pylorus, and into the duodenum. This can be achieved by endoscopic or fluoroscopic guidance. With weighted catheter tips and guidewires, the tube can be further advanced past the ligament of Treitz. However, the incidence of long-term PEG-J tube malfunction has been reported to be >50% as a result of ret-rograde tube migration into the stomach, kinking, or clogging.Direct percutaneous endoscopic jejunostomy (DPEJ) tube placement uses the same techniques as PEG tube placement but requires an enteroscope or colonoscope to reach the jejunum. DPEJ tube malfunctions are probably less frequent than PEG-J tube malfunctions, and kinking or clogging is usually averted by placement of larger-caliber catheters. The success rate of DPEJ tube placement is variable because of the complexity of endo-scopic skills required to locate a suitable jejunal site. In such cases where endoscopic means are not feasible, surgical jeju-nostomy tube placement is more appropriate, especially when minimally invasive techniques are available.Surgical Gastrostomy and Jejunostomy. For a patient undergoing complex abdominal or trauma surgery, thought should be given during surgery to the possible routes for sub-sequent nutritional support because laparotomy affords direct access to the stomach or small bowel. The only absolute contra-indication to feeding jejunostomy is distal intestinal obstruction. Relative contraindications include severe edema of the intestinal wall, radiation enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, and bowel ischemia. Needle-catheter jejunostomies also can be done with a minimal learning curve. The biggest drawback usually is possible clogging and knotting of the 6F catheter.274Abdominal distention and cramps are common adverse effects of early enteral nutrition. Some have also reported impaired respiratory mechanics as a result of intolerance to enteral feedings. These are mostly correctable by temporarily discontinuing feedings and resuming at a lower infusion rate.Pneumatosis intestinalis and small-bowel necrosis are infrequent but significant problems in patients receiving jejunal tube feedings. Several contributing factors have been proposed, including the hyperosmolarity of enteral solutions, bacte-rial overgrowth, fermentation, and accumulation of metabolic breakdown products. The common pathophysiology is believed to be bowel distention and consequent reduction in bowel wall perfusion. Risk factors for these complications include cardio-genic and circulatory shock, vasopressor use, diabetes mellitus, and chronic obstructive pulmonary disease. Therefore, enteral feedings in the critically ill patient should be delayed until adequate resuscitation has been achieved. As alternatives, dilut-ing standard enteral formula, delaying the progression to goal infusion rates, or using monomeric solutions with low osmolal-ity requiring less digestion by the gastrointestinal tract all have been successfully used.PARENTERAL NUTRITIONParenteral nutrition is the continuous infusion of a hyperosmo-lar solution containing carbohydrates, proteins, fat, and other necessary nutrients through an indwelling catheter inserted into the superior vena cava. To obtain the maximum benefit, the calorie to protein ratio must be adequate (at least 100 to 150 kcal/g nitrogen), and both carbohydrates and proteins must be infused simultaneously. When the sources of calories and nitrogen are given at different times, there is a significant decrease in nitrogen utilization. These nutrients can be given in quantities considerably greater than the basic caloric and nitro-gen requirements, and this method has proved to be highly suc-cessful in achieving growth and development, positive nitrogen balance, and weight gain in a variety of clinical situations. Clini-cal trials and meta-analysis of studies of parenteral feeding in the perioperative period have suggested that preoperative nutri-tional support may benefit some surgical patients, particularly those with extensive malnutrition.Historically, short-term use of parenteral nutrition (PN) in critically ill patients (i.e., duration of <7 days) when enteral Brunicardi_Ch02_p0027-p0082.indd 7201/03/19 6:50 PM 73SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2nutrition (EN) may have been instituted was associated with higher rates of infectious complications. It appears, however, that the increased mortality associated with PN may have been associated with excessive caloric delivery. More recent data have shown no mortality difference between EN and PN when caloric delivery was reduced and matched. A recent meta-analysis confirmed this result and noted no increase in infectious complications.250 That being said, the risk/benefit for PN in the ICU is much smaller and in a patient with low nutritional risk provides little benefit over the first week of hospitalization in the ICU.Rationale for Parenteral NutritionThe principal indications for parenteral nutrition are malnu-trition, sepsis, or surgical or traumatic injury in seriously ill patients for whom use of the gastrointestinal tract for feedings is not possible.247 Parenteral nutrition should not be used based solely on the medical diagnosis or disease state. Rather, PN use is recommended for those critically ill or injured patients who are at high nutritional risk, when EN is not possible. Alter-nately, PN can also be used to supplement EN after 1 week of use if use of EN is unable to meet >60% of energy and protein requirements.247The safe and successful use of parenteral nutrition requires proper selection of patients with specific nutritional needs, expe-rience with the technique, and an awareness of the associated complications. In patients with significant malnutrition, paren-teral nutrition can rapidly improve nitrogen balance, which may enhance immune function. Routine postoperative use of paren-teral nutrition is not shown to have clinical benefit and may be associated with a significant increase in complication rate. As with enteral nutrition, the fundamental goals are to provide suf-ficient calories and nitrogen substrate to promote tissue repair and to maintain the integrity or growth of lean tissue mass.Total Parenteral NutritionTotal parenteral nutrition (TPN), also referred to as central parenteral nutrition, requires access to a large-diameter vein to deliver the entire nutritional requirements of the individual. Dextrose content of the solution is high (15%–25%), and all other macronutrients and micronutrients are deliverable by this route.Peripheral Parenteral NutritionThe lower osmolarity of the solution used for peripheral par-enteral nutrition (PPN), secondary to reduced levels of dex-trose (5% to 10%) and protein (3%), allows its administration via peripheral veins. Some nutrients cannot be supplemented because they cannot be concentrated into small volumes. There-fore, PPN is not appropriate for repleting patients with severe malnutrition. It can be considered if central routes are not avail-able or if supplemental nutritional support is required. Typi-cally, PPN is used for short periods (<2 weeks). Beyond this time, TPN should be instituted.Initiation of Parenteral NutritionThe basic solution for parenteral nutrition contains a final con-centration of 15% to 25% dextrose and 3% to 5% crystalline amino acids. The solutions usually are prepared in sterile condi-tions in the pharmacy from commercially available kits contain-ing the component solutions and transfer apparatus. Preparation in the pharmacy under laminar flow hoods reduces the incidence of bacterial contamination of the solution. Proper preparation with suitable quality control is absolutely essential to avoid sep-tic complications.The proper provision of electrolytes and amino acids must take into account routes of fluid and electrolyte loss, renal function, metabolic rate, cardiac function, and the under-lying disease state.Intravenous vitamin preparations also should be added to parenteral formulas. Vitamin deficiencies are rare occurrences if such preparations are used. In addition, because vitamin K is not part of any commercially prepared vitamin solution, it should be supplemented on a weekly basis. During prolonged parenteral nutrition with fat-free solutions, essential fatty acid deficiency may become clinically apparent and manifests as dry, scaly der-matitis and loss of hair. The syndrome may be prevented by periodic infusion of a fat emulsion at a rate equivalent to 10% to 15% of total calories. Essential trace minerals may be required after prolonged TPN and may be supplied by direct addition of commercial preparations. The most frequent presentation of trace mineral deficiencies is the eczematoid rash develop-ing both diffusely and at intertriginous areas in zinc-deficient patients. Other rare trace mineral deficiencies include a micro-cytic anemia associated with copper deficiency, and glucose intolerance presumably related to chromium deficiency. The latter complications are seldom seen except in patients receiving parenteral nutrition for extended periods. The daily administra-tion of commercially available trace mineral supplements will obviate most such problems.Depending on fluid and nitrogen tolerance, parenteral nutrition solutions generally can be increased over 2 to 3 days toward the desired infusion rate. Current recommendations sug-gest that hypocaloric nutrition (high protein with lower caloric dosing) be considered in the critically ill or injured over the first week in the ICU. The suggested target dose is <20 kcal/kg per day or <80% of estimated caloric needs with adequate pro-tein (>1.2 g/kg per day). This strategy is suggested to minimize risk of both hyperglycemia and insulin resistance, which may reduce infectious complications. Insulin may be supplemented as necessary to ensure glucose tolerance, with a targeted blood glucose range of 140 or 150 to 180 mg/dL for the general ICU population.247 Administration of additional intravenous fluids and electrolytes may occasionally be necessary in patients with persistently high fluid losses.The patient should be carefully monitored for development of electrolyte, volume, acid-base, and septic complications. Vital signs and urinary output should be measured regularly, and the patient should be weighed regularly. Frequent adjust-ments of the volume and composition of the solutions are neces-sary during the course of therapy. Samples for measurement of electrolytes are drawn daily until levels are stable and every 2 or 3 days thereafter. Blood counts, blood urea nitrogen level, lev-els of liver function indicators, and phosphate and magnesium levels are determined at least weekly.The urine or capillary blood glucose level is checked every 6 hours, and serum glucose concentration is checked at least once daily during the first few days of the infusion and at fre-quent intervals thereafter. Relative glucose intolerance, which often manifests as glycosuria, may occur after initiation of par-enteral nutrition. If blood glucose levels remain elevated or gly-cosuria persists, the dextrose concentration may be decreased, the infusion rate slowed, or regular insulin added to each bottle. The rise in blood glucose concentration observed after initiating parenteral nutrition may be temporary, as the normal pancreas Brunicardi_Ch02_p0027-p0082.indd 7301/03/19 6:50 PM 74BASIC CONSIDERATIONSPART Iincreases its output of insulin in response to the continuous car-bohydrate infusion. In patients with diabetes mellitus, additional insulin may be required.Potassium is essential to achieve positive nitrogen bal-ance and replace depleted intracellular stores. In addition, a significant shift of potassium ion from the extracellular to the intracellular space may take place because of the large glucose infusion, with resultant hypokalemia, metabolic alkalosis, and poor glucose utilization. In some cases, as much as 240 mEq of potassium ion daily may be required. Hypokalemia may cause glycosuria, which would be treated with potassium, not insulin. Thus, before giving insulin, the serum potassium level must be checked to avoid exacerbating the hypokalemia.Patients with insulin-dependent diabetes mellitus may exhibit wide fluctuations in blood glucose levels while receiving parenteral nutrition. This may require protocol-driven intrave-nous insulin therapy. In addition, partial replacement of dex-trose calories with lipid emulsions may alleviate these problems in selected patients.Lipid emulsions derived from soybean or safflower oils are widely used as an adjunctive nutrient to prevent the development of essential fatty acid deficiency, although recent data support reducing the overall omega-6 PUFA load in favor of omega-3 PUFA or MCT. Current recommendations are to limit intrave-nous fat emulsion infusion over the first week of hospitalization to a maximum of 100 g per week delivered in two divided doses. This is based on standard emulsions that are soy-based. As data is acquired for omega-3 PUFAs, including fish-oil or olive-oil based emulsions, these recommendations may alter.The delivery of parenteral nutrition requires central intra-venous access. Temporary or short-term access can be achieved with a 16-gauge percutaneous catheter inserted into a subclavian or internal jugular vein and threaded into the superior vena cava. More permanent access with the intention of providing long-term or home parenteral nutrition can be achieved by placement of a catheter with a subcutaneous port for access by tunneling a catheter with a substantial subcutaneous length or threading a long catheter through the basilic or cephalic vein into the supe-rior vena cava.Complications of Parenteral NutritionTechnical Complications. One of the more common and seri-ous complications associated with long-term parenteral feed-ing is sepsis secondary to contamination of the central venous catheter. Contamination of solutions should also be considered, but it is rare when proper pharmacy protocols have been fol-lowed. Central line-associated blood stream infections (CLA-BSI) occur as a consequence of hematogenous seeding of the cath-eter with bacteria. One of the earliest signs of systemic sepsis from CVA-BSI may be the sudden development of glucose intolerance (with or without temperature increase) in a patient who previously has been maintained on parenteral alimen-tation without difficulty. When this occurs, or if high fever (> 38.5°C [101.3°F]) develops without obvious cause, a dili-gent search for a potential septic focus is indicated. Other causes of fever should also be investigated. If fever persists, the infu-sion catheter should be removed and submitted for culture. If the catheter is the cause of the fever, removal of the infectious source is usually followed by rapid defervescence. Some centers are now replacing catheters considered at low risk for infec-tion over a guidewire. However, if blood cultures are positive and the catheter tip is also positive, then the catheter should be removed and placed in a new site. Should evidence of infec-tion persist over 24 to 48 hours without a definable source, the catheter should be replaced into the opposite subclavian vein or into one of the internal jugular veins, and the infusion should be restarted.275The use of multilumen catheters may be associated with a slightly increased risk of infection. This is most likely asso-ciated with greater catheter manipulation and intensive use. The rate of catheter infection is highest for those placed in the femoral vein, lower for those in the jugular vein, and lowest for those in the subclavian vein. When catheters are indwelling for <3 days, infection risks are negligible. If indwelling time is 3 to 7 days, the infection risk is 3% to 5%. Indwelling times of >7 days are associated with a catheter infection risk of 5% to 10%. Strict adherence to barrier precautions also reduces the rate of infection as can the implementation of procedure checklists to ensure compliance with evidence-based guidelines shown to reduce infectious risk.276Other complications related to catheter placement include the development of pneumothorax, hemothorax, hydrothorax, subclavian artery injury, thoracic duct injury, cardiac arrhyth-mia, air embolism, catheter embolism, and cardiac perforation with tamponade. All of these complications may be avoided by strict adherence to proper techniques. Further, the use of ultra-sonographic guidance during CV line placement has been dem-onstrated to significantly decrease the failure rate, complication rate, and number of attempts required for successful access.277Metabolic Complications. Hyperglycemia may develop with normal rates of infusion in patients with impaired glucose toler-ance or in any patient if the hypertonic solutions are adminis-tered too rapidly. This is a particularly common complication in patients with latent diabetes and in patients subjected to severe surgical stress or trauma. Treatment of the condition consists of volume replacement with correction of electrolyte abnormali-ties and the administration of insulin. This complication can be avoided with careful attention to daily fluid balance and frequent monitoring of blood glucose levels and serum electrolytes.Increasing experience has emphasized the importance of not overfeeding the parenterally nourished patient. This is particularly true for the depleted patient in whom excess calo-rie infusion may result in carbon dioxide retention and respi-ratory insufficiency. In addition, excess feeding also has been related to the development of hepatic steatosis or marked gly-cogen deposition in selected patients. Cholestasis and forma-tion of gallstones are common in patients receiving long-term parenteral nutrition. Mild but transient abnormalities of serum transaminase, alkaline phosphatase, and bilirubin levels occur in many parenterally nourished patients. Failure of the liver enzymes to plateau or return to normal over 7 to 14 days should suggest another etiology.Intestinal Atrophy. Lack of intestinal stimulation is associ-ated with intestinal mucosal atrophy, diminished villous height, bacterial overgrowth, reduced lymphoid tissue size, reduced immunoglobulin A production, and impaired gut immunity. The full clinical implications of these changes are not well real-ized, although bacterial translocation has been demonstrated in animal models. The most efficacious method to prevent these changes is to provide at least some nutrients enterally. In patients requiring TPN, it may be feasible to infuse small amounts of feedings via the gastrointestinal tract.Brunicardi_Ch02_p0027-p0082.indd 7401/03/19 6:50 PM 75SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2REFERENCESEntries highlighted in bright blue are key references. 1. Horiguchi H, Loftus TJ, Hawkins RB, et al. Innate immu-nity in the persistent inflammation, immunosuppression, and catabolism syndrome and its implications for therapy. Front Immunol. 2018;9:595. doi: 10.3389/fimmu.2018.00595 2. Minei JP, Cuschieri J, Sperry J, et al. The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock. Crit Care Med. 2012;40(4):1129-1135. doi: 10.1097/CCM.0b013e3182376e9f 3. 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Introduction 83Body Fluids 83Total Body Water / 83Fluid Compartments / 83Composition of Fluid Compartments / 83Osmotic Pressure / 84Body Fluid Changes 85Normal Exchange of Fluid and Electrolytes / 85Classification of Body Fluid Changes / 85Disturbances in Fluid Balance / 85Volume Control / 86Concentration Changes / 86Composition Changes: Etiology and Diagnosis / 88Acid-Base Balance / 91Metabolic Derangements / 91Fluid and Electrolyte Therapy 93Parenteral Solutions / 93Alternative Resuscitative Fluids / 94Correction of Life-Threatening Electrolyte Abnormalities / 94Preoperative Fluid Therapy / 96Intraoperative Fluid Therapy / 97Postoperative Fluid Therapy / 97Fluid Management in Enhanced Recovery After Surgery (ERAS) Pathways / 97Special Considerations for the Postoperative Patient / 98Electrolyte Abnormalities in Specific  Surgical Patients 98Neurologic Patients / 98Malnourished Patients: Refeeding Syndrome / 98Acute Renal Failure Patients / 99Cancer Patients / 99Fluid and Electrolyte Management of the Surgical PatientMatthew D. Neal 3chapterINTRODUCTIONFluid and electrolyte management is paramount to the care of the surgical patient. Changes in both fluid volume and electro-lyte composition occur preoperatively, intraoperatively, and postoperatively, as well as in response to trauma and sepsis. The sections that follow review the normal anatomy of body fluids, electrolyte composition and concentration abnormalities and treatments, common metabolic derangements, and alternative resuscitative fluids. These concepts are then discussed in relationship to management of specific surgical patients and their commonly encountered fluid and electrolyte abnormalities.BODY FLUIDSTotal Body WaterWater constitutes approximately 50% to 60% of total body weight. The relationship between total body weight and total body water (TBW) is relatively constant for an individual and is primarily a reflection of body fat. Lean tissues such as muscle and solid organs have higher water content than fat and bone. As a result, young, lean males have a higher proportion of body weight as water than elderly or obese individuals. In an average young adult male, TBW accounts for 60% of total body weight, whereas in an average young adult female, it is 50%.1 The lower percent-age of TBW in females correlates with a higher percentage of adipose tissue and lower percentage of muscle mass in most. Estimates of percentage of TBW should be adjusted downward approximately 10% to 20% for obese individuals and upward by 10% for malnourished individuals. The highest percentage of TBW is found in newborns, with approximately 80% of their total body weight comprised of water. This decreases to approximately 65% by 1 year of age and thereafter remains fairly constant.1Fluid CompartmentsTBW is divided into three functional fluid compartments: plasma, extravascular interstitial fluid, and intracellular fluid (Fig. 3-1). The extracellular fluids (ECF), plasma, and intersti-tial fluid together compose about one-third of the TBW, and the intracellular compartment composes the remaining two thirds. The extracellular water composes 20% of the total body weight and is divided between plasma (5% of body weight) and inter-stitial fluid (15% of body weight). Intracellular water makes up approximately 40% of an individual’s total body weight, with the largest proportion in the skeletal muscle mass.Composition of Fluid CompartmentsThe normal chemical composition of the body fluid compart-ments is shown in Fig. 3-2. The ECF compartment is bal-anced between sodium, the principal cation, and chloride and bicarbonate, the principal anions. The intracellular fluid compartment is composed primarily of the cations potassium and magnesium, the anions phosphate and sulfate, and proteins. The concentration gradient between compartments is maintained by adenosine triphosphate–driven sodium-potassium pumps located within the cell membranes. The composition of the plasma and interstitial fluid differs only slightly in ionic compo-sition. The slightly higher protein content (organic anions) in plasma results in a higher plasma cation composition relative to the interstitial fluid, as explained by the Gibbs-Donnan equilib-rium equation. Proteins add to the osmolality of the plasma and contribute to the balance of forces that determine fluid balance across the capillary endothelium. Although the movement of ions and proteins between the various fluid compartments is restricted, water is freely diffusible. Water is distributed evenly throughout all fluid compartments of the body so that a given volume of water increases the volume of any one compartment 2Brunicardi_Ch03_p0083-p0102.indd 8308/12/18 10:07 AM 84Figure 3-1. Functional body fluid compartments. TBW = total body water.Key Points1 Proper management of fluid and electrolytes facilitates cru-cial homeostasis that allows cardiovascular perfusion, organ system function, and cellular mechanisms to respond to sur-gical illness.2 Knowledge of the compartmentalization of body fluids forms the basis for understanding pathologic shifts in these fluid spaces in disease states. Although difficult to quantify, a deficiency in the functional extracellular fluid compart-ment often requires resuscitation with isotonic fluids in sur-gical and trauma patients.3 Alterations in the concentration of serum sodium have pro-found effects on cellular function due to water shifts between the intracellular and extracellular spaces.4 Different rates of compensation between respiratory and metabolic components of acid-base homeostasis require fre-quent laboratory reassessment during therapy.5 Although active investigation continues, alternative resusci-tation fluids have limited clinical utility, other than the cor-rection of specific electrolyte abnormalities.6 Enhanced recovery after surgery (ERAS) protocols have markedly changed perioperative fluid management and are being used more frequently. ERAS minimizes perioperative fluid administration and focuses on early enteral intake to reduce morbidity associated with IV fluid administration.7 Most acute surgical illnesses are accompanied by some degree of volume loss or redistribution. Consequently, iso-tonic fluid administration is the most common initial intra-venous fluid strategy, while attention is being given to alterations in concentration and composition.8 Some surgical patients with neurologic illness, malnutrition, acute renal failure, or cancer require special attention to well-defined, disease-specific abnormalities in fluid and electrolyte status.% of Total body weightPlasma 5%Interstitialfluid 15%Intracellularvolume 40%Volume of TBWExtracellular volumePlasmaInterstitialIntracellular volume14,000 mL3500 mL10,500 mL28,000 mL42,000 mLMale (70 kg)10,000 mL2500 mL7500 mL20,000 mL30,000 mLFemale (60 kg)relatively little. Sodium, however, is confined to the ECF com-partment, and because of its osmotic and electrical properties, it remains associated with water. Therefore, sodium-containing fluids are distributed throughout the ECF and add to the volume of both the intravascular and interstitial spaces. Although the administration of sodium-containing fluids expands the intra-vascular volume, it also expands the interstitial space by approx-imately three times as much as the plasma.Osmotic PressureThe physiologic activity of electrolytes in solution depends on the number of particles per unit volume (millimoles per liter, or mmol/L), the number of electric charges per unit volume (milli-equivalents per liter, or mEq/L), and the number of osmotically active ions per unit volume (milliosmoles per liter, or mOsm/L). The concentration of electrolytes usually is expressed in terms of the chemical combining activity, or equivalents. An equiva-lent of an ion is its atomic weight expressed in grams divided by the valence:Equivalent = atomic weight (g)/valenceFor univalent ions such as sodium, 1 mEq is same as 1 mmol. For divalent ions such as magnesium, 1 mmol equals 2 mEq. The number of milliequivalents of cations must be bal-anced by the same number of milliequivalents of anions. How-ever, the expression of molar equivalents alone does not allow a physiologic comparison of solutes in a solution.The movement of water across a cell membrane depends primarily on osmosis. To achieve osmotic equilibrium, water moves across a semipermeable membrane to equalize the con-centration on both sides. This movement is determined by the concentration of the solutes on each side of the membrane. Osmotic pressure is measured in units of osmoles (osm) or milliosmoles (mOsm) that refer to the actual number of osmotically active particles. For example, 1 mmol of sodium chloride contributes to 2 mOsm (one from sodium and one from chloride). The principal determinants of osmolality are the concentrations of sodium, glucose, and urea (blood urea nitrogen, or BUN):Calculated serum osmolality = 2 sodium + (glucose/18) + (BUN/2.8)The osmolality of the intracellular and extracellular fluids is maintained between 290 and 310 mOsm in each compart-ment. Because cell membranes are permeable to water, any Brunicardi_Ch03_p0083-p0102.indd 8408/12/18 10:07 AM 85FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3change in osmotic pressure in one compartment is accompanied by a redistribution of water until the effective osmotic pressure between compartments is equal. For practical clinical purposes, most significant gains and losses of body fluid are directly from the extracellular compartment.BODY FLUID CHANGESNormal Exchange of Fluid and ElectrolytesThe healthy person consumes an average of 2000 mL of water per day, approximately 75% from oral intake and the rest extracted from solid foods. Daily water losses include 800 to 1200 mL in urine, 250 mL in stool, and 600 mL in insensible losses. Insensible losses of water occur through both the skin (75%) and lungs (25%) and can be increased by such factors as fever, hypermetabolism, and hyperventilation. Sensible water losses such as sweating or pathologic loss of gastrointestinal (GI) fluids vary widely, but these include the loss of electrolytes as well as water (Table 3-1). To clear the products of metabo-lism, the kidneys must excrete a minimum of 500 to 800 mL of urine per day, regardless of the amount of oral intake.The typical individual consumes 3 to 5 g of dietary salt per day, with the balance maintained by the kidneys. With hypo-natremia or hypovolemia, sodium excretion can be reduced to as little as 1 mEq/d or maximized to as much as 5000 mEq/d to achieve balance except in people with salt-wasting kidneys. Sweat is hypotonic, and sweating usually results in only a small sodium loss. GI losses are isotonic to slightly hypotonic and contribute little to net gain or loss of free water when measured and appropriately replaced by isotonic salt solutions.Classification of Body Fluid ChangesDisorders in fluid balance may be classified into three general categories: disturbances in (a) volume, (b) concentration, and (c) composition. Although each of these may occur simultaneously, each is a separate entity with unique mechanisms demanding individual correction. Isotonic gain or loss of salt solution results in extracellular volume changes, with little impact on intracellular fluid volume. If free water is added or lost from the ECF, water will pass between the ECF and intracellular fluid until solute concentration or osmolarity is equalized between the compartments. Unlike with sodium, the concentration of most other ions in the ECF can be altered without significant change in the total number of osmotically active particles, producing only a compositional change.Disturbances in Fluid BalanceExtracellular volume deficit is the most common fluid disorder in surgical patients and can be either acute or chronic. Acute volume deficit is associated with cardiovascular and central ner-vous system signs, whereas chronic deficits display tissue signs, such as a decrease in skin turgor and sunken eyes, in addition to cardiovascular and central nervous system signs (Table 3-2). Laboratory examination may reveal an elevated BUN level if the deficit is severe enough to reduce glomerular filtration and hemoconcentration. Urine osmolality usually will be higher than serum osmolality, and urine sodium will be low, typically <20 mEq/L. Serum sodium concentration does not necessar-ily reflect volume status and therefore may be high, normal, or low when a volume deficit is present. The most common cause of volume deficit in surgical patients is a loss of GI flu-ids (Table 3-3) from nasogastric suction, vomiting, diarrhea, or Figure 3-2. Chemical composition of body fluid compartments.PlasmaCATIONS154 mEq/L154 mEq/LCI−SO42–PO43–ProteinOrganicacids103HCO3−273516Na+142K+4Ca2+5Mg2+3ANIONSInterstitialfluidCATIONS153 mEq/L153 mEq/LCI−PO43–SO42–ProteinOrganicacids114HCO3−30531Na+144K+4Ca2+3Mg2+2ANIONSIntracellularfluidCATIONS200 mEq/L200 mEq/LK+150ProteinHCO3−SO42–HPO43–1015040Mg2+40Na+10ANIONSBrunicardi_Ch03_p0083-p0102.indd 8508/12/18 10:07 AM 86BASIC CONSIDERATIONSPART Ienterocutaneous fistula. In addition, sequestration secondary to soft tissue injuries, burns, and intra-abdominal processes such as peritonitis, obstruction, or prolonged surgery can also lead to massive volume deficits.Extracellular volume excess may be iatrogenic or second-ary to renal dysfunction, congestive heart failure, or cirrhosis. Both plasma and interstitial volumes usually are increased. Symptoms are primarily pulmonary and cardiovascular (see Table 3-2). In fit patients, edema and hyperdynamic circula-tion are common and well tolerated. However, the elderly and patients with cardiac disease may quickly develop congestive heart failure and pulmonary edema in response to only a moder-ate volume excess.Volume ControlVolume changes are sensed by both osmoreceptors and baro-receptors. Osmoreceptors are specialized sensors that detect even small changes in fluid osmolality and drive changes in thirst and diuresis through the kidneys.2 For example, when plasma osmolality is increased, thirst is stimulated and water consumption increases, although the exact cell mechanism is not known.3 Additionally, the hypothalamus is stimulated to secrete vasopressin, which increases water reabsorption in the kidneys. Together, these two mechanisms return the plasma osmolality to normal. Baroreceptors also modulate volume in response to changes in pressure and circulating volume through specialized pressure sensors located in the aortic arch and carotid sinuses.4 Baroreceptor responses are both neural, through sympathetic and parasympathetic pathways, and hormonal, through substances including renin-angiotensin, aldosterone, atrial natriuretic pep-tide, and renal prostaglandins. The net result of alterations in renal sodium excretion and free water reabsorption is restoration of volume to the normal state.Concentration ChangesChanges in serum sodium concentration are inversely propor-tional to TBW. Therefore, abnormalities in TBW are reflected by abnormalities in serum sodium levels.Hyponatremia. A low serum sodium level occurs when there is an excess of extracellular water relative to sodium. Extracel-lular volume can be high, normal, or low (Fig. 3-3). In most cases of hyponatremia, sodium concentration is decreased as a consequence of either sodium depletion or dilution.5 Dilutional hyponatremia frequently results from excess extracellular water and therefore is associated with a high extracellular volume status. Excessive oral water intake or iatrogenic intravenous (IV) excess free water administration can cause hyponatremia. Post-operative patients are particularly prone to increased secretion of antidiuretic hormone (ADH), which increases reabsorption 3Table 3-2Signs and symptoms of volume disturbancesSYSTEMVOLUME DEFICITVOLUME EXCESSGeneralizedWeight lossWeight gain Decreased skin turgorPeripheral edemaCardiacTachycardiaIncreased cardiac output Orthostasis/hypotensionIncreased central venous pressure Collapsed neck veinsDistended neck veins  MurmurRenalOliguria— Azotemia GIIleusBowel edemaPulmonary—Pulmonary edemaTable 3-1Water exchange (60to 80-kg man)ROUTESAVERAGE DAILY VOLUME (mL)MINIMAL (mL)MAXIMAL (mL)H2O gain:    Sensible:     Oral fluids800–150001500/h  Solid foods500–70001500 Insensible:     Water of oxidation250125800  Water of solution00500H2O loss:    Sensible:     Urine800–15003001400/h  Intestinal0–25002500/h  Sweat004000/h Insensible:     Lungs and skin6006001500Brunicardi_Ch03_p0083-p0102.indd 8608/12/18 10:07 AM 87FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3of free water from the kidneys with subsequent volume expan-sion and hyponatremia. This is usually self-limiting in that both hyponatremia and volume expansion decrease ADH secretion. Additionally, a number of drugs can cause water retention and subsequent hyponatremia, such as antipsychotics and tricyclic antidepressants as well as angiotensin-converting enzyme inhib-itors. The elderly are particularly susceptible to drug-induced hyponatremia. Physical signs of volume overload usually are absent, and laboratory evaluation reveals hemodilution. Deple-tional causes of hyponatremia are associated with either a decreased intake or increased loss of sodium-containing fluids. A concomitant ECF volume deficit is common. Causes include decreased sodium intake, such as consumption of a low-sodium diet or use of enteral feeds, which are typically low in sodium; Table 3-3Composition of GI secretionsTYPE OF SECRETIONVOLUME (mL/24 h)NA (mEq/L)K (mEq/L)CL (mEq/L)HCO3− (mEq/L)Stomach1000–200060–9010–30100–1300Small intestine2000–3000120–1405–1090–12030–40Colon—6030400Pancreas600–800135–1455–1070–9095–115Bile300–800135–1455–1090–11030–40Figure 3-3. Evaluation of sodium abnormalities. ADH = antidiuretic hormone; SIADH = syndrome of inappropriate secretion of antidi-uretic hormone.HighIncreased intakePostoperative ADH secretionDrugsHighIatrogenic sodium administrationMineralocorticoid excessAldosteronismCushing’s diseaseCongenital adrenal hyperplasiaHyponatremiaVolume statusNormalHyperglycemia˜Plasma lipids/proteinsSIADHWater intoxicationDiureticsHypernatremiaVolume statusNormalNonrenal water lossSkinGIRenal water lossRenal diseaseDiureticsDiabetes insipidusLowDecreased sodium intakeGI lossesRenal lossesDiureticsPrimary renal diseaseLowNonrenal water lossSkinGI Renal water lossRenal (tubular) diseaseOsmotic diureticsDiabetes insipidusAdrenal failureBrunicardi_Ch03_p0083-p0102.indd 8708/12/18 10:07 AM 88BASIC CONSIDERATIONSPART IGI losses from vomiting, prolonged nasogastric suctioning, or diarrhea; and renal losses due to diuretic use or primary renal disease.Hyponatremia also can be seen with an excess of solute relative to free water, such as with untreated hyperglycemia or mannitol administration. When hyponatremia in the presence of hyperglycemia is being evaluated, the corrected sodium concen-tration should be calculated as follows:For every 100-mg/dL increment in plasma glucose above normal, the plasma sodium should decrease by 1.6 mEq/LLastly, extreme elevations in plasma lipids and proteins can cause pseudohyponatremia because there is no true decrease in extracellular sodium relative to water.Signs and symptoms of hyponatremia (Table 3-4) are dependent on the degree of hyponatremia and the rapidity with which it occurred. Clinical manifestations primarily have a central nervous system origin and are related to cellular water intoxication and associated increases in intracranial pressure. Oliguric renal failure also can be a rapid complication in the setting of severe hyponatremia.A systematic review of the etiology of hyponatremia should reveal its cause in a given instance. Hyperosmolar causes, including hyperglycemia or mannitol infusion and pseu-dohyponatremia, should be easily excluded. Next, depletional versus dilutional causes of hyponatremia are evaluated. In the absence of renal disease, depletion is associated with low urine sodium levels (<20 mEq/L), whereas renal sodium wasting shows high urine sodium levels (>20 mEq/L). Dilutional causes of hyponatremia usually are associated with hypervolemic cir-culation. A normal volume status in the setting of hyponatremia should prompt an evaluation for a syndrome of inappropriate secretion of ADH.Hypernatremia. Hypernatremia results from either a loss of free water or a gain of sodium in excess of water. Like hypo-natremia, it can be associated with an increased, normal, or decreased extracellular volume (see Fig. 3-3). Hypervolemic hypernatremia usually is caused either by iatrogenic adminis-tration of sodium-containing fluids, including excess sodium bicarbonate, or mineralocorticoid as seen in hyperaldosteronism, Cushing’s syndrome, and congenital adrenal hyperplasia. Urine sodium concentration is typically >20 mEq/L, and urine osmo-larity is >300 mOsm/L. Normovolemic hypernatremia can result from renal causes, including diabetes insipidus, diuretic use, and renal disease, or from nonrenal water loss from the GI tract or skin, although the same conditions can result in hypovolemic hypernatremia. When hypovolemia is present, the urine sodium concentration is <20 mEq/L and urine osmolarity is <300 to 400 mOsm/L. Nonrenal water loss can occur secondary to rela-tively isotonic GI fluid losses such as that caused by diarrhea, to hypotonic skin fluid losses such as loss due to fever, or to losses via tracheotomies during hyperventilation. Additionally, thyrotoxicosis can cause water loss, as can the use of hyper-tonic glucose solutions for peritoneal dialysis. With nonrenal water loss, the urine sodium concentration is <15 mEq/L, and the urine osmolarity is >400 mOsm/L.Symptomatic hypernatremia usually occurs only in patients with impaired thirst or restricted access to fluid because thirst will result in increased water intake. Symptoms are rare until the serum sodium concentration exceeds 160 mEq/L but, once present, are associated with significant morbidity and mortality. Because symptoms are related to hyperosmolarity, central nervous system effects predominate (see Table 3-4). Water shifts from the intracellular to the extracellular space in response to a hyperosmolar extracellular space, which results in cellular dehydration. This can put traction on the cerebral vessels and lead to subarachnoid hemorrhage. Central nervous system symptoms can range from restlessness and irritability to seizures, coma, and death. The classic signs of hypovolemic hypernatremia (tachycardia, orthostasis, and hypotension) may be present, as well as the unique findings of dry, sticky mucous membranes.Composition Changes: Etiology and DiagnosisPotassium Abnormalities. The average dietary intake of potassium is approximately 50 to 100 mEq/d, which in the absence of hypokalemia is excreted primarily in the urine. Extra-cellular potassium is maintained within a narrow range, princi-pally by renal excretion of potassium, which can range from 10 to 700 mEq/d. Although only 2% of the total body potassium (4.5 mEq/L × 14 L = 63 mEq) is located within the extracellular compartment, this small amount is critical to cardiac and neu-romuscular function; thus, even minor changes can have major effects on cardiac activity. The intracellular and extracellular distribution of potassium is influenced by a number of factors, including surgical stress, injury, acidosis, and tissue catabolism.Table 3-4Clinical manifestations of abnormalities in serum sodium levelBODY SYSTEMHYPONATREMIACentral nervous systemHeadache, confusion, hyperactive or hypoactive deep tendon reflexes, seizures, coma, increased intracranial pressureMusculoskeletalWeakness, fatigue, muscle cramps/twitchingGIAnorexia, nausea, vomiting, watery diarrheaCardiovascularHypertension and bradycardia if intracranial pressure increases significantlyTissueLacrimation, salivationRenalOliguriaBODY SYSTEMHYPERNATREMIACentral nervous systemRestlessness, lethargy, ataxia, irritability, tonic spasms, delirium, seizures, comaMusculoskeletalWeaknessCardiovascularTachycardia, hypotension, syncopeTissueDry sticky mucous membranes, red swollen tongue, decreased saliva and tearsRenalOliguriaMetabolicFeverBrunicardi_Ch03_p0083-p0102.indd 8808/12/18 10:07 AM 89FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3Hyperkalemia Hyperkalemia is defined as a serum potassium concentration above the normal range of 3.5 to 5.0 mEq/L. It is caused by excessive potassium intake, increased release of potassium from cells, or impaired potassium excretion by the kidneys (Table 3-5).6 Increased intake can be either from oral or IV supplementation, or from red cell lysis after transfu-sion. Hemolysis, rhabdomyolysis, and crush injuries can dis-rupt cell membranes and release intracellular potassium into the ECF. Acidosis and a rapid rise in extracellular osmolality from hyperglycemia or IV mannitol can raise serum potassium levels by causing a shift of potassium ions to the extracellular compartment.7 Because 98% of total body potassium is in the intracellular fluid compartment, even small shifts of intracel-lular potassium out of the intracellular fluid compartment can lead to a significant rise in extracellular potassium. A number of medications can contribute to hyperkalemia, particularly in the presence of renal insufficiency, including potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). Spironolactone and angiotensin-converting enzyme inhibitors interfere with aldosterone activity, inhibiting the normal renal mechanism of potassium excretion. Acute and chronic renal insufficiency also impairs potassium excretion.Symptoms of hyperkalemia are primarily GI, neuromus-cular, and cardiovascular (Table 3-6). GI symptoms include nausea, vomiting, intestinal colic, and diarrhea. Neuromuscu-lar symptoms range from weakness to ascending paralysis to respiratory failure. Early cardiovascular signs may be appar-ent from electrocardiogram (ECG) changes and eventually lead to hemodynamic symptoms of arrhythmia and cardiac arrest. ECG changes that may be seen with hyperkalemia include high peaked T waves (early), widened QRS complex, flattened P wave, prolonged PR interval (first-degree block), sine wave formation, and ventricular fibrillation.Hypokalemia Hypokalemia is much more common than hyper-kalemia in the surgical patient. It may be caused by inadequate potassium intake; excessive renal potassium excretion; potas-sium loss in pathologic GI secretions, such as with diarrhea, fis-tulas, vomiting, or high nasogastric output; or intracellular shifts from metabolic alkalosis or insulin therapy (see Table 3-5). Table 3-5 Etiology of potassium abnormalitiesHyperkalemiaIncreased intake Potassium supplementation Blood transfusions Endogenous load/destruction: hemolysis, rhabdomyolysis,  crush injury, gastrointestinal hemorrhageIncreased release Acidosis Rapid rise of extracellular osmolality (hyperglycemia or  mannitol)Impaired excretion Potassium-sparing diuretics Renal insufficiency/failureHypokalemiaInadequate intake Dietary, potassium-free intravenous fluids, potassium deficient TPNExcessive potassium excretion Hyperaldosteronism MedicationsGI losses Direct loss of potassium from GI fluid (diarrhea) Renal loss of potassium (to conserve sodium in response  to gastric losses)Table 3-6Clinical manifestations of abnormalities in potassium, magnesium, and calcium levelsINCREASED SERUM LEVELSSYSTEMPOTASSIUMMAGNESIUMCALCIUMGINausea/vomiting, colic, diarrheaNausea/vomitingAnorexia, nausea/vomiting, abdominal painNeuromuscularWeakness, paralysis, respiratory failureWeakness, lethargy, decreased reflexesWeakness, confusion, coma, bone painCardiovascularArrhythmia, arrestHypotension, arrestHypertension, arrhythmia, polyuriaRenal——PolydipsiaDECREASED SERUM LEVELSSYSTEMPOTASSIUMMAGNESIUMCALCIUMGIIleus, constipation——NeuromuscularDecreased reflexes, fatigue, weakness, paralysisHyperactive reflexes, muscle tremors, tetany, seizuresHyperactive reflexes, paresthesias, carpopedal spasm, seizuresCardiovascularArrestArrhythmiaHeart failureBrunicardi_Ch03_p0083-p0102.indd 8908/12/18 10:07 AM 90BASIC CONSIDERATIONSPART IThe change in potassium associated with alkalosis can be calcu-lated by the following formula:Potassium decreases by 0.3 mEq/L for every 0.1 increase in pH above normal.Additionally, drugs such as amphotericin, aminoglyco-sides, cisplatin, and ifosfamide that induce magnesium depletion cause renal potassium wastage.8,9 In cases in which potassium deficiency is due to magnesium depletion,10 potassium repletion is difficult unless hypomagnesemia is first corrected.The symptoms of hypokalemia (see Table 3-6), like those of hyperkalemia, are primarily related to failure of normal con-tractility of GI smooth muscle, skeletal muscle, and cardiac mus-cle. Findings may include ileus, constipation, weakness, fatigue, diminished tendon reflexes, paralysis, and cardiac arrest. In the setting of ECF depletion, symptoms may be masked initially and then worsened by further dilution during volume repletion. ECG changes suggestive of hypokalemia include U waves, T-wave flattening, ST-segment changes, and arrhythmias (with digitalis therapy).Calcium Abnormalities. The vast majority of the body’s calcium is contained within the bone matrix, with <1% found in the ECF. Serum calcium is distributed among three forms: protein found (40%), complexed to phosphate and other anions (10%), and ionized (50%). It is the ionized fraction that is responsible for neuromuscular stability and can be measured directly. When total serum calcium levels are measured, the albumin concentration must be taken into consideration:Adjust total serum calcium down by 0.8 mg/dL for every 1 g/dL decrease in albumin.Unlike changes in albumin, changes in pH will affect the ionized calcium concentration. Acidosis decreases protein bind-ing, thereby increasing the ionized fraction of calcium.Daily calcium intake is 1 to 3 g/d. Most of this is excreted via the bowel, with urinary excretion relatively low. Total body calcium balance is under complex hormonal control, but distur-bances in metabolism are relatively long term and less important in the acute surgical setting. However, attention to the critical role of ionized calcium in neuromuscular function often is required.Hypercalcemia Hypercalcemia is defined as a serum calcium level above the normal range of 8.5 to 10.5 mEq/L or an increase in the ionized calcium level above 4.2 to 4.8 mg/dL. Primary hyperparathyroidism in the outpatient setting and malignancy in hospitalized patients, from either bony metastasis or secre-tion of parathyroid hormone–related protein, account for most cases of symptomatic hypercalcemia.11 Symptoms of hypercal-cemia (see Table 3-6), which vary with the degree of sever-ity, include neurologic impairment, musculoskeletal weakness and pain, renal dysfunction, GI symptoms of nausea, vomiting, and abdominal pain. Cardiac symptoms can be manifested as hypertension, cardiac arrhythmias, and a worsening of digitalis toxicity. ECG changes in hypercalcemia include shortened QT interval, prolonged PR and QRS intervals, increased QRS volt-age, T-wave flattening and widening, and atrioventricular block (which can progress to complete heart block and cardiac arrest).Hypocalcemia Hypocalcemia is defined as a serum calcium level below 8.5 mEq/L or a decrease in the ionized calcium level below 4.2 mg/dL. The causes of hypocalcemia include pancreatitis, massive soft tissue infections such as necrotizing fasciitis, renal failure, pancreatic and small bowel fistulas, hypo-parathyroidism, toxic shock syndrome, abnormalities in mag-nesium levels, and tumor lysis syndrome. In addition, transient hypocalcemia commonly occurs after removal of a parathyroid adenoma due to atrophy of the remaining glands and avid bone remineralization, and sometimes requires high-dose calcium supplementation.12 Additionally, malignancies associated with increased osteoblastic activity, such as breast and prostate can-cer, can lead to hypocalcemia from increased bone formation.13 Calcium precipitation with organic anions is also a cause of hypocalcemia and may occur during hyperphosphatemia from tumor lysis syndrome or rhabdomyolysis. Pancreatitis may sequester calcium via chelation with free fatty acids. Massive blood transfusion with citrate binding is another mechanism.14,15 Hypocalcemia rarely results solely from decreased intake because bone reabsorption can maintain normal levels for pro-longed periods.Asymptomatic hypocalcemia may occur when hypopro-teinemia results in a normal ionized calcium level. Conversely, symptoms can develop with a normal serum calcium level during alkalosis, which decreases ionized calcium. In general, neuromuscular and cardiac symptoms do not occur until the ion-ized fraction falls below 2.5 mg/dL (see Table 3-6). Clinical findings may include paresthesias of the face and extremities, muscle cramps, carpopedal spasm, stridor, tetany, and seizures. Patients will demonstrate hyperreflexia and may exhibit positive Chvostek’s sign (spasm resulting from tapping over the facial nerve) and Trousseau’s sign (spasm resulting from pressure applied to the nerves and vessels of the upper extremity with a blood pressure cuff). Hypocalcemia may lead to decreased cardiac contractility and heart failure. ECG changes of hypocal-cemia include prolonged QT interval, T-wave inversion, heart block, and ventricular fibrillation.Phosphorus Abnormalities. Phosphorus is the primary intra-cellular divalent anion and is abundant in metabolically active cells. Phosphorus is involved in energy production during gly-colysis and is found in high-energy phosphate products such as adenosine triphosphate. Serum phosphate levels are tightly controlled by renal excretion.Hyperphosphatemia Hyperphosphatemia can be due to decreased urinary excretion, increased intake, or endogenous mobilization of phosphorus. Most cases of hyperphosphatemia are seen in patients with impaired renal function. Hypoparathy-roidism or hyperthyroidism also can decrease urinary excretion of phosphorus and thus lead to hyperphosphatemia. Increased release of endogenous phosphorus can be seen in association with any clinical condition that results in cell destruction, includ-ing rhabdomyolysis, tumor lysis syndrome, hemolysis, sepsis, severe hypothermia, and malignant hyperthermia. Excessive phosphate administration from IV hyperalimentation solutions or phosphorus-containing laxatives may also lead to elevated phosphate levels. Most cases of hyperphosphatemia are asymp-tomatic, but significant prolonged hyperphosphatemia can lead to metastatic deposition of soft tissue calcium-phosphorus complexes.Hypophosphatemia Hypophosphatemia can be due to a decrease in phosphorus intake, an intracellular shift of phospho-rus, or an increase in phosphorus excretion. Decreased GI uptake due to malabsorption or administration of phosphate binders and decreased dietary intake from malnutrition are causes of chronic hypophosphatemia. Most acute cases are due to an intracellular Brunicardi_Ch03_p0083-p0102.indd 9008/12/18 10:07 AM 91FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3shift of phosphorus in association with respiratory alkalosis, insulin therapy, refeeding syndrome, and hungry bone syn-drome. Clinical manifestations of hypophosphatemia usually are absent until levels fall significantly. In general, symptoms are related to adverse effects on the oxygen availability of tissue and to a decrease in high-energy phosphates, and can be mani-fested as cardiac dysfunction or muscle weakness.Magnesium Abnormalities. Magnesium is the fourth most common mineral in the body and, like potassium, is found pri-marily in the intracellular compartments. Approximately one-half of the total body content of 2000 mEq is incorporated in bone and is slowly exchangeable. Of the fraction found in the extracellular space, one-third is bound to serum albumin. There-fore, the plasma level of magnesium may be a poor indicator of total body stores in the presence of hypoalbuminemia. Mag-nesium should be replaced until levels are in the upper limit of normal. The normal dietary intake is approximately 20 mEq/d and is excreted in both the feces and urine. The kidneys have a remarkable ability to conserve magnesium, with renal excretion <1 mEq/d during magnesium deficiency.Hypermagnesemia Hypermagnesemia is rare but can be seen with severe renal insufficiency and parallel changes in potas-sium excretion. Magnesium-containing antacids and laxatives can produce toxic levels in patients with renal failure. Excess intake in conjunction with total parenteral nutrition (TPN), or, rarely, massive trauma, thermal injury, and severe acidosis, may be associated with symptomatic hypermagnesemia. Clini-cal examination (see Table 3-6) may find nausea and vomit-ing; neuromuscular dysfunction with weakness, lethargy, and hyporeflexia; and impaired cardiac conduction leading to hypo-tension and arrest. ECG changes are similar to those seen with hyperkalemia and include increased PR interval, widened QRS complex, and elevated T waves.Hypomagnesemia Magnesium depletion is a common prob-lem in hospitalized patients, particularly in the critically ill.16 The kidney is primarily responsible for magnesium homeostasis through regulation by calcium/magnesium receptors on the renal tubular cells that respond to serum magnesium concentrations.17 Hypomagnesemia may result from alterations of intake, renal excretion, and pathologic losses. Poor intake may occur in cases of starvation, alcoholism, prolonged IV fluid therapy, and TPN with inadequate supplementation of magnesium. Losses are seen in cases of increased renal excretion from alcohol abuse, diuretic use, administration of amphotericin B, and primary aldosteronism, as well as GI losses from diarrhea, malabsorp-tion, and acute pancreatitis. The magnesium ion is essential for proper function of many enzyme systems. Depletion is characterized by neuromuscular and central nervous system hyperactivity. Symptoms are similar to those of calcium defi-ciency, including hyperactive reflexes, muscle tremors, tetany, and positive Chvostek’s and Trousseau’s signs (see Table 3-6). Severe deficiencies can lead to delirium and seizures. A number of ECG changes also can occur and include prolonged QT and PR intervals, ST-segment depression, flattening or inversion of P waves, torsades de pointes, and arrhythmias. Hypomagnese-mia is important not only because of its direct effects on the nervous system but also because it can produce hypocalcemia and lead to persistent hypokalemia. When hypokalemia or hypo-calcemia coexists with hypomagnesemia, magnesium should be aggressively replaced to assist in restoring potassium or calcium homeostasis.Acid-Base BalanceAcid-Base Homeostasis. The pH of body fluids is maintained within a narrow range despite the ability of the kidneys to gen-erate large amounts of HCO3− and the normal large acid load produced as a by-product of metabolism. This endogenous acid load is efficiently neutralized by buffer systems and ultimately excreted by the lungs and kidneys.Important buffers include intracellular proteins and phos-phates and the extracellular bicarbonate–carbonic acid system. Compensation for acid-base derangements can be by respiratory mechanisms (for metabolic derangements) or metabolic mecha-nisms (for respiratory derangements). Changes in ventilation in response to metabolic abnormalities are mediated by hydrogen-sensitive chemoreceptors found in the carotid body and brain stem. Acidosis stimulates the chemoreceptors to increase venti-lation, whereas alkalosis decreases the activity of the chemore-ceptors and thus decreases ventilation. The kidneys provide compensation for respiratory abnormalities by either increasing or decreasing bicarbonate reabsorption in response to respira-tory acidosis or alkalosis, respectively. Unlike the prompt change in ventilation that occurs with metabolic abnormalities, the compensatory response in the kidneys to respiratory abnor-malities is delayed. Significant compensation may not begin for 6 hours and then may continue for several days. Because of this delayed compensatory response, respiratory acid-base derange-ments before renal compensation are classified as acute, whereas those persisting after renal compensation are categorized as chronic. The predicted compensatory changes in response to metabolic or respiratory derangements are listed in Table 3-7.18 If the predicted change in pH is exceeded, then a mixed acid-base abnormality may be present (Table 3-8).Metabolic DerangementsMetabolic Acidosis. Metabolic acidosis results from an increased intake of acids, an increased generation of acids, or an increased loss of bicarbonate (Table 3-9). The body responds by several mechanisms, including producing buffers (extracellular bicarbonate and intracellular buffers from bone and muscle), increasing ventilation (Kussmaul’s respirations), and increas-ing renal reabsorption and generation of bicarbonate. The kid-ney also will increase secretion of hydrogen and thus increase urinary excretion of NH4+ (H+ + NH3+ = NH4+). Evaluation of a patient with a low serum bicarbonate level and metabolic 4Table 3-7 Predicted changes in acid-base disordersDISORDERPREDICTED CHANGEMetabolic Metabolic acidosis Metabolic alkalosisRespiratory Acute respiratory acidosis Chronic respiratory  acidosis Acute respiratory alkalosis Chronic respiratory  alkalosisPco2 = 1.5 × HCO3− + 8Pco2 = 0.7 × HCO3− + 21Δ pH = (Pco2 – 40) × 0.008Δ pH = (Pco2 – 40) × 0.003 Δ pH = (40 – Pco2) × 0.008Δ pH = (40 – Pco2) × 0.017Pco2 = partial pressure of carbon dioxide.Brunicardi_Ch03_p0083-p0102.indd 9108/12/18 10:07 AM 92BASIC CONSIDERATIONSPART Iacidosis includes determination of the anion gap (AG), an index of unmeasured anions.AG = (Na) – (Cl + HCO3)The normal AG is <12 mmol/L and is due primarily to the albumin effect, so that the estimated AG must be adjusted for albumin (hypoalbuminemia reduces the AG).19Corrected AG = actual AG – (2.5[4.5 – albumin])Metabolic acidosis with an increased AG occurs either from ingestion of exogenous acid such as from ethylene gly-col, salicylates, or methanol, or from increased endogenous acid production of the following:• β-Hydroxybutyrate and acetoacetate in ketoacidosis• Lactate in lactic acidosis• Organic acids in renal insufficiencyA common cause of severe metabolic acidosis in surgi-cal patients is lactic acidosis. In circulatory shock, lactate is produced in the presence of hypoxia from inadequate tissue perfusion. The treatment is to restore perfusion with volume resuscitation rather than to attempt to correct the abnormality with exogenous bicarbonate. With adequate perfusion, the lactic acid is rapidly metabolized by the liver, and the pH level returns to normal. In clinical studies of lactic acidosis and ketoacidosis, the administration of bicarbonate has not reduced morbidity or mortality or improved cellular function.20 Administered bicar-bonate can combine with the excess hydrogen ions to form car-bonic acid; this is then converted to CO2 and water, which thus raises the partial pressure of CO2 (Pco2). This hypercarbia could compound ventilation abnormalities in patients with underlying acute respiratory distress syndrome. This CO2 can diffuse into cells, but bicarbonate remains extracellular, which thus worsens intracellular acidosis. Clinically, lactate levels may not be useful in directing resuscitation, although lactate levels may be higher in nonsurvivors of serious injury.21Metabolic acidosis with a normal AG results from exog-enous acid administration (HCl or NH4+), from loss of bicar-bonate due to GI disorders such as diarrhea and fistulas or ureterosigmoidostomy, or from renal losses. In these settings, the bicarbonate loss is accompanied by a gain of chloride; thus, the AG remains unchanged. To determine whether the loss of bicarbonate has a renal cause, the urinary (NH4+) can be mea-sured. A low urinary (NH4+) in the face of hyperchloremic acidosis would indicate that the kidney is the site of loss, and evaluation for renal tubular acidosis should be undertaken. Prox-imal renal tubular acidosis results from decreased tubular reab-sorption of HCO3−, whereas distal renal tubular acidosis results from decreased acid excretion. The carbonic anhydrase inhibitor acetazolamide also causes bicarbonate loss from the kidneys.Metabolic Alkalosis Normal acid-base homeostasis prevents metabolic alkalosis from developing unless both an increase in bicarbonate generation and impaired renal excretion of bicar-bonate occur (Table 3-10). Metabolic alkalosis results from the loss of fixed acids or the gain of bicarbonate and is worsened by potassium depletion. The majority of patients also will have hypokalemia because extracellular potassium ions exchange with intracellular hydrogen ions and allow the hydrogen ions to buffer excess HCO3–. Hypochloremic and hypokalemic meta-bolic alkalosis can occur from isolated loss of gastric contents in infants with pyloric stenosis or adults with duodenal ulcer disease. Unlike vomiting associated with an open pylorus, which involves a loss of gastric as well as pancreatic, biliary, Table 3-9 Etiology of metabolic acidosisIncreased Anion Gap Metabolic AcidosisExogenous acid ingestion Ethylene glycol Salicylate MethanolEndogenous acid production Ketoacidosis Lactic acidosis Renal insufficiencyNormal Anion GapAcid administration (HCl)Loss of bicarbonateGI losses (diarrhea, fistulas)UreterosigmoidostomyRenal tubular acidosisCarbonic anhydrase inhibitorTable 3-8 Respiratory and metabolic components of acid-base disorders ACUTE UNCOMPENSATEDCHRONIC (PARTIALLY COMPENSATED)TYPE OF ACID-BASE DISORDERpHPco2 (RESPIRATORY COMPONENT)PLASMA HCO3−a (METABOLIC COMPONENT)pHPco2 (RESPIRATORY COMPONENT)PLASMA HCO3−a (METABOLIC COMPONENT)Respiratory acidosis↓↓↑↑N↓↑↑↑Respiratory alkalosis↑↑↓↓N↑↓↓↓Metabolic acidosis↓↓N↓↓↓↓↓Metabolic alkalosis↑↑N↑↑↑↑↑aMeasured as standard bicarbonate, whole blood buffer base, CO2 content, or CO2 combining power. The base excess value is positive when the standard bicarbonate is above normal and negative when the standard bicarbonate is below normal.N = normal; Pco2 = partial pressure of carbon dioxide.Brunicardi_Ch03_p0083-p0102.indd 9208/12/18 10:07 AM 93FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3and intestinal secretions, vomiting with an obstructed pylorus results only in the loss of gastric fluid, which is high in chloride and hydrogen, and therefore results in a hypochloremic alkalo-sis. Initially, the urinary bicarbonate level is high in compensa-tion for the alkalosis. Hydrogen ion reabsorption also ensues, with an accompanied potassium ion excretion. In response to the associated volume deficit, aldosterone-mediated sodium reabsorption increases potassium excretion. The resulting hypo-kalemia leads to the excretion of hydrogen ions in the face of alkalosis, a paradoxic aciduria. Treatment includes replacement of the volume deficit with isotonic saline and then potassium replacement once adequate urine output is achieved.Respiratory Derangements. Under normal circumstances, blood Pco2 is tightly maintained by alveolar ventilation, con-trolled by the respiratory centers in the pons and medulla oblongata.Respiratory Acidosis Respiratory acidosis is associated with the retention of CO2 secondary to decreased alveolar ventila-tion. The principal causes are listed in Table 3-11. Because compensation is primarily a renal mechanism, it is a delayed response. Treatment of acute respiratory acidosis is directed at the underlying cause. Measures to ensure adequate ventila-tion are also initiated. This may entail patient-initiated volume expansion using noninvasive bilevel positive airway pressure or may require endotracheal intubation to increase minute ven-tilation. In the chronic form of respiratory acidosis, the partial pressure of arterial CO2 remains elevated, and the bicarbonate concentration rises slowly as renal compensation occurs.Respiratory Alkalosis In the surgical patient, most cases of respiratory alkalosis are acute and secondary to alveolar hyper-ventilation. Causes include pain, anxiety, and neurologic dis-orders, including central nervous system injury and assisted ventilation. Drugs such as salicylates, fever, gram-negative bacteremia, thyrotoxicosis, and hypoxemia are other possibili-ties. Acute hypocapnia can cause an uptake of potassium and phosphate into cells and increased binding of calcium to albu-min, leading to symptomatic hypokalemia, hypophosphatemia, and hypocalcemia with subsequent arrhythmias, paresthesias, muscle cramps, and seizures. Treatment should be directed at the underlying cause, but direct treatment of the hyperventila-tion using controlled ventilation may also be required.FLUID AND ELECTROLYTE THERAPYParenteral SolutionsA number of commercially available electrolyte solutions are available for parenteral administration. The most commonly used solutions are listed in Table 3-12. The type of fluid admin-istered depends on the patient’s volume status and the type of concentration or compositional abnormality present. Plasma-Lyte, lactated Ringer’s solution, and normal saline are consid-ered isotonic and are useful in replacing GI losses and correcting extracellular volume deficits. Lactated Ringer’s is slightly hypotonic in that it contains 130 mEq of lactate. Lactate is used rather than bicarbonate because it is more stable in IV fluids during storage. It is converted into bicarbonate by the liver after infusion, even in the face of hemorrhagic shock.Sodium chloride is mildly hypertonic, containing 154 mEq of sodium that is balanced by 154 mEq of chloride. The high chloride concentration imposes a significant chloride load on the kidneys and may lead to a hyperchloremic metabolic acido-sis. Sodium chloride is an ideal solution, however, for correcting volume deficits associated with hyponatremia, hypochloremia, and metabolic alkalosis.Plasma-Lyte is the crystalloid preparation that most closely resembles the electrolyte composition of human plasma. In addi-tion to the favorable, isotonic electrolyte composition, Plasma-Lyte contains a number of additional buffers that create a favorable profile for addressing acidosis.22 These characteristics have resulted in Plasma-Lyte emerging as one of the most popular isotonic fluids for use in surgery. It should be noted that Plasma-Lyte contains small quantities of potassium; although the likeli-hood of inducing hyperkalemia is very low, care should be taken when using Plasma-Lyte in patients at risk for renal impairment. The less concentrated sodium solutions, such as 0.45% sodium chloride, are useful for replacement of ongoing GI losses as well as for maintenance fluid therapy in the post-operative period. This solution provides sufficient free water for insensible losses and enough sodium to aid the kidneys in adjustment of serum sodium levels. The addition of 5% dextrose Table 3-10 Etiology of metabolic alkalosisIncreased bicarbonate generation1. Chloride losing (urinary chloride >20 mEq/L)Mineralocorticoid excessProfound potassium depletion2. Chloride sparing (urinary chloride <20 mEq/L)Loss from gastric secretions (emesis or nasogastric suction)Diuretics3. Excess administration of alkaliAcetate in parenteral nutritionCitrate in blood transfusionsAntacidsBicarbonateMilk-alkali syndromeImpaired bicarbonate excretion1. Decreased glomerular filtration2. Increased bicarbonate reabsorption (hypercarbia or potassium depletion)Table 3-11Etiology of respiratory acidosis: hypoventilationNarcoticsCentral nervous system injuryPulmonary: significant Secretions Atelectasis Mucus plug Pneumonia Pleural effusionPain from abdominal or thoracic injuries or incisionsLimited diaphragmatic excursion from intra-abdominal pathology Abdominal distention Abdominal compartment syndrome AscitesBrunicardi_Ch03_p0083-p0102.indd 9308/12/18 10:07 AM 94BASIC CONSIDERATIONSPART I(50 g of dextrose per liter) supplies 200 kcal/L, and dextrose is always added to solutions containing <0.45% sodium chloride to maintain osmolality and thus prevent the lysis of red blood cells that may occur with rapid infusion of hypotonic fluids. The addition of potassium is useful once adequate renal function and urine output are established.Alternative Resuscitative FluidsA number of alternative solutions for volume expansion and resuscitation are available (Table 3-13).23 Hypertonic saline solutions (3.5% and 5%) are used for correction of severe sodium deficits and are discussed elsewhere in this chap-ter. Hypertonic saline (7.5%) has been used as a treatment modality in patients with closed head injuries. It has been shown to increase cerebral perfusion and decrease intracranial pressure, thus decreasing brain edema.24 However, there have also been concerns about increased bleeding because hypertonic saline is an arteriolar vasodilator. A recent meta-analysis of hypertonic saline in severe traumatic brain injury revealed that, in a total of 11 eligible studies, there was no mortality benefit associated with hypertonic saline compared to other solutions.25 Colloids also are used in surgical patients, and their effectiveness as vol-ume expanders compared with isotonic crystalloids has long been debated. Due to their molecular weight, they are confined to the intravascular space, and their infusion results in more effi-cient transient plasma volume expansion. However, under con-ditions of severe hemorrhagic shock, capillary membrane permeability increases; this permeability permits colloids to enter the interstitial space, which can worsen edema and impair tissue oxygenation. Four major types of colloids are available—albumin, dextrans, hetastarch, and gelatins—and are described by their molecular weight and size in Table 3-13. In a large randomized trial of patients admitted to an intensive care unit with hypovolemic shock, administration of colloid showed no improvement in mortality at 30 days as compared to crystalloid resuscitation.26 Interestingly, there was a suggestion of improve-ment of 90-day mortality and more days alive without mechani-cal ventilation in patients receiving colloid; however, these were not trial primary endpoints and were considered exploratory. Furthermore, a Cochrane Database systematic review on the topic concluded that there is no available evidence from ran-domized trials to support colloid use over crystalloid to reduce the risk of death following trauma, burns, or surgery.27 Colloids are markedly more expensive than crystalloids, and certain col-loids, such as hydroxyethyl starch, have been associated with increased morbidity including the need for renal replacement therapy.28 Taken together, the use of colloid for resuscitation of critically ill and surgical patients has limited application.Correction of Life-Threatening Electrolyte AbnormalitiesSodium Hypernatremia Treatment of hypernatremia usually consists of treatment of the associated water deficit. In hypovolemic patients, volume should be restored with normal saline before the concentration abnormality is addressed. Once adequate volume has been achieved, the water deficit is replaced using a hypotonic fluid such as 5% dextrose, 5% dextrose in onequarter normal saline, or enterally administered water. The for-mula used to estimate the amount of water required to correct hypernatremia is as follows:Waterdeficit(L)serumsodium140=−×140TBWEstimate TBW as 50% of lean body mass in men and 40% in women5Table 3-12 Electrolyte solutions for parenteral administration ELECTROLYTE COMPOSITION (mEq/L)SOLUTIONNaClKHCO3−CaMgmOsmExtracellular fluid14210342753280–310Lactated Ringer’s1301094283 2730.9% Sodium chloride154154    308D5 0.45% Sodium chloride7777    407D5W      2533% Sodium chloride513513    1026Plasma-Lyte14098527 3295D5 = 5% dextrose; D5W = 5% dextrose in water.Table 3-13 Alternative resuscitative fluidsSOLUTIONMOLECULAR WEIGHTOSMOLALITY (mOsm/L)SODIUM (mEq/L)Hypertonic saline (7.5%)—25651283Albumin 5%70,000300130–160Albumin 25%70,0001500130–160Dextran 4040,000308154Dextran 7070,000308154Hetastarch450,000310154Hextend670,000307143Gelofusine30,000NA154NA = not available.Brunicardi_Ch03_p0083-p0102.indd 9408/12/18 10:07 AM 95FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3The rate of fluid administration should be titrated to achieve a decrease in serum sodium concentration of no more than 1 mEq/h and 12 mEq/d for the treatment of acute symp-tomatic hypernatremia. Even slower correction should be under-taken for chronic hypernatremia (0.7 mEq/h) because overly rapid correction can lead to cerebral edema and herniation. The type of fluid used depends on the severity and ease of correc-tion. Oral or enteral replacement is acceptable in most cases, or IV replacement with halfor quarter-normal saline can be used. Caution also should be exercised when using 5% dextrose in water to avoid overly rapid correction. Frequent neurologic evaluation as well as frequent evaluation of serum sodium levels also should be performed. Hypernatremia is less common than hyponatremia, but has a worse prognosis, and is an independent predictor of mortality in critical illness.29Hyponatremia Most cases of hyponatremia can be treated by free water restriction and, if severe, the administration of sodium. In patients with normal renal function, symptomatic hyponatremia usually does not occur until the serum sodium level is ≤120 mEq/L. If neurologic symptoms are present, 3% normal saline should be used to increase the sodium by no more than 1 mEq/L per hour until the serum sodium level reaches 130 mEq/L or neurologic symptoms are improved. Correction of asymptomatic hyponatremia should increase the sodium level by no more than 0.5 mEq/L per hour to a maxi-mum increase of 12 mEq/L per day, and even more slowly in chronic hyponatremia. The rapid correction of hyponatremia can lead to pontine myelinolysis,30 with seizures, weakness, paresis, akinetic movements, and unresponsiveness, and may result in permanent brain damage and death. Serial magnetic resonance imaging may be necessary to confirm the diagnosis.31Potassium Hyperkalemia Treatment options for symptomatic hyperka-lemia are listed in Table 3-14. The goals of therapy include reducing the total body potassium, shifting potassium from the extracellular to the intracellular space, and protecting the cells from the effects of increased potassium. For all patients, exogenous sources of potassium should be removed, including potassium supplementation in IV fluids and enteral and paren-teral solutions. Potassium can be removed from the body using a cation-exchange resin such as Kayexalate that binds potas-sium in exchange for sodium. It can be administered either orally, in alert patients, or rectally. Immediate measures also should include attempts to shift potassium intracellularly with glucose and bicarbonate infusion. Nebulized albuterol (10 to 20 mg) may also be used. Use of glucose alone will cause a rise in insulin secretion, but in the acutely ill, this response may be blunted, and therefore both glucose and insulin may be necessary. Circulatory overload and hypernatremia may result from the administration of Kayexalate and bicarbonate, so care should be exercised when administering these agents to patients with fragile cardiac function. When ECG changes are present, calcium chloride or calcium gluconate (5 to 10 mL of 10% solution) should be administered immediately to counteract the myocardial effects of hyperkalemia. Calcium infusion should be used cautiously in patients receiving digitalis because digitalis toxicity may be precipitated. All of the aforementioned mea-sures are temporary, lasting from 1 to approximately 4 hours. Dialysis should be considered in severe hyperkalemia when conservative measures fail.Hypokalemia Treatment for hypokalemia consists of potas-sium repletion, the rate of which is determined by the symptoms (Table 3-15). Oral repletion is adequate for mild, asymptomatic hypokalemia. If IV repletion is required, usually no more than 10 mEq/h is advisable in an unmonitored setting. This amount can be increased to 40 mEq/h when accompanied by continu-ous ECG monitoring, and even more in the case of imminent cardiac arrest from a malignant arrhythmia-associated hypoka-lemia. Caution should be exercised when oliguria or impaired renal function is coexistent.Calcium Hypercalcemia Treatment is required when hypercalcemia is symptomatic, which usually occurs when the serum level exceeds 12 mg/dL. The critical level for serum calcium is 15 mg/dL, when symptoms noted earlier may rapidly progress to death. The initial treatment is aimed at repleting the associated volume deficit and then inducing a brisk diuresis with normal saline. Treatment of hypercalcemia associated with malignancies is discussed later in this chapter.Hypocalcemia Asymptomatic hypocalcemia can be treated with oral or IV calcium (see Table 3-15). Acute symptomatic hypocalcemia should be treated with IV 10% calcium gluconate to achieve a serum concentration of 7 to 9 mg/dL. Associated deficits in magnesium, potassium, and pH must also be cor-rected. Hypocalcemia will be refractory to treatment if coex-isting hypomagnesemia is not corrected first. Routine calcium supplementation is no longer recommended in association with massive blood transfusions.32Phosphorus Hyperphosphatemia Phosphate binders such as sucralfate or aluminum-containing antacids can be used to lower serum phosphorus levels. Calcium acetate tablets also are useful when hypocalcemia is simultaneously present. Dialysis usually is reserved for patients with renal failure.Hypophosphatemia Depending on the level of depletion and tolerance to oral supplementation, a number of enteral and par-enteral repletion strategies are effective for the treatment of hypophosphatemia (see Table 3-15).Magnesium Hypermagnesemia Treatment for hypermagnesemia consists of measures to eliminate exogenous sources of magnesium, Table 3-14Treatment of symptomatic hyperkalemiaPotassium removal Kayexalate  Oral administration is 15–30 g in 50–100 mL of 20%  sorbitol  Rectal administration is 50 g in 200 mL of 20% sorbitol DialysisShift potassium Glucose 1 ampule of D50 and regular insulin 5–10 units IV Bicarbonate 1 ampule IVCounteract cardiac effects Calcium gluconate 5–10 mL of 10% solutionD50 = 50% dextrose.Brunicardi_Ch03_p0083-p0102.indd 9508/12/18 10:07 AM 96BASIC CONSIDERATIONSPART ITable 3-15Electrolyte replacement therapy protocolPotassiumSerum potassium level <4.0 mEq/L: Asymptomatic, tolerating enteral nutrition: KCl 40 mEq per enteral access × 1 dose Asymptomatic, not tolerating enteral nutrition: KCl 20 mEq IV q2h × 2 doses Symptomatic: KCl 20 mEq IV q1h × 4 doses Recheck potassium level 2 h after end of infusion; if <3.5 mEq/L and asymptomatic, replace as per above protocolMagnesiumMagnesium level 1.0–1.8 mEq/L: Magnesium sulfate 0.5 mEq/kg in normal saline 250 mL infused IV over 24 h × 3 d Recheck magnesium level in 3 dMagnesium level <1.0 mEq/L: Magnesium sulfate 1 mEq/kg in normal saline 250 mL infused IV over 24 h × 1 d, then 0.5 mEq/kg in normal saline 250 mL  infused IV over 24 h × 2 d Recheck magnesium level in 3 dIf patient has gastric access and needs a bowel regimen: Milk of magnesia 15 mL (approximately 49 mEq magnesium) q24h per gastric tube; hold for diarrheaCalciumIonized calcium level <4.0 mg/dL: With gastric access and tolerating enteral nutrition: Calcium carbonate suspension 1250 mg/5 mL q6h per gastric access;  recheck ionized calcium level in 3 d Without gastric access or not tolerating enteral nutrition: Calcium gluconate 2 g IV over 1 h × 1 dose; recheck ionized calcium  level in 3 dPhosphatePhosphate level 1.0–2.5 mg/dL: Tolerating enteral nutrition: Neutra-Phos 2 packets q6h per gastric tube or feeding tube No enteral nutrition: KPHO4 or NaPO4 0.15 mmol/kg IV over 6 h × 1 dose Recheck phosphate level in 3 dPhosphate level <1.0 mg/dL: Tolerating enteral nutrition: KPHO4 or NaPO4 0.25 mmol/kg over 6 h × 1 dose Recheck phosphate level 4 h after end of infusion; if <2.5 mg/dL, begin Neutra-Phos 2 packets q6h Not tolerating enteral nutrition: KPHO4 or NaPO4 0.25 mmol/kg (LBW) over 6 h × 1 dose; recheck phosphate level 4 h after  end of infusion; if <2.5 mg/dL, then KPHO4 or NaPO4 0.15 mmol/kg (LBW) IV over 6 h × 1 dose3 mmol KPHO4 = 3 mmol Phos and 4.4 mEq K+ = 1 mL3 mmol NaPO4 = 3 mmol Phos and 4 mEq Na+ = 1 mLNeutra-Phos 1 packet = 8 mmol Phos, 7 mEq K+, 7 mEq Na+Use patient’s lean body weight (LBW) in kilograms for all calculations.Disregard protocol if patient has renal failure, is on dialysis, or has a creatinine clearance <30 mL/min.correct concurrent volume deficits, and correct acidosis if present. To manage acute symptoms, calcium chloride (5 to 10 mL) should be administered to immediately antagonize the cardiovascular effects. If elevated levels or symptoms persist, hemodialysis may be necessary.Hypomagnesemia Correction of magnesium depletion can be oral if asymptomatic and mild. Otherwise, IV repletion is indicated and depends on severity (see Table 3-15) and clini-cal symptoms. For those with severe deficits (<1.0 mEq/L) or those who are symptomatic, 1 to 2 g of magnesium sulfate may be administered IV over 15 minutes. Under ECG monitoring, it may be given over 2 minutes if necessary to correct torsades de pointes (irregular ventricular rhythm). Caution should be taken when giving large amounts of magnesium because magnesium toxicity may develop. The simultaneous administration of cal-cium gluconate will counteract the adverse side effects of a rap-idly rising magnesium level and correct hypocalcemia, which is frequently associated with hypomagnesemia.Preoperative Fluid TherapyThe administration of maintenance fluids should be all that is required in an otherwise healthy individual who may be under orders to receive nothing by mouth for some period before the time of surgery. This does not, however, include replenishment of a preexisting deficit or ongoing fluid losses. The following is a frequently used formula for calculating the volume of mainte-nance fluids in the absence of preexisting abnormalities:For the first 0–10 kgFor the next 10–20 kgFor weight >20 kgGive 100 mL/kg per dayGive an additional 50 mL/kg per dayGive an additional 20 mL/kg per dayFor example, a 60-kg female would receive a total of 2300 mL of fluid daily: 1000 mL for the first 10 kg of body Brunicardi_Ch03_p0083-p0102.indd 9608/12/18 10:07 AM 97FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3weight (10 kg × 100 mL/kg per day), 500 mL for the next 20 kg (10 kg × 50 mL/kg per day), and 800 mL for the last 40 kg (40 kg × 20 mL/kg per day).An alternative approach is to replace the calculated daily water losses in urine, stool, and insensible loss with a hypotonic saline solution rather than water alone, which allows the kid-ney some sodium excess to adjust for concentration. Although there should be no “routine” maintenance fluid orders, both of these methods would yield an appropriate choice of 5% dex-trose in 0.45% sodium chloride at 100 mL/h as initial therapy, with potassium added for patients with normal renal function. However, many surgical patients have volume and/or electrolyte abnormalities associated with their surgical disease. Preopera-tive evaluation of a patient’s volume status and preexisting elec-trolyte abnormalities is an important part of overall preoperative assessment and care. Volume deficits should be considered in patients who have obvious GI losses, such as through emesis or diarrhea, as well as in patients with poor oral intake second-ary to their disease. Less obvious are those fluid losses known as third-space or nonfunctional ECF losses that occur with GI obstruction, peritoneal or bowel inflammation, ascites, crush injuries, burns, and severe soft tissue infections such as nec-rotizing fasciitis. The diagnosis of an acute volume deficit is primarily clinical (see Table 3-2), although the physical signs may vary with the duration of the deficit. Cardiovascular signs of tachycardia and orthostasis predominate with acute volume loss, usually accompanied by oliguria and hemoconcentration. Acute volume deficits should be corrected as much as possible before the time of operation.Once a volume deficit is diagnosed, prompt fluid replace-ment should be instituted, usually with an isotonic crystalloid, depending on the measured serum electrolyte values. Patients with cardiovascular signs of volume deficit should receive a bolus of 1 to 2 L of isotonic fluid followed by a continuous infu-sion. Close monitoring during this period is imperative. Resus-citation should be guided by the reversal of the signs of volume deficit, such as restoration of acceptable values for vital signs, maintenance of adequate urine output (0.5 to 1 mL/kg per hour in an adult), and correction of base deficit. Patients whose vol-ume deficit is not corrected after this initial volume challenge and those with impaired renal function and the elderly should be considered for more intensive monitoring in an intensive care unit setting. In these patients, early invasive monitoring of cen-tral venous pressure or cardiac output may be necessary.If symptomatic electrolyte abnormalities accompany vol-ume deficit, the abnormality should be corrected to the point that the acute symptom is relieved before surgical interven-tion. For correction of severe hypernatremia associated with a volume deficit, an unsafe rapid fall in extracellular osmolarity from 5% dextrose infusion is avoided by slowly correcting the hypernatremia with 0.45% saline or even lactated Ringer’s solu-tion rather than 5% dextrose alone. This will safely and slowly correct the hypernatremia while also correcting the associated volume deficit.Intraoperative Fluid TherapyWith the induction of anesthesia, compensatory mechanisms are lost, and hypotension will develop if volume deficits are not appropriately corrected before the time of surgery. Hemody-namic instability during anesthesia is best avoided by correct-ing known fluid losses, replacing ongoing losses, and providing adequate maintenance fluid therapy preoperatively. In addition to measured blood loss, major open abdominal surgeries are associated with continued extracellular losses in the form of bowel wall edema, peritoneal fluid, and the wound edema dur-ing surgery. Large soft tissue wounds, complex fractures with associated soft tissue injury, and burns are all associated with additional third-space losses that must be considered in the operating room. These represent distributional shifts, in that the functional volume of ECF is reduced but fluid is not externally lost from the body. These functional losses have been referred to as parasitic losses, sequestration, or third-space edema because the lost volume no longer participates in the normal functions of the ECF.Until the 1960s saline solutions were withheld during sur-gery. Administered saline was retained and was felt to be an inappropriate challenge to a physiologic response of intraopera-tive salt intolerance. Basic and clinical research began to change this concept,33,34 eventually leading to the current concept that saline administration is necessary to restore the obligate ECF losses noted earlier. Although no accurate formula can predict intraoperative fluid needs, replacement of ECF during surgery often requires 500 to 1000 mL/h of a balanced salt solution to support homeostasis. The addition of albumin or other colloidcontaining solutions to intraoperative fluid therapy is not neces-sary. Manipulation of colloid oncotic forces by albumin infusion during major vascular surgery showed no advantage in support-ing cardiac function or avoiding the accumulation of extravas-cular lung water.35Postoperative Fluid TherapyPostoperative fluid therapy should be based on the patient’s current estimated volume status and projected ongoing fluid losses. Any deficits from either preoperative or intraoperative losses should be corrected, and ongoing requirements should be included along with maintenance fluids. Third-space losses, although difficult to measure, should be included in fluid replacement strategies. In the initial postoperative period, an isotonic solution should be administered. The adequacy of resuscitation should be guided by the restoration of acceptable values for vital signs and urine output and, in more complicated cases, by the correction of base deficit or lactate. Adjuncts to assessing volume status in the postoperative patient include such tools as a straight leg raise, point-of-care ultrasound, and assessment of respiratory variation via use of an arterial cath-eter in a mechanically ventilated patient. After the initial 24 to 48 hours, fluids can be changed to 5% dextrose in 0.45% saline in patients unable to tolerate enteral nutrition. If normal renal function and adequate urine output are present, potassium may be added to the IV fluids. Daily fluid orders should begin with assessment of the patient’s volume status and assessment of electrolyte abnormalities. There is rarely a need to check elec-trolyte levels in the first few days of an uncomplicated post-operative course. However, postoperative diuresis may require attention to replacement of urinary potassium loss. All measured losses, including losses through vomiting, nasogastric suction-ing, drains, and urine output, as well as insensible losses, are replaced with the appropriate parenteral solutions as previously reviewed.Fluid Management in Enhanced Recovery After Surgery (ERAS) PathwaysAs pioneered by the Danish surgeon Henrik Kehlet, ERAS path-ways have been designed to guide the perioperative management Brunicardi_Ch03_p0083-p0102.indd 9708/12/18 10:07 AM 98BASIC CONSIDERATIONSPART Iof various types of surgical procedures. ERAS consists of a mul-timodal strategy to maximize and maintain preoperative organ function, and implementation of ERAS protocols has resulted in a decrease in length of stay, improved patient satisfaction, cost savings, and a reduction in complications. A full discussion of ERAS is outside the scope of this chapter; however, it is impor-tant to note that perioperative fluid management is a major tenet of ERAS protocols. The 2011 European Society of Anaesthesi-ology guidelines were among the first formal recommendations to alter standard recommendations for preoperative enteral intake. These recommendations include allowance of clear liq-uids up to 2 hours prior to surgery.36 Many ERAS protocols include the use of carbohydrate and electrolyte-rich fluids to enhance hydration and metabolic response to surgery. In addi-tion to preoperative enteral hydration, a major focus of ERAS protocols is the restriction of intraand postoperative sodium and intravenous fluids. Fluid overload has been associated with prolonged ileus and coagulation abnormalities.37 Goal-directed fluid therapy has been shown to reduce postoperative morbidity and length of stay independent of the other multimodal compo-nents of ERAS, making minimizing fluids a major target of intervention.38 Postoperatively, early enteral intake is advised, with prompt discontinuation of intravenous fluids. These strate-gies targeting euvolemia have been shown to be safe and improve outcomes, making ERAS a rapidly evolving strat-egy that will continue to influence the perioperative fluid and electrolyte management of surgical patients.39,40Special Considerations for the Postoperative PatientVolume excess is a common disorder in the postoperative period. The administration of isotonic fluids in excess of actual needs may result in excess volume expansion. This may be due to the overestimation of third-space losses or to ongoing GI losses that are difficult to measure accurately. The earliest sign of volume overload is weight gain. The average postopera-tive patient who is not receiving nutritional support should lose approximately 0.25 to 0.5 lb/d (0.11 to 0.23 kg/d) from catabo-lism. Additional signs of volume excess may also be present as listed in Table 3-2. Peripheral edema may not necessarily be associated with intravascular volume overload because overex-pansion of total ECF may exist in association with a deficit in the circulating plasma volume.Volume deficits also can be encountered in surgical patients if preoperative losses were not completely corrected, intraoperative losses were underestimated, or postoperative losses were greater than appreciated. The clinical manifestations are described in Table 3-2 and include tachycardia, orthostasis, and oliguria. Hemoconcentration also may be present. Treat-ment will depend on the amount and composition of fluid lost. In most cases of volume depletion, replacement with an isotonic fluid will be sufficient while alterations in concentration and composition are being evaluated.ELECTROLYTE ABNORMALITIES IN SPECIFIC SURGICAL PATIENTSNeurologic PatientsSyndrome of Inappropriate Secretion of Antidiuretic Hormone. The syndrome of inappropriate secretion of antidi-uretic hormone (SIADH) can occur after head injury or surgery to the central nervous system, but it also is seen in association with administration of drugs such as morphine, nonsteroidals, and oxytocin, and in a number of pulmonary and endocrine dis-eases, including hypothyroidism and glucocorticoid deficiency. Additionally, it can be seen in association with a number of malignancies, most often small cell cancer of the lung but also pancreatic carcinoma, thymoma, and Hodgkin’s disease.41 SIADH should be considered in patients who are euvolemic and hyponatremic with elevated urine sodium levels and urine osmolality. ADH secretion is considered inap-propriate when it is not in response to osmotic or volume-related conditions. Correction of the underlying problem should be attempted when possible. In most cases, restriction of free water will improve the hyponatremia. The goal is to achieve net water balance while avoiding volume depletion that may compromise renal function. Furosemide also can be used to induce free water loss. If hyponatremia persists after fluid restriction, the addition of isotonic or hypertonic fluids may be effective. The adminis-tration of isotonic saline may sometimes worsen the problem if the urinary sodium concentration is higher than the infused sodium concentration. The use of loop diuretics may be helpful in this situation by preventing further urine concentration. In chronic SIADH, when long-term fluid restriction is difficult to maintain or is ineffective, demeclocycline and lithium can be used to induce free water loss.Diabetes Insipidus. Diabetes insipidus (DI) is a disorder of ADH stimulation and is manifested by dilute urine in the case of hypernatremia. Central DI results from a defect in ADH secre-tion, and nephrogenic DI results from a defect in end-organ responsiveness to ADH. Central DI is frequently seen in asso-ciation with pituitary surgery, closed head injury, and anoxic encephalopathy.42 Nephrogenic DI occurs in association with hypokalemia, administration of radiocontrast dye, and use of certain drugs such as aminoglycosides and amphotericin B. In patients tolerating oral intake, volume status usually is normal because thirst stimulates increased intake. However, volume depletion can occur rapidly in patients who are incapable of oral intake. The diagnosis can be confirmed by documenting a paradoxical increase in urine osmolality in response to a period of water deprivation. In mild cases, free water replacement may be adequate therapy. In more severe cases, vasopressin can be added. The usual dosage of vasopressin is 5 U subcutaneously every 6 to 8 hours. However, serum electrolytes and osmolality should be monitored to avoid excess vasopressin administration with resulting iatrogenic SIADH.Cerebral Salt Wasting. Cerebral salt wasting is a diagnosis of exclusion that occurs in patients with a cerebral lesion and renal wasting of sodium and chloride with no other identifiable cause.43 Natriuresis in a patient with a contracted extracellular volume should prompt the possible diagnosis of cerebral salt wasting. Hyponatremia is frequently observed but is nonspecific and occurs as a secondary event, which differentiates it from SIADH.Malnourished Patients: Refeeding SyndromeRefeeding syndrome is a potentially lethal condition that can occur with rapid and excessive feeding of patients with severe underlying malnutrition due to starvation, alcoholism, delayed nutritional support, anorexia nervosa, or massive weight loss in obese patients.44 With refeeding, a shift in metabolism from fat to carbohydrate substrate stimulates insulin release, which 678Brunicardi_Ch03_p0083-p0102.indd 9808/12/18 10:07 AM 99FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3results in the cellular uptake of electrolytes, particularly phos-phate, magnesium, potassium, and calcium. However, severe hyperglycemia may result from blunted basal insulin secretion. The refeeding syndrome can be associated with enteral or par-enteral refeeding, and symptoms from electrolyte abnormalities include cardiac arrhythmias, confusion, respiratory failure, and even death. To prevent the development of refeeding syndrome, underlying electrolyte and volume deficits should be corrected. Additionally, thiamine should be administered before the initia-tion of feeding. Caloric repletion should be instituted slowly and should gradually increase over the first week.45 Vital signs, fluid balance, and electrolytes should be closely monitored and any deficits corrected as they evolve.Acute Renal Failure PatientsA number of fluid and electrolyte abnormalities are specific to patients with acute renal failure. With the onset of renal failure, an accurate assessment of volume status must be made. If prerenal azotemia is present, prompt correction of the underlying volume deficit is mandatory. Once acute tubular necrosis is established, measures should be taken to restrict daily fluid intake to match urine output and insensible and GI losses. Oliguric renal failure requires close monitoring of serum potassium levels. Measures to correct hyperkalemia as reviewed in Table 3-14 should be instituted early, including consideration of early hemodialysis. Hyponatremia is common in established renal failure as a result of the breakdown of proteins, carbohydrates, and fats, as well as the administration of free water. Dialysis may be required for severe hyponatremia. Hypocalcemia, hypermagnesemia, and hyperphosphatemia also are associated with acute renal failure. Hypocalcemia should be verified by measuring ionized calcium, because many patients also are hypoalbuminemic. Phosphate binders can be used to control hyperphosphatemia, but dialy-sis may be required in more severe cases. Metabolic acidosis is commonly seen with renal failure, as the kidneys lose their ability to clear acid by-products. Bicarbonate can be useful, but dialysis often is needed. Although dialysis may be either intermittent or continuous, renal recovery may be improved by continuous renal replacement.46Cancer PatientsFluid and electrolyte abnormalities are common in patients with cancer. The causes may be common to all patient populations or may be specific to cancer patients and their treatment.47 Hypo-natremia is frequently hypovolemic due to renal loss of sodium caused by diuretics or salt-wasting nephropathy as seen with some chemotherapeutic agents such as cisplatin. Cerebral salt wasting also can occur in patients with intracerebral lesions. Normovolemic hyponatremia may occur in association with SIADH from cervical cancer, lymphoma, and leukemia, or from certain chemotherapeutic agents. Hypernatremia in can-cer patients most often is due to poor oral intake or GI volume losses, which are common side effects of chemotherapy. Central DI also can lead to hypernatremia in patients with central ner-vous system lesions.Hypokalemia can develop from GI losses associated with diarrhea caused by radiation enteritis or chemotherapy, or from tumors such as villous adenomas of the colon. Tumor lysis syn-drome can precipitate severe hyperkalemia from massive tumor cell destruction.Hypocalcemia can be seen after removal of a thyroid or parathyroid tumor or after a central neck dissection, which can damage the parathyroid glands. Hungry bone syndrome produces acute and profound hypocalcemia after parathyroid surgery for secondary or tertiary hyperparathyroidism because calcium is rapidly taken up by bones. Prostate and breast cancer can result in increased osteoblastic activity, which decreases serum calcium by increasing bone formation. Acute hypocalce-mia also can occur with hyperphosphatemia because phospho-rus complexes with calcium. Hypomagnesemia is a side effect of ifosfamide and cisplatin therapy. Hypophosphatemia can be seen in hyperparathyroidism, due to decreased phosphorus reabsorption, and in oncogenic osteomalacia, which increases the urinary excretion of phosphorus. Other causes of hypophos-phatemia in cancer patients include renal tubular dysfunction from multiple myeloma, Bence Jones proteins, and certain che-motherapeutic agents. Acute hypophosphatemia can occur as rapidly proliferating malignant cells take up phosphorus in acute leukemia. Tumor lysis syndrome or the use of bisphosphonates to treat hypercalcemia also can result in hyperphosphatemia.Malignancy is the most common cause of hypercalcemia in hospitalized patients and is due to increased bone resorption or decreased renal excretion. Bone destruction occurs from bony metastasis as seen in breast or renal cell cancer but also can occur in multiple myeloma. With Hodgkin’s and non-Hodgkin’s lymphoma, hypercalcemia results from increased calcitriol for-mation, which increases both absorption of calcium from the GI tract and mobilization from bone. Humoral hypercalcemia of malignancy is a common cause of hypercalcemia in cancer patients. As in primary hyperparathyroidism, a parathyroid-related protein is secreted that binds to parathyroid receptors, stimulating calcium resorption from bone and decreasing renal excretion of calcium. The treatment of hypercalcemia of malig-nancy should begin with saline volume expansion, which will decrease renal reabsorption of calcium as the associated volume deficit is corrected. Once an adequate volume status has been achieved, a loop diuretic may be added. Unfortunately, these measures are only temporary, and additional treatment is often necessary. A variety of drugs are available with varying times of onset, durations of action, and side effects.48 The bisphos-phonates etidronate and pamidronate inhibit bone resorption and osteoclastic activity. They have a slow onset of action, but effects can last for 2 weeks. Calcitonin also is effective, inhibit-ing bone resorption and increasing renal excretion of calcium. It acts quickly, within 2 to 4 hours, but its use is limited by the development of tachyphylaxis. Corticosteroids may decrease tachyphylaxis in response to calcitonin and can be used alone to treat hypercalcemia. Gallium nitrates are potent inhibitors of bone resorption. They display a long duration of action but can cause nephrotoxicity. Mithramycin is an antibiotic that blocks osteoclastic activity, but it can be associated with liver, renal, and hematologic abnormalities, which limits its use to the treatment of Paget’s disease of bone. For patients with severe, refractory hypercalcemia who are unable to tolerate volume expansion due to pulmonary edema or congestive heart failure, dialysis is an option.Tumor lysis syndrome results when the release of intracel-lular metabolites overwhelms the kidneys’ excretory capacity. This rapid release of uric acid, potassium, and phosphorus can result in marked hyperuricemia, hyperkalemia, hyperphospha-temia, hypocalcemia, and acute renal failure. It is typically seen with poorly differentiated lymphomas and leukemias but also can occur with a number of solid tumor malignancies. Tumor lysis syndrome most commonly develops during treatment Brunicardi_Ch03_p0083-p0102.indd 9908/12/18 10:07 AM 100BASIC CONSIDERATIONSPART Iwith chemotherapy or radiotherapy. Once it develops, volume expansion should be undertaken and any associated electrolyte abnormalities corrected. In this setting, hypocalcemia should not be treated unless it is symptomatic to avoid metastatic calci-fications. Dialysis may be required for management of impaired renal function or correction of electrolyte abnormalities.REFERENCESEntries highlighted in bright blue are key references. 1. Aloia JF, Vaswani A, Flaster E, et al. Relationship of body water compartment to age, race and fat-free mass. J Lab Clin Med. 1998;132:483. 2. Bourque CW, Oliet SHR. Osmoreceptors in the central nervous system. Annu Rev Physiol. 1997;59:601. 3. Verbalis JG. How does the brain sense osmolality? J Am Soc Nephrol. 2007;18(12):3056. 4. Stauss HM. Baroreceptor reflex function. Am J Physiol Regul Integr Comp Physiol. 2002;283:R284. 5. Miller M. Syndromes of excess antidiuretic hormone release. Crit Care Clin. 2001;17:11. 6. Kapoor M, Chan G. Fluid and electrolyte abnormalities. Crit Care Clin. 2001;17:571. 7. Adrogue HJ, Lederer ED, Suki WN, et al. Determinants of plasma potassium in diabetic ketoacidosis. Medicine. 1986;65:163. 8. Zietse R, Zuotendijk R, Hoorn EJ. Fluid, electrolyte and acid-base disorders associated with antibiotic therapy. Nat Rev Nephrol. 2009;5(4):193. 9. Cobos E, Hall RR. Effects of chemotherapy on the kidney. Semin Nephrol. 1993;13:297. 10. Gennari FJ. Hypokalemia. N Engl J Med. 1998;339:451. 11. French S, Subauste J, Geraci S. Calcium abnormalities in hos-pitalized patients. South Med J. 2012;105(4):231. 12. Witteveen JE, van Theil S, Romijn JA. Therapy of endo-crine disease: hungry bone syndrome. Eur J Endocrinol. 2013;168(3):R45. 13. Bushinsky DA, Monk RD. Calcium. Lancet. 1998;352:306. 14. Dunlay RW, Camp MA, Allon M, et al. Calcitriol in prolonged hypocalcemia due to tumor lysis syndrome. Ann Intern Med. 1989;110:162. 15. Reber PM, Heath H. Hypocalcemic emergencies. Med Clin North Am. 1995;19:93. 16. Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med. 2005;20(1):3. 17. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52:1180. 18. Marino PL. Acid-base interpretations. In: Marino PL, ed. The ICU Book. 2nd ed. Baltimore: Williams & Wilkins; 1998:581. 19. Gluck SL. Acid-base. Lancet. 1998;352:474. 20. Kraut JA, Madias NE. Treatment of acute metabolic acidosis: a pathophysiologic approach. Nat Rev Nephrol. 2012;8(10):589. 21. Pal JD, Victorino GP, Twomey P, et al. Admission serum lactate levels do not predict mortality in the acutely injured patient. J Trauma. 2006;60:583. 22. Rizoli S. PlasmaLyte. J Trauma. 2011 May;70(5 Suppl):S17-8. 23. Roberts JS, Bratton SL. Colloid volume expanders: problems, pitfalls, and possibilities. Drugs. 1998;55:621. 24. Cottenceau V, Masson F, Mahamid E, et al. Comparison effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011;28(10):2003. 25. Berger-Pelleiter E, Emond M, Lauzier F, et al. Hypertonic saline in severe traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials. CJEM. 2016 Mar;18(2):112-120. This meta-analysis demonstrated no mortality benefit or effect on intracranial pressure control utilizing hypertonic saline and was a key summary of eleven major trials in the field. 26. Annane D, Siami S, Jaber S, et al. Effects of fluid resuscita-tion with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013 Nov 6;310(17):1809-1817. This multi-center randomized trial found no difference in mor-tality at 28 days in a mixed ICU population of patients with hypovolemia when comparing colloid to crystalloid resuscita-tion. The authors observed a reduction in 90-day mortality in the group receiving colloids; however, they cautioned that this observation was exploratory and required further analysis. 27. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Data-base Syst Rev. 2013 Feb 28;(2):CD000567. This Cochrane review of 70 trials including mortality data found no benefit to colloid resuscitation for reduction of risk of mor-tality, while the use of hydroxyethyl starch (HES) was found to have a possible association with increased mortality. The recom-mendation of the review was that colloid use in the ICU could not be supported due to increased cost and no mortality benefit. 28. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901-1911. In a randomized trial designed to address a primary outcome of 90-day mortality, the use of HES revealed no mortality benefit over saline with a statistically significant increase in the rate of renal replacement therapy after HES use. 29. Overgaard-Steensen C, Ring T. Clinical review: practical approach to hyponatremia and hypernatremia in critically ill patients. Crit Care. 2013;17(1):206. 30. Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis. 2010;25(1):97. 31. Graff-Radford J, Fugate JE, Kauffmann TJ. Clinical and radio-logic correlations of central pontine myelinolysis syndrome. Mayo Clin Proc. 2011;86(11):1063. 32. American College of Surgeons. Shock. In: American College of Surgeons Advanced Trauma Life Support Manual. 9th ed. Chicago: American College of Surgeons; 2012. 33. Shires GT, Williams J, Brown F. Acute changes in extracel-lular fluids associated with major surgical procedures. Ann Surg. 1961;154:803. This early paper by Shires and colleagues produced important early observations of fluid shifts and resuscitation strategies fol-lowing surgery and shaped some of the early questions in the field of resuscitation science after surgery. 34. Shires GT, Jackson DE. Postoperative salt tolerance. Arch Surg. 1962;84:703. 35. Shires GT III, Peitzman AB, Albert SA, et al. Response of extravascular lung water to intraoperative fluids. Ann Surg. 1983;197:515. 36. Smith I, Kranke P, Murat I, et al. Perioperative fasting in adults and children: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2011;28:556-569. Index guidelines published by the European Society of Anaes-thesiology were among the first to support the use of ERAS principles and provided a template for the design of the rapidly evolving practice of ERAS worldwide. 37. Horosz B, Nawrocka K, Malec-Milewska M. Anaesthetic peri-operative management according to the ERAS protocol. Anaes-thesiol Intensive Ther. 2016;48(1):49-54. 38. Rollins KE, Lobo DN. Intraoperative goal-directed fluid therapy in elective major abdominal surgery: a meta-analysis of randomized controlled trials. Ann Surg. 2016 Mar;263(3):465-476. Meta-analysis of randomized controlled trials demonstrated a marked reduction in morbidity, hospital length of stay (LOS), Brunicardi_Ch03_p0083-p0102.indd 10008/12/18 10:07 AM 101FLUID AND ELECTROLYTE MANAGEMENT OF THE SURGICAL PATIENTCHAPTER 3ICU LOS, and time to passage of feces utilizing goal-directed fluid therapy (GDFT) for intraoperative fluid management. Of note, in those studies where a multimodal ERAS pathway was utilized, the benefits of GDFT were reduced, although reduc-tion in major morbidities remained. These data suggest that the multimodal benefits of ERAS may extend beyond just fluid management. 39. Miller TE, Roche AM, Mythen M. Fluid management and goal-directed therapy as an adjunct to enhanced recovery after sur-gery (ERAS). Can J Anaesth. 2015 Feb;62(2):158-168. 40. Liu VX, Rosas E, Hwang J, et al. Enhanced recovery after surgery program implementation in 2 surgical populations in an integrated health care delivery system. JAMA Surg. 2017 Jul 19;152(7):e171032. 41. Ellison DH, Burl T. Clinical practice. The syndrome of inap-propriate antidiuresis. N Engl J Med. 2007;356(20):2064. 42. Tisdall M, Crocker M, Watkiss J, et al. Disturbances of sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol. 2006;18(1):57. 43. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: patho-physiology, diagnosis, and treatment. Neurosurg Clin N Am. 2010;21(2):339. 44. Kozar RA, McQuiggan MM, Moore FA. Nutritional support in trauma patients. In: Shikora SA, Martindale RG, Schwaitzberg SD, eds. Nutritional Considerations in the Intensive Care Unit. 1st ed. Dubuque, IA: Kendall/Hunt Publishing; 2002:229. 45. Boateng AA, Sriram K, Mequid MM, et al. Refeeding syn-drome: treatment considerations based on collective analysis of literature case reports. Nutrition. 2010;26(2):156. 46. Glassford NJ, Bellomo R. Acute kidney injury: how can we facilitate recovery? Curr Opin Crit Care. 2011;17(6):562. 47. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin. 2002;17:503. 48. Clines GA. Mechanisms and treatment of hypercalce-mia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011;18(6):339.Brunicardi_Ch03_p0083-p0102.indd 10108/12/18 10:07 AM

Brunicardi_Ch03_p0083-p0102.indd 10208/12/18 10:07 AMThis page intentionally left blankHemostasis, Surgical Bleeding, and TransfusionRonald Chang, John B. Holcomb, Evan Leibner, Matthew Pommerening, and Rosemary A. Kozar 4chapterBIOLOGY OF HEMOSTASISHemostasis is a complex process whose function is to limit blood loss from an injured vessel. Four major physiologic events participate in the hemostatic process: vascular constric-tion, platelet plug formation, fibrin formation, and fibrinolysis. Although each tends to be activated in order, the four processes are interrelated so that there is a continuum and multiple rein-forcements. The process is shown schematically in Fig. 4-1.Vascular ConstrictionVascular constriction is the initial response to vessel injury. It is more pronounced in vessels with medial smooth muscles and is dependent on local contraction of smooth muscle. Vasoconstric-tion is subsequently linked to platelet plug formation. Throm-boxane A2 (TXA2) is produced locally at the site if injury via the release of arachidonic acid from platelet membranes and is a potent constrictor of smooth muscle. Similarly, endothelin synthesized by injured endothelium and serotonin (5-hydroxy-tryptamine [5-HT]) released during platelet aggregation are potent vasoconstrictors. Lastly, bradykinin and fibrinopeptides, which are involved in the coagulation schema, are also capable of contracting vascular smooth muscle.The extent of vasoconstriction varies with the degree of vessel injury. A small artery with a lateral incision may remain open due to physical forces, whereas a similarly sized vessel that is completely transected may contract to the extent that bleeding ceases spontaneously.Platelet FunctionPlatelets are anucleate fragments of megakaryocytes. The nor-mal circulating number of platelets ranges between 150,000 and 400,000/μL. Up to 30% of circulating platelets may be sequestered in the spleen. If not consumed in a clotting reaction, platelets are normally removed by the spleen and have an aver-age life span of 7 to 10 days.Platelets play an integral role in hemostasis by forming a hemostatic plug and by contributing to thrombin formation (Fig. 4-2). Platelets do not normally adhere to each other or to the vessel wall but can form a plug that aids in cessation of bleeding when vascular disruption occurs. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere. This process requires von Willebrand factor (vWF), a protein in the subendothelium that is lacking in patients with von Willebrand’s disease. vWF binds to glycopro-tein (GP) I/IX/V on the platelet membrane. Following adhesion, platelets initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel. Up to this point, this process is known as primary hemostasis. Platelet aggregation is reversible and is not associated with secretion. Additionally, heparin does not interfere with this reaction, and thus, hemostasis can occur in the heparinized patient. Adenosine diphosphate (ADP) and serotonin are the principal mediators in platelet aggregation.Arachidonic acid released from the platelet membranes is converted by cyclooxygenase to prostaglandin G2 (PGG2) and then to prostaglandin H2 (PGH2), which, in turn, is converted to TXA2. TXA2 has potent vasoconstriction and platelet aggrega-tion effects. Arachidonic acid may also be shuttled to adjacent endothelial cells and converted to prostacyclin (PGI2), which is a vasodilator and acts to inhibit platelet aggregation. Platelet cyclooxygenase is irreversibly inhibited by aspirin and revers-ibly blocked by nonsteroidal anti-inflammatory agents but is not affected by cyclooxygenase-2 (COX-2) inhibitors.In the second wave of platelet aggregation, a release reaction occurs in which several substances including ADP, Ca2+, serotonin, TXA2, and α-granule proteins are discharged. Biology of Hemostasis 103Vascular Constriction / 103Platelet Function / 103Coagulation / 104Fibrinolysis / 106Congenital Factor Deficiencies 106Coagulation Factor Deficiencies / 106Platelet Functional Defects / 107Acquired Hemostatic Defects 108Platelet Abnormalities / 108Acquired Hypofibrinogenemia / 110Myeloproliferative Diseases / 110Coagulopathy of Liver Disease / 110Coagulopathy of Trauma / 111Acquired Coagulation Inhibitors / 112Anticoagulation and Bleeding / 112Topical Hemostatic Agents / 115Transfusion 115Background / 115Replacement Therapy/ 115Indications for Replacement of Blood and Its Elements / 117Volume Replacement / 117New Concepts in Resuscitation / 117Prehospital Transfusion / 119Whole Blood Resuscitation / 121Fibrinogen Replacement / 121Complications of Transfusion (Table 4-9) / 121Tests of Hemostasis and Blood  Coagulation 123Evaluation of Excessive Intraoperative or Postoperative  Bleeding 124Brunicardi_Ch04_p0103-p0130.indd 10329/01/19 11:05 AM 104Figure 4-1. Biology of hemostasis. The four phys-iologic processes that interrelate to limit blood loss from an injured vessel are illustrated and include vascular constriction, platelet plug formation, fibrin clot formation, and fibrinolysis.Key Points1 The life span of platelets ranges from 7 to 10 days. Drugs that interfere with platelet function include aspirin, clopido-grel, prasugrel, dipyridamole, and the glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors. Approximately 5 to 7 days should pass from the time the drug is stopped until an elective pro-cedure is performed.2 Laboratory evidence of trauma-induced coagulopathy is found in up to one-third of severely injured patients at admission. It is distinct from disseminated intravascular coagulopathy and iatrogenic causes of coagulopathy such as hemodilution. Several non–mutually exclusive mechanisms have been proposed. However, the relationship between laboratory coagulation abnormalities and clinically evident coagulopathic bleeding is unclear.3 Direct oral anticoagulants have no readily available method for monitoring anticoagulation. A new monoclonal antibody has been approved to reverse coagulopathy due to dabiga-tran, and agents are currently in clinical trials for the reversal of direct factor Xa oral anticoagulants.4 When determining the need for bridging of therapeutic anti-coagulation in the preoperative and postoperative setting, the patient’s risk of bleeding should be carefully considered against the risk of thromboembolism and used to guide the need for reversal of anticoagulation therapy preoperatively and the timing of its reinstatement postoperatively.5 Damage control resuscitation has three basic components: permissive hypotension, minimizing crystalloid-based resus-citation, and the administration of balanced ratios of blood products.6 The need for massive transfusion should be anticipated, and guidelines should be in place to provide early and balanced amounts of red blood cells, plasma, and platelets.Fibrinogen is a required cofactor for this process, acting as a bridge for the GP IIb/IIIa receptor on the activated platelets. The release reaction results in compaction of the platelets into a plug, a process that is no longer reversible. Thrombospondin, another protein secreted by the α-granule, stabilizes fibrino-gen binding to the activated platelet surface and strengthens the platelet-platelet interactions. Platelet factor 4 (PF4) and α-thromboglobulin are also secreted during the release reac-tion. PF4 is a potent heparin antagonist. The second wave of platelet aggregation is inhibited by aspirin and nonsteroidal anti-inflammatory drugs, by cyclic adenosine monophosphate (cAMP), and by nitric oxide. As a consequence of the release reaction, alterations occur in the phospholipids of the platelet membrane that allow calcium and clotting factors to bind to the platelet surface, forming enzymatically active complexes. The altered lipoprotein surface (sometimes referred to as platelet factor 3) catalyzes reactions that are involved in the conversion of prothrombin (factor II) to thrombin (factor IIa) by activated factor X (Xa) in the presence of factor V and calcium, and it is involved in the reaction by which activated factor IX (IXa), fac-tor VIII, and calcium activated factor X. Platelets may also play a role in the initial activation of factors XI and XII.CoagulationHemostasis involves a complex interplay and combination of interactions between platelets, the endothelium, and multiple circulating or membrane-bound coagulation factors. While overly simplistic and not reflective of the depth or complexity of these interactions, the coagulation cascade has traditionally been depicted as two possible pathways converging into a single Common pathwayIntrinsic pathwayClotting factorsVIII, IX, X, XI, XIIFibrin1. Vascular phase(Vasoconstriction)2. Platelet phase(Platelets aggregate)3. Coagulation phase (Clot formation)(Clot retraction)4. Fibrinolysis(Clot destruction)Extrinsic pathwayClotting factorsVIIProthrombinThrombinCA2+vCA2+Brunicardi_Ch04_p0103-p0130.indd 10429/01/19 11:05 AM 105HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4common pathway (Fig. 4-3). While this pathway reflects the basic process and sequences that lead to the formation of a clot, the numerous feedback loops, endothelial interplay, and platelet functions are not included. The intrinsic pathway begins with the activation of factor XII that subsequently activates factors XI, IX, and VIII. In this pathway, each of the primary factors is “intrinsic” to the circulating plasma, whereby no surface is required to initi-ate the process. In the extrinsic pathway, tissue factor (TF) is released or exposed on the surface of the endothelium, binding to circulating factor VII, facilitating its activation to VIIa. Each of these pathways continues on to a common sequence that begins with the activation of factor X to Xa (in the presence of VIIIa). Subsequently, Xa (with the help of factor Va) converts factor II (prothrombin) to thrombin and then factor I (fibrinogen) to fibrin. Clot formation occurs after fibrin monomers are cross-linked to polymers with the assistance of factor XIII.One convenient feature of depicting the coagulation cas-cade with two merging arms is that commonly used laboratory tests segregate abnormalities of clotting to one of the two arms. An elevated activated partial thromboplastin time (aPTT) is associated with abnormal function of the intrinsic arm of the cascade (II, IX, X, XI, XII), while the prothrombin time (PT) is associated with the extrinsic arm (II, VII, X). Vitamin K defi-ciency or warfarin use affects factors II, VII, IX, and X.Expanding from the basic concept of Fig. 4-3, the cell-based model of hemostasis, divided into the initiation, ampli-fication, and propagation phases, provides a more complete picture of clot formation. During initiation, the primary pathway for coagulation is initiated by TF exposure following suben-dothelial injury. TF binds to VIIa, and this complex catalyzes the activation of factor X to Xa and IX to IXa, which in turn activates factor V to Va. This “prothrombinase” complex gener-ates small amounts of thrombin from prothrombin in a calcium-dependent process. During amplification, platelets adhere to extracellular matrix components at the site of injury and become activated upon exposure to thrombin and other stimuli. Finally, during the propagation phase, “tenase” (factor VIIIa/IXa) and prothrombinase (factor Va/Xa) complexes are assembled on the surfaces of activated platelets. This results in large-scale genera-tion of thrombin (“thrombin burst”) and fibrin.In building on the redundancy inherent in the coagulation system, factor VIIIa combines with IXa to form the intrinsic factor complex. Factor IXa is responsible for the bulk of the conversion of factor X to Xa. This complex (VIIIa-IXa) is 50 times more effective at catalyzing factor X activation than is the extrinsic (TF-VIIa) complex and five to six orders of mag-nitude more effective than factor IXa alone.Once formed, thrombin leaves the membrane surface and converts fibrinogen by two cleavage steps into fibrin and two small peptides termed fibrinopeptides A and B. Removal of fibrinopeptide A permits end-to-end polymerization of the fibrin molecules, whereas cleavage of fibrinopeptide B allows side-to-side polymerization of the fibrin clot. This latter step is Platelet hemostaticfunctionVasoconstrictionADP, serotonin,Ca2+, fibrinogenADP, serotonin,Ca2+, fibrinogenSubendothelial collagenPlatelet adhesion secretionPlatelet aggregation secretionPlatelet aggregationPlatelet-fibrinthrombus(Reversible)(Irreversible)Coagulation activationvia tissue factor-factor VIIaIXa, XaComplexes onactivated plateletsThrombin+FibrinogenVascular endothelialinjuryFigure 4-2. Schematic of platelet activation and thrombus function.Figure 4-3. Schematic of the coagulation system. HMW = high molecular weight.Tissue factor-Factor VIIaInflammationComplement activationFibrinolysisPhysiologicFactor VFactor VaCa2+PhospholipidCa2+Ca2+Prothrombin(factor II) Thrombin(factor IIa)IntrinsicSurfaceFactor XIIFactor XIIa KallikreinPrekallikreinHMW kininogenSurfaceFactor XIaFactor IXaFactor XIFactor IXExtrinsicVascular injuryTissue factor +factor VIIFactor XaFactor XCa2+FibrinFactor XIIIFibrinFactor XIIIaX-Linked fibrinFibrinogenFactor VIIIaCa2+PhospholipidFactor VIIIBrunicardi_Ch04_p0103-p0130.indd 10529/01/19 11:05 AM 106BASIC CONSIDERATIONSPART Ifacilitated by thrombin-activatable fibrinolysis inhibitor (TAFI), which acts to stabilize the resultant clot.In seeking to balance profound bleeding with overwhelm-ing clot burden, several related processes exist to prevent prop-agation of the clot beyond the site of injury.1 First, feedback inhibition on the coagulation cascade deactivates the enzyme complexes leading to thrombin formation. Thrombomodulin (TM) presented by the endothelium serves as a “thrombin sink” by forming a complex with thrombin, rendering it no longer available to cleave fibrinogen. This then activates protein C (APC) and reduces further thrombin generation by inhibiting factors V and VIII. Second, tissue plasminogen activator (tPA) is released from the endothelium following injury, cleaving plasminogen to initiate fibrinolysis. APC then consumes plas-minogen activator inhibitor-1 (PAI-1), leading to increased tPA activity and fibrinolysis. Building on the anticoagulant response to inhibit thrombin formation, tissue factor pathway inhibitor (TFPI) is released, blocking the TF-VIIa complex and reducing the production of factors Xa and IXa. Antithrombin III (AT-III) then neutralizes all of the procoagulant serine proteases and also inhibits the TF-VIIa complex. The most potent mechanism of thrombin inhibition involves the APC system. APC forms a complex with its cofactor, protein S, on a phospholipid surface. This complex then cleaves factors Va and VIIIa so that they are no longer able to participate in the formation of TF-VIIa or pro-thrombinase complexes. This is of interest clinically in the form of a genetic mutation, called factor V Leiden. In this setting, factor V is resistant to cleavage by APC, thereby remaining active as a procoagulant. Patients with factor V Leiden are pre-disposed to venous thromboembolic events.Degradation of fibrin clot is accomplished by plasmin, a serine protease derived from the proenzyme plasminogen. Plas-min formation occurs as a result of one of several plasminogen activators. tPA is made by the endothelium and other cells of the vascular wall and is the main circulating form of this family of enzymes. tPA is selective for fibrin-bound plasminogen so that endogenous fibrinolytic activity occurs predominately at the site of clot formation. The other major plasminogen activa-tor, urokinase plasminogen activator (uPA), also produced by endothelial cells as well as by urothelium, is not selective for fibrin-bound plasminogen. Of note, the thrombin-TM complex activates TAFI, leading to a mixed effect on clot stability. In addition to inhibiting fibrinolysis directly, removal of the termi-nal lysine on the fibrin molecule by TAFI renders the clot more susceptible to lysis by plasmin.FibrinolysisFibrin clot breakdown (lysis) allows restoration of blood flow during the healing process following injury and begins at the same time clot formation is initiated. Fibrin polymers are degraded by plasmin, a serine protease derived from the pro-enzyme plasminogen. Plasminogen is converted to plasmin by one of several plasminogen activators, including tPA. Plasmin then degrades the fibrin mesh at various places, leading to the production of circulating fragments, termed fibrin degradation products (FDPs), cleared by other proteases or by the kidney and liver (Fig. 4-4). Fibrinolysis is directed by circulating kinases, tissue activators, and kallikrein present in vascular endothelium. tPA is synthesized by endothelial cells and released by the cells on thrombin stimulation. Bradykinin, a potent endothelial-dependent vasodilator, is cleaved from high molecular weight kininogen by kallikrein and enhances the release of tPA. Both tPA and plasminogen bind to fibrin as it forms, and this trimo-lecular complex cleaves fibrin very efficiently. After plasmin is generated, however, it cleaves fibrin somewhat less efficiently.As with clot formation, fibrinolysis is also kept in check through several robust mechanisms. tPA activates plasmino-gen more efficiently when it is bound to fibrin, so that plasmin is formed selectively on the clot. Plasmin is inhibited by α2-antiplasmin, a protein that is cross-linked to fibrin by factor XIII, which helps to ensure that clot lysis does not occur too quickly. Any circulating plasmin is also inhibited by α2-antiplasmin and circulating tPA or urokinase. Clot lysis yields FDPs including E-nodules and D-dimers. These smaller fragments interfere with normal platelet aggregation, and the larger fragments may be incorporated into the clot in lieu of normal fibrin monomers. This may result in an unstable clot as seen in cases of severe coagu-lopathy such as hyperfibrinolysis associated with trauma-induced coagulopathy or disseminated intravascular coagulopathy. The presence of D-dimers in the circulation may serve as a marker of thrombosis or other conditions in which a significant activa-tion of the fibrinolytic system is present. Another inhibitor of the fibrinolytic system is TAFI, which removes lysine residues from fibrin that are essential for binding plasminogen.CONGENITAL FACTOR DEFICIENCIESCoagulation Factor DeficienciesInherited deficiencies of all of the coagulation factors are seen. However, the three most frequent are factor VIII deficiency (hemophilia A or von Willebrand’s disease), factor IX defi-ciency (hemophilia B or Christmas disease), and factor XI deficiency. Hemophilia A and hemophilia B are inherited as sex-linked recessive disorders with males being affected almost exclusively. The clinical severity of hemophilia A and hemo-philia B depends on the measurable level of factor VIII or factor IX in the patient’s plasma. Plasma factor levels less than 1% of normal are considered severe disease, factor levels between 1% and 5% moderately severe disease, and levels between 5% and 30% mild disease. Patients with severe hemophilia have spontaneous bleeds, frequently into joints, leading to crippling arthropathies. Intracranial bleeding, intramuscular hematomas, retroperitoneal hematomas, and gastrointestinal, genitourinary, and retropharyngeal bleeding are added clinical sequelae seen with severe disease. Patients with moderately severe hemophilia have less spontaneous bleeding but are likely to bleed severely EndotheliumPlateletThrombinPlasminogentPAPlasminFibrinFDPFigure 4-4. Formation of fibrin degradation products (FDPs). tPA = tissue plasminogen activator.Brunicardi_Ch04_p0103-p0130.indd 10629/01/19 11:05 AM 107HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4after trauma or surgery. Mild hemophiliacs do not bleed sponta-neously and have only minor bleeding after major trauma or sur-gery. Since platelet function is normal in hemophiliacs, patients may not bleed immediately after an injury or minor surgery as they have a normal response with platelet activation and forma-tion of a platelet plug. At times, the diagnosis of hemophilia is not made in these patients until after their first minor procedure (e.g., tooth extraction or tonsillectomy).Patients with hemophilia A or B are treated with factor VIII or factor IX concentrate, respectively. Recombinant factor VIII is strongly recommended for patients not treated previously and is generally recommended for patients who are both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) seronegative. For factor IX replacement, the preferred products are recombinant or high-purity factor IX. In general, activity levels should be restored to 30% to 40% for mild hemorrhage, 50% for severe bleeding, and 80% to 100% for life-threatening bleeding. Up to 20% of hemophiliacs with factor VIII defi-ciency develop inhibitors that can neutralize FVIII. For patients with low titers, inhibitors can be overcome with higher doses of factor VIII. For patients with high titer inhibitors, alternate treat-ments should be used and may include porcine factor VIII, pro-thrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa. For patients undergo-ing elective surgical procedures, a multidisciplinary approach with preoperative planning and replacement is recommended.2von Willebrand’s Disease. von Willebrand’s disease (vWD), the most common congenital bleeding disorder, is characterized by a quantitative or qualitative defect in vWF, a large glycopro-tein responsible for carrying factor VIII and platelet adhesion. The latter is important for normal platelet adhesion to exposed subendothelium and for aggregation under high shear condi-tions. Patients with vWD have bleeding that is characteristic of platelet disorders such as easy bruising and mucosal bleed-ing. Menorrhagia is common in women. vWD is classified into three types. Type I is a partial quantitative deficiency; type II is a qualitative defect; type III is total deficiency. For bleeding, type I patients usually respond well to desmopressin (DDAVP). Type II patients may respond, depending on the particular defect. Type III patients are usually unresponsive. These patients may require vWF concentrates.3Factor XI Deficiency. Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemo-philia C, is more prevalent in the Ashkenazi Jewish population but found in all races. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures. Treat-ment of patients with factor XI deficiency who present with bleeding or in whom surgery is planned and who are known to have bled previously is with fresh frozen plasma (FFP). Each milliliter of plasma contains 1 unit of factor XI activity, so the volume needed depends on the patient’s baseline level, the desired level, and the plasma volume. Antifibrinolytics may be useful in patients with menorrhagia. Factor VIIa is recom-mended for patients with anti-factor XI antibodies, although thrombosis has been reported.4 There has been renewed interest in factor XI inhibitors as antithrombotic agents because patients with factor XI deficiency generally have only minimal bleeding risk unless a severe deficiency is present and seem to be pro-tected from thrombosis.5Deficiency of Factors II (Prothrombin), V, and X. Inher-ited deficiencies of factors II, V, and X are rare. These deficiencies are inherited as autosomal recessive. Significant bleeding in homozygotes with less than 1% of normal activ-ity is encountered. Bleeding with any of these deficiencies is treated with FFP. Similar to factor XI, FFP contains one unit of activity of each per milliliter. However, factor V activity is decreased because of its inherent instability. The half-life of prothrombin (factor II) is long (approximately 72 hours), and only about 25% of a normal level is needed for hemostasis. Prothrombin complex concentrates can be used to treat defi-ciencies of prothrombin or factor X. Daily infusions of FFP are used to treat bleeding in factor V deficiency, with a goal of 20% to 25% activity. Factor V deficiency may be coinherited with factor VIII deficiency. Treatment of bleeding in individuals with the combined deficiency requires factor VIII concentrate and FFP. Some patients with factor V deficiency are also lacking the factor V normally present in platelets and may need platelet transfusions as well as FFP.Factor VII Deficiency. Inherited factor VII deficiency is a rare autosomal recessive disorder. Clinical bleeding can vary widely and does not always correlate with the level of FVII coagulant activity in plasma. Bleeding is uncommon unless the level is less than 3%. The most common bleeding manifesta-tions involve easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Postoperative bleeding is also common, reported in 30% of surgical procedures.6 Treat-ment is with FFP or recombinant factor VIIa. The half-life of recombinant factor VIIa is only approximately 2 hours, but excellent hemostasis can be achieved with frequent infusions. The half-life of factor VII in FFP is up to 4 hours.Factor XIII Deficiency. Congenital factor XIII (FXIII) defi-ciency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis.7 The male-to-female ratio is 1:1. Although acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in chil-dren is the inherited deficiency.8 Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis. Umbilical stump bleeding is characteristic, and there is a high risk of intracranial bleeding. Spontaneous abortion is usual in women with factor XIII deficiency unless they receive replace-ment therapy. Replacement can be accomplished with FFP, cryoprecipitate, or a factor XIII concentrate. Levels of 1% to 2% are usually adequate for hemostasis.Platelet Functional DefectsInherited platelet functional defects include abnormalities of platelet surface proteins, abnormalities of platelet granules, and enzyme defects. The major surface protein abnormalities are thrombasthenia and Bernard-Soulier syndrome. Thrombasthe-nia, or Glanzmann thrombasthenia, is a rare genetic platelet disorder, inherited in an autosomal recessive pattern, in which the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either lacking or present but dysfunctional. This defect leads to faulty platelet aggregation and subsequent bleeding. The disorder was first described by Dr. Eduard Glanzmann in 1918.9 Bleeding in thrombasthenic patients must be treated with platelet transfu-sions. Bernard-Soulier syndrome is caused by a defect in the GP Ib/IX/V receptor for vWF, which is necessary for platelet adhesion to the subendothelium. Transfusion of normal platelets is required for bleeding in these patients.Brunicardi_Ch04_p0103-p0130.indd 10729/01/19 11:05 AM 108BASIC CONSIDERATIONSPART IThe most common intrinsic platelet defect is storage pool disease. It involves loss of dense granules (storage sites for ADP, adenosine triphosphate [ATP], Ca2+, and inorganic phosphate) and α-granules. Dense granule deficiency is the most prevalent of these. It may be an isolated defect or occur with partial albinism in Hermansky-Pudlak syndrome. Bleed-ing is variable, depending on the severity of the granule defect. Bleeding is caused by the decreased release of ADP from these platelets. A few patients have been reported who have decreased numbers of both dense and α-granules. They have a more severe bleeding disorder. Patients with mild bleeding as a consequence of a form of storage pool disease can be treated with DDAVP. It is likely that the high levels of vWF in the plasma after DDAVP somehow compensate for the intrinsic platelet defect. With more severe bleeding, platelet transfusion is required.ACQUIRED HEMOSTATIC DEFECTSPlatelet AbnormalitiesAcquired congenital abnormalities of platelets are much more common than acquired defects and may be quantitative or quali-tative, although some patients have both types of defects. Quan-titative defects may be a result of failure of production, shortened survival, or sequestration. Failure of production is generally a result of bone marrow disorders such as leukemia, myelodys-plastic syndrome, severe vitamin B12 or folate deficiency, che-motherapeutic drugs, radiation, acute ethanol intoxication, or viral infection. If a quantitative abnormality exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized. The etiologies of both qualitative and quantitative defects are reviewed in Table 4-1.Quantitative Defects. Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagu-lation, or disorders characterized by platelet thrombi such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Immune thrombocytopenia may be idiopathic or associated with other autoimmune disorders or low-grade B-cell malignancies, and it may also be secondary to viral infections (including HIV) or drugs. Secondary immune thrombocytopenia often presents with a very low platelet count, petechiae and pur-pura, and epistaxis. Large platelets are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh posi-tive. Both gamma globulin and anti-D immunoglobulin are rapid in onset. Platelet transfusions are not usually needed unless cen-tral nervous system bleeding or active bleeding from other sites occurs. Survival of the transfused platelets is usually short.Primary immune thrombocytopenia is also known as idio-pathic thrombocytopenic purpura (ITP). In children, it is usually acute in onset, short lived, and typically follows a viral illness. In contrast, ITP in adults is gradual in onset, chronic in nature, and has no identifiable cause. Because the circulating platelets in ITP are young and functional, bleeding is less for a given platelet count than when there is failure of platelet production. The patho-physiology of ITP is believed to involve both impaired platelet production and T cell–mediated platelet destruction.10 Manage-ment options are summarized in Table 4-2.11 Treatment of drug-induced immune thrombocytopenia may simply entail withdrawal of the offending drug, but corticosteroids, gamma globulin, and anti-D immunoglobulin may hasten recovery of the count.12,13Table 4-1Etiology of acquired platelet disordersA. Quantitative Disorders1. Failure of production: related to impairment in bone marrow functiona. Leukemiab. Myeloproliferative disordersc. B12 or folate deficienciesd. Chemotherapy or radiation therapye. Acute alcohol intoxicationf. Viral infections2. Decreased survivala. Immune-mediated1) Idiopathic thrombocytopenia (ITP)2) Heparin-induced thrombocytopenia3) Autoimmune disorders or B-cell malignancies4) Secondary thrombocytopeniab. Disseminated intravascular coagulation (DIC)c. Related to platelet thrombi1) Thrombocytopenic purpura (TTP)2) Hemolytic uremic syndrome (HUS)3. Sequestrationa. Portal hypertensionb. Sarcoidc. Lymphomad. Gaucher’s DiseaseB. Qualitative Disorders1. Massive transfusion2. Therapeutic platelet inhibitors3. Disease statesa. Myeloproliferative disordersb. Monoclonal gammopathiesc. Liver diseaseTable 4-2Management of idiopathic thrombocytopenic purpura (ITP) in adultsFirst line: a. Corticosteroids: Longer courses of corticosteroids are preferred over shorter courses of corticosteroids b. Intravenous immunoglobulin (IVIG) or anti-D immunoglobulin: the dose should initially be 1 g/kg as a one-time dose. This dosage may be repeated if necessarySecond line: a. Splenectomy b. Rituximab, an anti-CD 20 monoclonal antibody c. Thrombopoietin (TPO) receptor agonists d. Immunosuppressive agentsThird line: (failing first and second line therapy) a. Thrombopoietin (TPO) receptor agonists b. Combination of first and second line therapies c. Combination chemotherapyBrunicardi_Ch04_p0103-p0130.indd 10829/01/19 11:05 AM 109HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia. It is an immunologic event during which antibodies against platelet factor 4 (PF4) formed during exposure to heparin affect platelet activation and endothelial function with resultant thrombocytopenia and intravascular thrombosis.14 The platelet count typically begins to fall 5 to 7 days after heparin has been started, but if it is a reexposure, the decrease in count may occur within 1 to 2 days. HIT should be suspected if the platelet count falls to less than 100,000 or if it drops by 50% from baseline in a patient receiv-ing heparin. While HIT is more common with full-dose unfrac-tionated heparin (1% to 3%), it can also occur with prophylactic doses or with low molecular weight heparins. Interestingly, approximately 17% of patients receiving unfractionated hepa-rin and 8% receiving low molecular weight heparin develop antibodies against PF4, yet a much smaller percentage develop thrombocytopenia, and even fewer develop clinical HIT.15 In addition to mild to moderate thrombocytopenia, this disorder is characterized by a high incidence of thrombosis that may be arterial or venous. Importantly, the absence of thrombo-cytopenia in these patients does not preclude the diagnosis of HIT. The 4Ts scoring system by Lo et al can be used to assess the pretest probability of HIT and incorporates the timing and magnitude of the platelet count fall, new thrombosis, and the likelihood of other reasons for thrombocytopenia.16 A low probability 4Ts score is quite accurate in excluding HIT, but patients with intermediate or high probability scores require further evaluation.Laboratory testing should include an anti–platelet fac-tor 4–heparin enzyme-linked immunosorbent assay (ELISA). Unfortunately, this test, like the 4Ts, has a high negative predic-tive value but a low positive predictive value. While a negative ELISA essentially rules out HIT, a positive ELISA does not confirm HIT. To increase the specificity of this assay, it can be restricted to IgG antibodies or obtained in conjunction with a functional assay such as the serotonin release assay and the heparin-induced platelet activation test. Both of these are avail-able only at specialized laboratories and should only be used as second-line diagnostic assays.l7The initial treatment of suspected HIT is to stop heparin and begin an alternative anticoagulant. Stopping heparin with-out addition of another anticoagulant is not adequate to prevent thrombosis in this setting. Alternative anticoagulants are pri-marily thrombin inhibitors. The most recent guideline by the American College of Chest Physicians recommends lepiru-din, argatroban, or danaparoid for patients with normal renal function and argatroban for patients with renal insufficiency.18 Because of warfarin’s early induction of a hypercoagulable state, warfarin should be instituted only once full anticoagula-tion with an alternative agent has been accomplished and the platelet count has begun to recover.These are also disorders in which thrombocytopenia is a result of platelet activation and formation of platelet thrombi. In thrombotic thrombocytopenic purpura (TTP), large vWF mol-ecules interact with platelets, leading to activation. These large molecules result from inhibition of a metalloproteinase enzyme, ADAM-S13, which cleaves the large vWF molecules.19 TTP is classically characterized by thrombocytopenia, microangio-pathic hemolytic anemia, fever, and renal and neurologic signs or symptoms. The finding of schistocytes on a peripheral blood smear aids in the diagnosis. Plasma exchange with replacement of FFP is the treatment for acute TTP.20 Additionally, rituximab, a monoclonal antibody against the CD20 protein on B lympho-cytes, is indicated in relapsing and/or refractory TTP.21Hemolytic uremic syndrome (HUS) often occurs second-ary to infection by Escherichia coli 0157:H7 or other Shiga toxin-producing bacteria. The metalloproteinase is normal in these cases. HUS is usually associated with some degree of renal failure, with many patients requiring renal replacement therapy. Neurologic symptoms are less frequent. A number of patients develop features of both TTP and HUS. This may occur with autoimmune diseases, especially systemic lupus erythematosus and HIV infection, or in association with certain drugs (such as ticlopidine, mitomycin C, gemcitabine) or immunosuppressive agents (such as cyclosporine and tacrolimus). Discontinuation of the involved drug is the mainstay of therapy. Plasmapheresis is frequently used, but it is not clear what etiologic factor is being removed by the pheresis.Sequestration is another important cause of thrombocyto-penia and usually involves trapping of platelets in an enlarged spleen typically related to portal hypertension, sarcoid, lym-phoma, or Gaucher’s disease. The total body platelet mass is essentially normal in patients with hypersplenism, but a much larger fraction of the platelets are in the enlarged spleen. Platelet survival is mildly decreased. Bleeding is less than anticipated from the count because sequestered platelets can be mobilized to some extent and enter the circulation. Platelet transfusion does not increase the platelet count as much as it would in a normal person because the transfused platelets are similarly sequestered in the spleen. Splenectomy is not indicated to correct the throm-bocytopenia of hypersplenism caused by portal hypertension.Thrombocytopenia and platelet dysfunction are the most common abnormalities of hemostasis that result in bleeding in the surgical patient. The patient may have a reduced platelet count as a result of a variety of disease processes, as discussed earlier. In these circumstances, the marrow usually demon-strates a normal or increased number of megakaryocytes. By contrast, when thrombocytopenia occurs in patients with leu-kemia or uremia and in patients on cytotoxic therapy, there are generally a reduced number of megakaryocytes in the marrow. Thrombocytopenia also occurs in surgical patients as a result of massive blood loss with product replacement deficient in platelets. Thrombocytopenia may also be induced by heparin administration during cardiac and vascular cases, as in the case of HIT, or may be associated with thrombotic and hemorrhagic complications. When thrombocytopenia is present in a patient for whom an elective operation is being considered, manage-ment is contingent upon the extent and cause of platelet reduc-tion and extent of platelet dysfunction.Early platelet administration has now become part of mas-sive transfusion protocols.22,23 Platelets are also administered preoperatively to rapidly increase the platelet count in surgical patients with underlying thrombocytopenia or platelet dysfunc-tion. One unit of platelet concentrate contains approximately 5.5 × 1010 platelets and would be expected to increase the cir-culating platelet count by about 10,000/μL in the average 70-kg person. Fever, infection, hepatosplenomegaly, and the pres-ence of antiplatelet alloantibodies decrease the effectiveness of platelet transfusions. In patients who are refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)-compatible platelets coupled with special processors has proved effective.Brunicardi_Ch04_p0103-p0130.indd 10929/01/19 11:05 AM 110BASIC CONSIDERATIONSPART IQualitative Platelet Defects. Impaired platelet function often accompanies thrombocytopenia but may also occur in the presence of a normal platelet count. The importance of this is obvious when one considers that 80% of overall clot strength is related to platelet function. The life span of platelets ranges from 7 to 10 days, placing them at increased risk for impairment by medical disorders and prescription and over-the-counter medications. Impairment of ADP-stimulated aggregation occurs with massive transfusion of blood products. Ure-mia may be associated with increased bleeding time and impaired aggregation. Defective aggregation and platelet dys-function are also seen in patients with severe trauma, thrombo-cythemia, polycythemia vera, and myelofibrosis.Drugs that interfere with platelet function include aspirin, clopidogrel, prasugrel, dipyridamole, and GP IIb/IIIa inhibitors. Aspirin, clopidogrel, and prasugrel all irreversibly inhibit plate-let function. Clopidogrel and prasugrel do so through selective irreversible inhibition of ADP-induced platelet aggregation.24 Aspirin works through irreversible acetylation of platelet pros-taglandin synthase.There are no prospective randomized trials in general sur-gical patients to guide the timing of surgery in patients on aspi-rin, clopidogrel, or prasugrel.25 The general recommendation is that approximately 5 to 7 days should pass from the time the drug is stopped until an elective procedure is performed.26 Tim-ing of urgent and emergent surgeries is even more unclear. Pre-operative platelet transfusions may be beneficial, but there are no good data to guide their administration. However, functional tests such as thromboelastography (TEG) with platelet mapping are becoming available that may better demonstrate defects in platelet function and may serve to guide the timing of operation or when platelet transfusions might be indicated.Other disorders associated with abnormal platelet func-tion include uremia, myeloproliferative disorders, monoclonal gammopathies, and liver disease. In the surgical patient, plate-let dysfunction of uremia can often be corrected by dialysis or the administration of DDAVP. Platelet transfusion may not be helpful if the patient is uremic when the platelets are given and only serve to increase antibodies. Platelet dysfunction in myelo-proliferative disorders is intrinsic to the platelets and usually improves if the platelet count can be reduced to normal with chemotherapy. If possible, surgery should be delayed until the count has been decreased. These patients are at risk for both bleeding and thrombosis. Platelet dysfunction in patients with monoclonal gammopathies is a result of interaction of the mono-clonal protein with platelets. Treatment with chemotherapy or, occasionally, plasmapheresis to lower the amount of monoclo-nal protein improves hemostasis.Acquired HypofibrinogenemiaDisseminated Intravascular Coagulation (DIC). DIC is an acquired syndrome characterized by systemic activation of coagulation pathways that result in excessive thrombin genera-tion and the diffuse formation of microthrombi. This distur-bance ultimately leads to consumption and depletion of platelets and coagulation factors with the resultant classic picture of dif-fuse bleeding. Fibrin thrombi developing in the microcirculation may cause microvascular ischemia and subsequent end-organ failure if severe. There are many different conditions that pre-dispose a patient to DIC, and the presence of an underlying condition is required for the diagnosis. For example, injuries resulting in embolization of materials such as brain matter, bone marrow, or amniotic fluid can act as potent thromboplastins that activate the DIC cascade.27 Additional etiologies include malig-nancy, organ injury (such as severe pancreatitis), liver failure, certain vascular abnormalities (such as large aneurysms), snake bites, illicit drugs, transfusion reactions, transplant rejection, and sepsis.28 In fact, DIC frequently accompanies sepsis and may be associated with multiple organ failure. The important interplay between sepsis and coagulation abnormalities was demonstrated by Dhainaut et al who showed that activated protein C was effective in septic patients with DIC, though this has subsequently been disproven.29 The diagnosis of DIC is made based on an inciting etiology with associated thrombo-cytopenia, prolongation of the prothrombin time, a low fibrino-gen level, and elevated fibrin markers (FDPs, D-dimer, soluble fibrin monomers). A scoring system developed by the Interna-tional Society for Thrombosis and Hemostasis has been shown to have high sensitivity and specificity for diagnosing DIC as well as a strong correlation between an increasing DIC score and mortality, especially in patients with infections.30The most important facets of treatment are relieving the patient’s causative primary medical or surgical problem and maintaining adequate perfusion. If there is active bleeding, hemostatic factors should be replaced with FFP, which is usually sufficient to correct the hypofibrinogenemia, although cryopre-cipitate, fibrinogen concentrates, or platelet concentrates may also be needed. Given the formation of microthrombi in DIC, heparin therapy has also been proposed. Heparin may be indi-cated in cases where thrombosis predominates, such as arterial or venous thromboembolism and severe purpura fulminans.31Primary Fibrinolysis. Other than due to trauma, an acquired hypofibrinogenic state in the surgical patient can be a result of pathologic fibrinolysis. This may occur in patients following prostate resection when urokinase is released during surgical manipulation of the prostate or in patients undergoing extracor-poreal bypass. The severity of fibrinolytic bleeding is dependent on the concentration of breakdown products in the circula-tion. Antifibrinolytic agents, such as ε-aminocaproic acid and tranexamic acid, interfere with fibrinolysis by inhibiting plas-minogen activation.Myeloproliferative DiseasesPolycythemia, or an excess of red blood cells, places surgical patients at risk. Spontaneous thrombosis is a complication of polycythemia vera, a myeloproliferative neoplasm, and can be explained in part by increased blood viscosity, increased plate-let count, and an increased tendency toward stasis. Paradoxi-cally, a significant tendency toward spontaneous hemorrhage also is noted in these patients. Thrombocytosis can be reduced by the administration of low-dose aspirin, phlebotomy, and hydroxyurea.32Coagulopathy of Liver DiseaseThe liver plays a key role in hemostasis because it is responsible for the synthesis of many of the coagulation factors (Table 4-3). Patients with liver disease, therefore, have decreased production of several key nonendothelial cell-derived coagulation factors as well as natural anticoagulant proteins, causing a disturbance in the balance between procoagulant and anticoagulant path-ways. This disturbance in coagulation mechanisms causes a complex paradigm of both increased bleeding risk and increased 1Brunicardi_Ch04_p0103-p0130.indd 11029/01/19 11:05 AM 111HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4thrombotic risk. The most common coagulation abnormalities associated with liver dysfunction are thrombocytopenia and impaired humoral coagulation function manifested as prolonga-tion of the prothrombin time and international normalized ratio (INR). The etiology of thrombocytopenia in patients with liver disease is typically related to hypersplenism, reduced produc-tion of thrombopoietin, and immune-mediated destruction of platelets. The total body platelet mass is often normal in patients with hypersplenism, but a much larger fraction of the platelets is sequestered in the enlarged spleen. Bleeding may be less than anticipated because sequestered platelets can be mobilized to some extent and enter the circulation. Thrombopoietin, the pri-mary stimulus for thrombopoiesis, may be responsible for some cases of thrombocytopenia in cirrhotic patients, although its role is not well delineated. Finally, immune-mediated thrombocyto-penia may also occur in cirrhotics, especially those with hepatitis C and primary biliary cirrhosis.33 In addition to thrombocytope-nia, these patients also exhibit platelet dysfunction via defective interactions between platelets and the endothelium, and possibly due to uremia and changes in endothelial function in the setting of concomitant renal insufficiency. Hypocoagulopathy is fur-ther exacerbated with low platelet counts because platelets help facilitate thrombin generation by assembling coagulation factors on their surfaces. In conditions mimicking intravascular flow, low hematocrit and low platelet counts contributed to decreased adhesion of platelets to endothelial cells, although increased vWF, a common finding in cirrhotic patients, may offset this change in patients with cirrhosis.34 Hypercoagulability of liver disease has recently gained increased attention, with more evi-dence demonstrating the increased incidence of thromboem-bolism despite thrombocytopenia and a hypocoagulable state on conventional blood tests.35,36 This is attributed to decreased production of liver-synthesized proteins C and S, antithrombin, and plasminogen levels, as well as elevated levels of endothe-lial-derived vWF and factor VIII, a potent driver of thrombin generation.37,38 Given the concomitant hypoand hypercoagu-lable features seen in patients with liver disease, conventional coagulation tests may be difficult to interpret, and whole blood functional tests such as thromboelastography (TEG) or ROTEM may be more informative of the status of clot formation and stability in cirrhotic patients. Small studies have indicated that TEG provides a better assessment of bleeding risk than standard tests of hemostasis in patients with liver disease; however, no large studies have directly tested this, and future larger trials are needed.39Before instituting any therapy to ameliorate thrombocy-topenia, the actual need for correction should be strongly con-sidered. In general, correction based solely on a low platelet count should be discouraged. Most often, treatment should be withheld for invasive procedures and surgery. When required, platelet transfusions are the mainstay of therapy; however, the effect typically lasts only several hours. Risks associated with transfusions in general and the development of antiplate-let antibodies in a patient population likely to need recurrent correction should be considered. A less well-accepted option is splenectomy or splenic embolization to reduce hypersplenism. In addition to the risks associated with these techniques, reduced splenic blood flow can reduce portal vein flow with subsequent portal vein thrombosis. Results are mixed following insertion of a transjugular intrahepatic portosystemic shunt (TIPS). There-fore, treatment of thrombocytopenia should not be the primary indication for a TIPS procedure.Decreased production or increased destruction of coagula-tion factors as well as vitamin K deficiency can all contribute to a prolonged PT and INR in patients with liver disease. As liver dysfunction worsens, so does the liver’s synthetic func-tion, which results in decreased production of coagulation fac-tors. Additionally, laboratory abnormalities may mimic those of DIC. Elevated D-dimers have been reported to increase the risk of variceal bleeding. The absorption of vitamin K is dependent on bile production. Therefore, liver patients with impaired bile production and cholestatic disease may be at risk for vitamin K deficiency.Similar to thrombocytopenia, correction of coagulopathy should be reserved for treatment of active bleeding and prophy-laxis for invasive procedures and surgery. Treatment of coagu-lopathy caused by liver disease is usually done with FFP, but because the coagulopathy is usually not a result of decreased levels of factor V, complete correction is not usually possible. If the fibrinogen is less than 200 mg/dL, administration of cryo-precipitate may be helpful. Cryoprecipitate is also a source of factor VIII for the rare patient with a low factor VIII level.Coagulopathy of TraumaTraditional teaching regarding trauma-related coagulopathy attributed its development to acidosis, hypothermia, and dilution of coagulation factors. Recent data, however, have shown that over one-third of severely injured patients have laboratory-based evidence of coagulopathy at the time of admission,40 a phenotype called trauma-induced coagulopathy (TIC). TIC is independent of traditional (iatrogenic) causes of posttraumatic coagulopathy such as hemodilution, is precipitated by tissue injury and/or hemorrhagic shock, and is associated with signifi-cantly higher risk of mortality, especially in the first 24 hours after injury. Furthermore, TIC is a separate and distinct process from disseminated intravascular coagulopathy with its own specific components of hemostatic failure.As shown in Fig. 4-5, several non–mutually exclusive mechanisms have been proposed as the etiology of TIC,41 includ-ing activated protein C-mediated clotting factor deactivation,42 endothelial injury and “auto-heparinization” due to shedding of endothelial heparin sulfate and chondroitin sulfate into the circulation,43 platelet dysfunction,44 and hyperfibrinolysis.45 Hemorrhagic shock was previously thought to be an essential component of TIC, but isolated traumatic brain injury46 and pulmonary contusions47 have been shown to induce laboratory-defined TIC in the absence of shock, possibly due to a high pro-portion of endothelium in these organs. Traumatic brain injury may also induce TIC via a consumptive mechanism by the release of large amounts of tissue factor into the circulation.48 2Table 4-3Coagulation factors synthesized by the liverVitamin K–dependent factors: II (prothrombin factor), VII, IX, XFibrinogenFactor VFactor VIIIFactors XI, XII, XIIIAntithrombin IIIPlasminogenProtein C and protein SBrunicardi_Ch04_p0103-p0130.indd 11129/01/19 11:05 AM 112BASIC CONSIDERATIONSPART IHowever, the relationship between laboratory-based coagula-tion abnormalities and true clinically evident coagulopathic bleeding is unclear. With the widespread application of damage control resuscitation, the frequency of clinical coagulopathy has decreased.Interestingly, the converse of hyperfibrinolysis, known as fibrinolytic shutdown, has also been associated with increased mortality after trauma.49 In a multicenter study of 2540 trauma patients, those with intermediate fibrinolytic activity (“physiologic,” 0.8% to 2.9% lysis) on admission had the lowest mortality (14%). Shutdown (<0.8% lysis) patients had increased mortality (22%), often due to late causes such as mul-tiple organ failure, while patients with hyperfibrinolysis (≥3% lysis) had the greatest mortality (34%) and most often died due to hemorrhage.50Acquired Coagulation InhibitorsAmong the most common acquired coagulation inhibitors is the antiphospholipid syndrome (APLS), which includes the lupus anticoagulant and anticardiolipin antibodies. These antibodies may be associated with either venous or arterial thrombosis, or both. In fact, patients presenting with recurrent thrombosis should be evaluated for APLS. Antiphospholipid antibodies are very common in patients with systemic lupus but may also be seen in association with rheumatoid arthritis and Sjögren’s syndrome. There are also individuals who will have no autoimmune disor-ders but develop transient antibodies in response to infections or those who develop drug-induced APLS. The hallmark of APLS is a prolonged aPTT in vitro but an increased risk of thrombosis in vivo.Anticoagulation and BleedingSpontaneous bleeding can be a complication of any antico-agulant therapy whether it is heparin, low molecular weight heparins, warfarin, factor Xa inhibitors, or new direct thrombin inhibitors. The risk of spontaneous bleeding related to heparin is reduced with a continuous infusion technique. Therapeutic anticoagulation is more reliably achieved with a low molecu-lar weight heparin. However, laboratory testing is more chal-lenging with these medications, as they are not detected with conventional coagulation testing. However, their more reli-able therapeutic levels (compared to heparin) make them an attractive option for outpatient anticoagulation and more costeffective for the inpatient setting. If monitoring is required (e.g., in the presence of renal insufficiency or severe obesity), the drug effect should be determined with an assay for anti-Xa activity.Warfarin is used for long-term anticoagulation in various clinical conditions, including deep vein thrombosis, pulmonary embolism, valvular heart disease, atrial fibrillation, recurrent systemic emboli, recurrent myocardial infarction, prosthetic heart valves, and prosthetic implants. Due to the interaction of the P450 system, the anticoagulant effect of the warfarin is reduced (e.g., increased dose required) in patients receiving barbiturates as well as in patients with diets low in vitamin K. Increased warfarin requirements may also be needed in patients taking contraceptives or estrogen-containing compounds, corti-costeroids, and adrenocorticotropic hormone (ACTH). Medica-tions that can alter warfarin requirements are shown in Table 4-4.Although warfarin use is often associated with a signifi-cant increase in morbidity and mortality in acutely injured and emergency surgery patients, with rapid reversal, these com-plications can be reduced. There are several reversal options that include vitamin K administration, plasma, cryoprecipi-tate, recombinant factor VIIa, and factor concentrates. The 2012 CHEST guidelines for the Management of Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombo-sis recommends patients with major life-threatening bleeding TRAUMATICCLINICALCOAGULOPATHICBLEEDING?PlateletactivationEGLsheddingEndothelial activationAcidosisHypothermiaHemorrhageShock˜˜˜tPA &°PAI-1Hypo-perfusionClotting factorconsumptionPre-injuryanticoagulantmedicationIatrogenicresuscitationinjuryHemodilution˜Acidosis˜HypothermiaAuto-heparinization°Clotting factoractivityPlatelet dysfunctionHyperfibrinolysis˜Catecholamines˜APCFigure 4-5. Illustration of the pathophysiologic mechanism responsible for the acute coagulopathy of trauma. APC = activated protein C; EGL = endothelial glycocalyx; PAI-1 = plasminogen activator inhibitor 1; tPA = tissue plasminogen activator; TIC = trauma-induced coagulopathy. (Reproduced with permission from Chang R, Cardenas JC, Wade CE, et al: Advances in the understanding of trauma-induced coagulopathy. Blood. 2016 Aug 25;128(8):1043-1049.)Table 4-4Medications that can alter warfarin dosing↓ warfarin effect↑ warfarin requirementsBarbiturates, oral contraceptives, estrogen-containing compounds, corticosteroids, adrenocorticotropic hormone↑ warfarin effect↓ warfarin requirementsPhenylbutazone, clofibrate, anabolic steroids, L-thyroxine, glucagons, amiodarone, quinidine, cephalosporinsBrunicardi_Ch04_p0103-p0130.indd 11229/01/19 11:05 AM 113HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4due to warfarin receive reversal with vitamin K and a rapid reversal agent such as plasma or prothrombin complex concen-trate (PCC).51 Vitamin K is given to sustain the effects of the plasma or PCC due to their short half-lives. In major bleeds, Vitamin K 10 mg given as a slow IV infusion is utilized for more rapid onset compared to the oral form. Studies have shown that PCC is superior to plasma for speed of reversal and has decreased risk of fluid overload, but it is equivalent in adverse and thromboembolic events and costlier.52,53 Prothrombin com-plex concentrate is available in two forms: three-factor PCC (factors II, IX, and X) and four-factor PCC (factors II, VII, IX, and X). Four-factor PCCs have been shown to have a more reli-able correction of INR compared to three-factor PCCs.54,55Direct oral anticoagulants (DOACs) include direct throm-bin inhibitors and factor Xa inhibitors and have no readily available method of detection of the degree of anticoagula-tion. More concerning is the difficulty in the reversal of these new anticoagulants. Recently, idarucizumab, a humanized monoclonal antibody fragment that binds dabigatran, has been approved for use for reversal of the thrombin inhibitor, dabiga-tran, and dabigatran-related coagulopathy. Clinical studies have demonstrated normalization of laboratory tests.56,57Factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban currently lack a specific antidote. Two novel anti-dotes, andexanet alfa and ciraparantag (PER977), are currently undergoing clinical trials. Andexanet alfa is a recombinant human FXa variant,58,59 and ciraparantag is a cationic small molecule.60 These are both being evaluated for reversal of the factor Xa inhibitors. Until these agents are approved, attempts to reverse Factor Xa inhibitors should include four factor PCCs.61 In less urgent states, these drugs can be held for 36 to 48 hours prior to surgery without increased risk of bleeding in those with normal renal function. Alternatively, activated clotting time (stand alone or with rapid TEG) or ecarin clotting time can be obtained in those on dabigatran, and anti-factor Xa assays can be obtained in those taking rivaroxaban.Bleeding complications in patients on anticoagulants include hematuria, soft tissue bleeding, intracerebral bleeding, skin necrosis, and abdominal bleeding. Bleeding secondary to anticoagulation therapy is also a common cause of rectus sheath hematomas.Surgical intervention may prove necessary in patients receiving anticoagulation therapy. Increasing experience suggests that surgical treatment can be undertaken without full reversal of the anticoagulant, depending on the procedure being performed.62 When the aPTT is less than 1.3 times control in a heparinized patient, or when the INR is less than 1.5 in a patient on warfarin, reversal of anticoagulation therapy may not be necessary. How-ever, meticulous surgical technique is mandatory, and the patient must be observed closely throughout the postoperative period.Certain surgical procedures should not be performed in concert with anticoagulation. In particular, cases where even minor bleeding can cause great morbidity, such as the central nervous system and the eye, surgery should be avoided. Emer-gency operations are occasionally necessary in patients who have been heparinized. The first step in these patients is to dis-continue heparin. For more rapid reversal, protamine sulfate is effective. However, significant adverse reactions, especially in patients with severe fish allergies, may be encountered when administering protamine.63 Symptoms include hypotension, flushing, bradycardia, nausea, and vomiting. Prolongation of the aPTT after heparin neutralization with protamine may also be a result of the anticoagulant effect of protamine. In the elective surgical patient who is receiving warfarin-derivative therapy sufficient to effect anticoagulation, the drug can be discontinued several days before operation and the prothrombin concentration then checked.64 Rapid reversal of anticoagulation can be accom-plished with plasma or prothrombin complex concentrates in the emergent situation. An example of a warfarin reversal guideline using four-factor prothrombin complex concentrate for patients with major or life-threatening bleeding or intracranial bleeding is shown in Fig. 4-6. Parenteral administration of vitamin K also is indicated in elective surgical treatment of patients with biliary obstruction or malabsorption who may be vitamin K deficient. However, if low levels of factors II, VII, IX, and X (vitamin K–dependent factors) exist as a result of hepatocellular dysfunc-tion, vitamin K administration is ineffective.The perioperative management of patients receiving long-term oral anticoagulation therapy is an increasingly common problem. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines from 2012 suggests periopera-tive “bridging” of anticoagulation.65 However, recent studies have found an increased risk of major bleeding without a change in thromboembolism rate when comparing bridging to no-bridg-ing for elective operations or procedures.66 Additional clinical trials are currently underway, but at the current time, physicians should carefully balance risks of bleeding vs. venous thromboembolism risks for individual patients when deciding on bridging of anticoagulation for procedures.67 For patients in whom the risk of venous thromboembolism out-weighs the risk of bleeding, a heparin infusion should be held for 4 to 6 hours before the procedure and restarted within 12 to 24 hours of the end of its completion. High-risk indications include mechanical heart valves, recent (within 30 days) myo-cardial infarction, stroke, or pulmonary embolism. Lower risk indications, such as thromboembolic events greater than 30 days prior, hypercoagulable history, and atrial fibrillation, do not require such stringent restarting strategies.Cardiopulmonary Bypass. Under normal conditions, homeo-stasis of the coagulation system is maintained by complex inter-actions between the endothelium, platelets, and coagulation factors. In patients undergoing cardiopulmonary bypass (CPB), contact with circuit tubing and membranes results in abnormal platelet and clotting factor activation, as well as activation of inflammatory cascades, that ultimately results in excessive fibri-nolysis and a combination of both quantitative and qualitative platelet defects. Platelets undergo reversible alterations in mor-phology and their ability to aggregate, which causes sequestra-tion in the filter, partially degranulated platelets, and platelet fragments. This multifactorial coagulopathy is compounded by the effects of shear stress in the system, induced hypothermia, hemodilution, and anticoagulation.68While on pump, activated clotting time measurements are obtained along with blood gas measurements; however, con-ventional coagulation assays and platelet counts are not nor-mally performed until rewarming and after a standard dose of protamine has been given. TEG may give a better estimate of the extent of coagulopathy and may also be used to anticipate transfusion requirements if bleeding is present.68Empiric treatment with FFP and cryoprecipitate is often used for bleeding patients; however, there are no universally accepted transfusion thresholds. Platelet concentrates are given for bleeding patients in the immediate postoperative period; however, studies have shown that indiscriminate plate-let therapy conferred no therapeutic advantage.69 It is in these 34Brunicardi_Ch04_p0103-p0130.indd 11329/01/19 11:05 AM 114BASIC CONSIDERATIONSPART Ipatients where rapid coagulation testing is required to assist with directed transfusion therapy.70 Many institutions now use antifibrinolytics, such as ε-aminocaproic acid and tranexamic acid, at the time of anesthesia induction after several studies have shown that such treatment reduced postoperative bleed-ing and reoperation. Aprotinin, a protease inhibitor that acts as an antifibrinolytic agent, has been shown to reduce transfusion requirements associated with cardiac surgery.71 Desmopressin acetate stimulates release of factor VIII from endothelial cells and may also be effective in reducing blood loss during cardiac surgery.Local Hemostasis. Significant surgical bleeding is usually caused by ineffective local hemostasis. The goal is therefore to prevent further blood loss from a disrupted vessel that has been incised or transected. Hemostasis may be accomplished by interrupting the flow of blood to the involved area or by direct closure of the blood vessel wall defect.Mechanical Procedures. The oldest mechanical method of bleeding cessation is application of direct digital pressure, either at the site of bleeding or proximally to permit more definitive action. An extremity tourniquet that occludes a major vessel proximal to the bleeding site or the Pringle maneuver for liver bleeding are good examples. Direct digital pressure is very effective and has the advantage of being less traumatic than hemostatic or even “atraumatic” clamps.When a small vessel is transected, a simple ligature is usu-ally sufficient. However, for larger pulsating arteries, a transfix-ion suture to prevent slipping is indicated. All sutures represent foreign material, and selection should be based on their intrinsic characteristics and the state of the wound. Direct pressure applied by “packing” a wound with gauze or laparotomy pads affords the best method of controlling diffuse bleeding from large areas, such as in the trauma situation. Packing bone wax on the raw surface to effect pressure can control bleeding from cut bone.Thermal Agents. Heat achieves hemostasis by denaturation of protein that results in coagulation of large areas of tissue. Elec-trocautery generates heat by induction from an alternating cur-rent source, which is then transmitted via conduction from the instrument directly to the tissue. The amplitude setting should be high enough to produce prompt coagulation, but not so high as to set up an arc between the tissue and the cautery tip. This avoids thermal injury outside of the operative field and also prevents exit of current through electrocardiographic leads, other moni-toring devices, or permanent pacemakers or defibrillators. A negative grounding plate should be placed beneath the patient to avoid severe skin burns, and caution should be used with certain Major bleeding/life-threatening bleeding orintracranial hemorrhage (lCH)Administer phytonadione 10 mg IV immediatelyCheck PT/INR, PTT, fibrinogen, platelets, Hgb/HctEvaluate for relative contraindications to PCC4 (Kcentra®)• Thrombotic event in the past 3 months – myocardial infarction,stroke, pulmonary embolism, deep vein thrombosis• Very high risk of thrombosis, such as patients with clinical orlaboratory evidence of overt disseminated intravascularcoagulopathy, heparin-induced thrombocytopenia (HIT), high-riskthrombophilia, or antiphospholipid syndromeCheck PT/INR 1 hr, 6 hrs, and 24 hrs after completion of Kcentra®• If INR >1.5 at 1 hr, consider switching to FFP therapy• If INR >1.5 at 6 hrs, repeat phytonadione 10 mg IV over 30 min• If INR >1.5 at 24 hrs, repeat phytonadione 10 mg IV over 30 minINR 1.5–3.9Kcentra®25 units/kg(maximum 2500 units)INR 4–6Kcentra®35 units/kg(maximum 3500 units)INR >6Kcentra®50 units/kg(maximum 5000 units)Administer FFPYesNoContraindication toKcentra®Figure 4-6. Example of a warfarin reversal guideline using four-factor prothrombin complex concentrate for patients with major or life-threatening bleeding or intracranial bleeding.Brunicardi_Ch04_p0103-p0130.indd 11429/01/19 11:05 AM 115HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4anesthetic agents (diethyl ether, divinyl ether, ethyl chloride, ethylene, and cyclopropane) because of the hazard of explosion.A direct current also can result in hemostasis. Because the protein moieties and cellular elements of blood have a nega-tive surface charge, they are attracted to a positive pole where a thrombus is formed. Direct currents in the 20to 100-mA range have successfully controlled diffuse bleeding from raw surfaces, as has argon gas.Topical Hemostatic AgentsTopical hemostatic agents can play an important role in help-ing to facilitate surgical hemostasis. These agents are classified based on their mechanism of action, and many act at specific stages in the coagulation cascade and take advantage of natural physiologic responses to bleeding.72 The ideal topical hemo-static agent has significant hemostatic action, minimal tissue reactivity, nonantigenicity, in vivo biodegradability, ease of sterilization, low cost, and can be tailored to specific needs.73Achneck et al have published a comprehensive overview of absorbable, biologic, and synthetic agents.74 Absorbable agents include gelatin foams (Gelfoam), oxidized cellulose (Surgicel), and microfibrillar collagens (Avitene). Both gelatin foam and oxidized cellulose provide a physical matrix for clotting initia-tion, while microfibrillar collagens facilitate platelet adherence and activation. Biologic agents include topical thrombin, fibrin sealants (FloSeal), and platelet sealants (Vitagel). Human or recombinant thrombin derivatives, which facilitate the forma-tion of fibrin clots and subsequent activation of several clotting factors, take advantage of natural physiologic processes, thereby avoiding foreign body or inflammatory reactions.73 Caution must be taken in judging vessel caliber in the wound because thrombin entry into larger caliber vessels can result in systemic exposure to thrombin with a risk of disseminated intravascular clotting or death. They are particularly effective in controlling capillary bed bleeding when pressure or ligation is insufficient; however, the bovine derivatives should be used with caution due to the potential immunologic response and worsened coagulopathy. Fibrin sealants are prepared from cryoprecipitate (homologous or synthetic) and have the advantage of not promoting inflam-mation or tissue necrosis.75 A recent study by Koea et al dem-onstrated in a prospective multicenter randomized trial that a fibrin sealant patch was safe and highly effective in controlling parenchymal bleeding following hepatectomy regardless of the type of resection.76 Platelet sealants are a mixture of collagen and thrombin combined with plasma-derived fibrinogen and platelets from the patient, which requires the additional need for centrifugation and processing.Topical agents are not a substitute for meticulous surgical technique and only function as adjuncts to help facilitate surgi-cal hemostasis. The advantages and disadvantages of each agent must be considered, and use should be limited to the minimum amount necessary to minimize toxicity, adverse reactions, inter-ference with wound healing, and procedural costs.TRANSFUSIONBackgroundHuman blood replacement therapy was accepted in the late nine-teenth century. This was followed by the introduction of blood grouping by Landsteiner who identified the major A, B, and O groups in 1900, resulting in widespread use of blood products in World War I. Levine and Stetson in 1939 followed with the concept of Rh grouping. These and other breakthroughs in blood product preservation, storage, and infectious disease screening established the foundation from which the field of transfusion medicine has grown. Whole blood was considered the standard in transfusion until the late 1970s when component therapy began to take prominence. This change in practice was driven in part by blood bank economics, increasing the availability of specific blood products for patients with isolated deficien-cies (anemia, thrombocytopenia, clotting factor deficiencies), especially those associated with chemotherapy.77 However, this change occurred for all patients simultaneously without studies to identify the clinical ramifications in different patient popu-lations requiring blood product therapy. Interestingly, whole blood transfusion (the ultimate balanced transfusion product) is making a resurgence in both military and civilian practice for resuscitation of acute hemorrhage.Replacement TherapyTyping and Crossmatching. Serologic compatibility for A, B, O, and Rh groups is established routinely. Crossmatching between the donors’ red blood cells and the recipients’ sera (the major crossmatch) is performed. Rh-negative recipients should be transfused only with Rh-negative red blood cells. However, this group represents only 15% of the population. Therefore, the administration of Rh-positive red blood cells is acceptable if Rh-negative red blood cells blood is not available. However, Rh-positive red blood cells should not be transfused to Rhnegative females who are of childbearing age.In emergency situations, universal donor type O-negative red blood cells and type AB plasma may be transfused to all recip-ients. Platelets do not require crossmatching. Due to a shortage of type AB plasma, low anti-B titer type A plasma has become widely adopted for emergency (uncrossmatched) transfusion.78 In the United States, 85% of individuals are type A or type O, mak-ing type A plasma compatible with the vast majority of poten-tial recipients. Uncrossmatched plasma is routinely transfused as part of platelet transfusions, with major transfusion reactions reported rarely,79 and type AB plasma currently carries a higher risk of TRALI compared to other plasma types.80 Many cen-ters have transitioned to low titer type A plasma for emergency transfusions, with no increase in adverse events.81 O negative and type-specific red blood cells are equally safe for emergency transfusion. In patients known to have clinically significant cold agglutinins, blood should be administered through a blood warmer. If these antibodies are present in high titer, hypother-mia is contraindicated.In patients who have been multiply transfused and who have developed alloantibodies or who have autoimmune hemo-lytic anemia with pan-red blood cell antibodies, typing and crossmatching is often difficult, and sufficient time should be allotted preoperatively to accumulate blood that might be required during the operation. Crossmatching should always be performed before the administration of dextran because it inter-feres with the typing procedure.81aBanked Whole Blood. Interest in whole blood as an ideal therapy for acute traumatic hemorrhagic shock has increased in the last several years with multiple reports of successful use in military and civilian trauma patients. However, there is still limited access in most civilian centers.Red Blood Cells and Frozen Red Blood Cells. Red blood cells are the traditional product of choice for most clinical Brunicardi_Ch04_p0103-p0130.indd 11529/01/19 11:05 AM 116BASIC CONSIDERATIONSPART Isituations requiring resuscitation, although deficits in oxygen delivery are rarely related to inadequate red cells. Concentrated suspensions of red blood cells can be prepared by removing most of the supernatant plasma after centrifugation. The prepa-ration reduces but does not eliminate reactions caused by plasma components. With sequential changes in storage solutions, the shelf life of red blood cells is now 42 days. However, recent evidence has demonstrated that the age of red cells may play a significant role in the inflammatory response and incidence of multiple organ failure.82 The changes in the red blood cells that occur during storage include reduction of intracellular ADP and 2,3-diphosphoglycerate (2,3-DPG), which alters the oxygen dissociation curve of hemoglobin, resulting in a decrease in oxy-gen transport. Stored RBCs progressively become acidotic with elevated levels of lactate, potassium, and ammonia. Addition-ally, the in vitro hemostatic potential of plasma83 and platelet84 products also decrease with storage.The morphologic and biochemical changes that occur over time in red cells may contribute to worsened outcomes. This limits the ability to bank large amounts of blood, particu-larly rarer blood types, for use in times of high demand and blood supply shortage, such as on the battlefield and after mass casualty events. Storage solutions, however, do not fully sup-press the metabolic and physical changes associated with aging RBCs. Newer evidence suggests that cryopreservation of red blood cells may provide a safe alternative means of storage. Cryopreservation uses the beneficial effects of ultra-low tem-peratures to suppress molecular motion and arrest metabolic and biochemical reactions. Frozen (cryopreserved) red blood cells have a shelf life of ten years at -80°C with improved cel-lular viability and maintenance of ATP and 2,3 DPG concen-trations.85 A trial of stable trauma patients randomized to old (>14 storage days) red blood cells, young (≤14 storage days) red blood cells, and cryopreserved red blood cells found that cryopreserved red blood cells were as safe and effective as stan-dard red blood cells.85 Cryopreserved red blood cells required a thawing and preparation period of about 90 minutes, limiting immediate availability for emergency use. A recent study sug-gests that the post-thaw characteristics of cryopreserved units may not, however, be comparable to fresh red cells.86 Additional research needs to be done to optimize the process, but frozen cells likely represent a viable option for storage in the future.Leukocyte-Reduced and Leukocyte-Reduced/Washed Red Blood Cells. These products are prepared by filtration that removes about 99.9% of the white blood cells and most of the platelets (leukocyte-reduced red blood cells) and, if necessary, by additional saline washing (leukocyte-reduced/washed red blood cells). Leukocyte reduction prevents almost all febrile, nonhemolytic transfusion reactions (fever and/or rigors), allo-immunization to HLA class I antigens, and platelet transfu-sion refractoriness and cytomegalovirus transmission. In most Western nations, it is the standard red blood cell transfusion product. Supporters of universal leukocyte reduction argue that allogenic transfusion of white cells predisposes to postoperative bacterial infection and multiorgan failure. Reviews of random-ized trials and meta-analyses have not provided convincing evi-dence either way,87,88 although a large Canadian retrospective study suggests a decrease in mortality and infections.89Platelet Concentrates. The indications for platelet transfu-sion include thrombocytopenia caused by massive blood loss and replacement with platelet-poor products, thrombocytopenia caused by inadequate production, and qualitative platelet dis-orders. Platelets are stored at room temperature under constant agitation to prevent clumping and have a shelf life of 5 days from time of donation due to risk of bacterial overgrowth. One unit of platelet concentrate has a volume of approximately 50 mL. Platelet preparations are capable of transmitting infec-tious diseases and can account for allergic reactions similar to those caused by red blood cell transfusion. A therapeutic level of platelets is in the range of 50,000 to 100,000/μL, but is very dependent on the clinical situation. Recent evidence suggests that earlier use of platelets may improve outcomes in bleeding patients.90In rare cases, in patients who become alloimmunized through previous transfusion or patients who are refractory from sensitization through prior pregnancies, HLA-matched platelets can be used.Plasma. Plasma is the usual source of the vitamin K–dependent factors, the only source of factor V, and carries similar infectious risks as other component therapies. Several plasma products are available. Fresh frozen plasma (FFP) is frozen within hours of donation and can be stored for up to two years at -18°C, but requires 20 to 30 minutes to thaw prior to use, limiting immedi-ate availability. Thawed FFP can be relabeled as thawed plasma, which is immediately transfusable and can be stored for up to 5 days at 2° to 4°C. Liquid plasma is never frozen and can be stored for up to 26 days at 2° to 4°C. In vitro studies demonstrate that liquid plasma has a better hemostatic profile than thawed plasma.91 Freeze-dried (lyophilized) plasma (FDP) has been recently “rediscovered” as an ideal resuscitation product for patients in remote and austere environments. FDP is distributed as a powder that is shelf-stable for up to 2 years at room tem-perature and relatively stable at temperature extremes.92 It was used extensively as a primary resuscitation fluid during World War II, but production was stopped due to risk of disease trans-mission. FDP is currently manufactured by updated processes in France, Germany, and South Africa. Several noncomparative studies in the literature have documented its ease of use, rapid reconstitution within minutes, clinical efficacy similar to other plasma products, and lack of apparent adverse events.93,94 The Israeli Defense Force has reported successful use of FDP at the point of injury,95 just as it was used in World War II. Beside limited use by U.S. Special Forces under the U.S. Federal Drug Administration’s (FDA) Investigational New Drug (IND) pro-gram, no FDP product is currently approved for general use in the United States. These products have the advantage of being pathogen reduced, have expanded storage capabilities, and can be quickly reconstituted.96Tranexamic Acid. Tranexamic acid (TXA; trade name: Cyk-lokapron) is an antifibrinolytic that inhibits both plasminogen activation and plasmin activity, thus preventing clot breakdown rather than promoting new clot formation. It occupies the lysine-binding sites on plasminogen, thus preventing its binding to lysine residues on fibrin. This reduces plasminogen activation to plasmin. Similarly, blockade of lysine-binding sites on circu-lating plasmin prevents binding to fibrin and thus prevents clot breakdown. TXA is 10 times more potent in vitro than aminoca-proic acid. At therapeutically relevant concentrations, TXA does not affect platelet count or aggregation or coagulation param-eters. It is excreted largely unchanged in urine and has a half-life of about 2 hours in circulation. It has been used to decrease bleeding and the need for blood transfusions in coronary artery Brunicardi_Ch04_p0103-p0130.indd 11629/01/19 11:05 AM 117HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4bypass grafting (CABG), orthotopic liver transplantation, hip and knee arthroplasty, and other surgical settings. TXA has been used to treat injured patients in both civilian and military settings.97,98 A recent practice guideline by the Eastern Associa-tion for the Surgery of Trauma (EAST) conditionally recom-mended the use of tranexamic acid as a hemostatic adjunct in severely injured patients when used early after injury.99 There is some controversy if its use should be empiric in patients with hemorrhage or based on documented hyperfibrinolysis. Results of prehospital studies with TXA are not yet available, but there are five ongoing trials. The true risk of venous thrombotic events is also not well established. Therefore, tranexamic acid should not be used with active intravascular clotting and should not be given with activated prothrombin complex concentrate or factor IX complex concentrates.Indications for Replacement of Blood and Its ElementsImprovement in Oxygen-Carrying Capacity. Oxygencarrying capacity is primarily a function of the red blood cells. Thus, transfusion of red blood cells should augment oxygen-carrying capacity. Additionally, hemoglobin is fundamental to arterial oxygen content and thus oxygen delivery. Despite this obvious association, there is little evidence that actually sup-ports the premise that transfusion of red blood cells equates with enhanced cellular delivery and utilization. The reasons for this apparent discrepancy are related to changes that occur with stor-age of blood. The decrease in 2,3-DPG and P50 impair oxygen offloading, and deformation of the red cells impairs microcir-culatory perfusion.100Treatment of Anemia: Transfusion Triggers. The concept of transfusion triggers refers primarily to the nonactively bleed-ing ICU patient. A 1988 National Institutes of Health Consensus Report challenged the dictum that a hemoglobin value of less than 10 g/dL or a hematocrit level less than 30% indicates a need for preoperative red blood cell transfusion. This was veri-fied in a prospective randomized controlled trial in critically ill patients that compared a restrictive transfusion threshold to a more liberal strategy and demonstrated that maintaining hemo-globin levels between 7 and 9 g/dL had no adverse effect on mortality. In fact, patients with APACHE II scores of ≤20 or patients age <55 years actually had a lower mortality.101One unresolved issue related to transfusion triggers is the safety of maintaining a hemoglobin of 7 g/dL in a patient with ischemic heart disease. Data on this subject are mixed, and many studies have significant design flaws, including their ret-rospective nature. However, the majority of the published data favors a restrictive transfusion trigger for patients with non–ST-elevation acute coronary syndrome, with many reporting worse outcomes in those patients receiving transfusions.102,103 Recent guidelines from the American Association of Blood Banks (AABB) recommend a minimum threshold of 7 g/dL for hemodynamically stable patients and 8 g/dL for patients under-going cardiac surgery, orthopedic surgery, and those with pre-existing cardiovascular disease.104 However, both the SCCM/EAST and AABB guidelines recommend taking into account patient-specific characteristics and the overall clinical context when considering RBC transfusions in non-acutely hemorrhag-ing patients. Patients with symptomatic anemia should be trans-fused one RBC unit at a time, and isolated asymptomatic anemia in and of itself is rarely an indication for RBC transfusion.Volume ReplacementThe most common indication for blood transfusion in surgical patients is the replenishment of the blood volume; however, the quantification of actual intravascular volume deficit is often difficult to accurately and quickly determine. Measure-ments of hemoglobin or hematocrit levels are frequently used to assess blood loss, but can be occasionally misleading in the face of acute loss.105 Both the amount and the rate of bleeding are factors in the development of signs and symptoms of blood loss.Loss of blood in the operating room can be roughly evalu-ated by estimating the amount of blood in the wound and on the drapes, weighing the sponges, and quantifying blood suctioned from the operative field. Significant blood loss will require a balanced resuscitation including red blood cells, FFP, and plate-lets (detailed later in this chapter) (Table 4-5).New Concepts in ResuscitationTraditional resuscitation algorithms were sequentially based on crystalloid followed by red blood cells and then plasma and platelet transfusions, and they have been in widespread use since the 1970s. No quality clinical data supported this concept. Recently the damage control resuscitation (DCR)105a strategy, with simultaneous measures to acquire mechanical hemorrhage control, has become the standard for treatment of substantial traumatic hemorrhage. DCR emphasizes rapid maneuvers that promote hemostasis (balanced resuscitation with early delivery of plasma and platelets) while limiting iatrogenic insults that exacerbate bleeding (i.e., minimization of crystalloid and artifi-cial colloid, permissive hypotension), combined with multiple adjuncts for hemorrhage control.Rationale. In urban civilian trauma systems, nearly half of all deaths happen before a patient reaches the hospital.106 Patients who survive to an emergency center have a high incidence of truncal hemorrhage, and deaths in this group of patients may be potentially preventable. Truncal hemorrhage patients in shock often present with the early coagulopathy of trauma in the emer-gency department and are at significant risk of dying.107-109Many of these patients have suffered substantial bleeding, generally defined as requiring the administration of ≥3 units of red blood cells within any hour of admission, and may have received a massive transfusion (MT), traditionally defined as ≥10 units of red blood cells in 24 hours.110 The traditional defi-nition is admittedly arbitrary and fails to identify many patients who truly receive large volume transfusions in a short period of time, further promoting survival bas. Newer definitions evaluating massive transfusion do so by taking into account both volume transfused as well as the rate at which transfu-sions are given. The critical administration threshold (CAT) has been prospectively validated and shown to be a superior predictor of mortality when compared to the conventional defi-nition of MT.110 By this measure, CAT-positive status is defined by transfusion of 3 units of red blood cells within a 60-minute period, and this is additive for each additional time this measure is reached. CAT-positive status is associated with a two-fold increase in risk of mortality. CAT is more sensitive than tra-ditional definitions of bleeding and allows for both earlier and more accurate identification of injured patients at greatest risk of death.Although 25% of all severely injured trauma admissions receive a unit of blood early after admission, only a small Brunicardi_Ch04_p0103-p0130.indd 11729/01/19 11:05 AM 118BASIC CONSIDERATIONSPART ITable 4-5Replacement of clotting factorsFACTORNORMAL LEVELLIFE SPAN IN VIVO (HALF-LIFE)FATE DURING COAGULATIONLEVEL REQUIRED FOR SAFE HEMOSTASISIDEAL AGENT ACD BANK BLOOD (4°C [39.2°F])IDEAL AGENT FOR REPLACING DEFICITI (fibrinogen)200–400 mg/100 mL72 hConsumed60–100 mg/100 mLVery stableBank blood; concentrated fibrinogenII (prothrombin)20 mg/100 mL (100% of normal level)72 hConsumed15%–20%StableBank blood; concentrated preparationV (proaccelerin, accelerator globulin, labile factor)100% of normal level36 hConsumed5%–20%Labile (40% of normal level at 1 wk)Fresh frozen plasma; blood under 7 dVII (proconvertin, serum prothrombin conversion accelerator, stable factor)100% of normal level5 hSurvives5%–30%StableBank blood; concentrated preparationVIII (antihemophilic factor, antihemophilic globulin)100% of normal level (50%–150% of normal level)6–12 hConsumed30%Labile (20%–40% of normal level at 1 wk)Fresh frozen plasma; concentrated antihemophilic factor; cryoprecipitateIX (Christmas factor, plasma thromboplastin component)100% of normal level24 hSurvives20%–30%StableFresh-frozen plasma; bank blood; concentrated preparationX (Stuart-Prower factor)100% of normal level40 hSurvives15%–20%StableBank blood; concentrated preparationXI (plasma thromboplastin antecedent)100% of normal levelProbably 40–80 hSurvives10%Probably stableBank bloodXII (Hageman factor)100% of normal levelUnknownSurvivesDeficit produces no bleeding tendencyStableReplacement not requiredXIII (fibrinase, fibrin-stabilizing factor)100% of normal level4–7 dSurvivesProbably <1%StableBank bloodPlatelets150,000–400,000/μL8–11 dConsumed60,000–100,000/μLVery labile (40% of normal level at 20 h; 0 at 48 h)Fresh blood or plasma; fresh platelet concentrate (not frozen plasma)ACD = acid-citrate-dextrose.Reproduced with permission from Kinney JM, Egdahl RH, Zuidema GD: Manual of Preoperative and Postoperative Care, 2nd ed. Philadelphia, PA: WB Saunders/Elsevier; 1971.Brunicardi_Ch04_p0103-p0130.indd 11829/01/19 11:05 AM 119HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4percentage of patients receive a massive transfusion. In the military setting, the percentage of massive transfusion patients almost doubles.111Damage Control Resuscitation. Prior to DCR, resuscitation guidelines advocated volume replacement with crystalloid, fol-lowed by packed red blood cell and only later plasma or platelets.112 This conventional massive transfusion practice was based on a several small uncontrolled retrospective studies that used blood products containing increased amounts of plasma, which are no longer available.113 Because of the known early coagulopathy of trauma, the current approach to managing the exsanguinating patient involves early implementation of DCR. Although most of the attention to hemorrhagic shock resuscitation has centered on higher ratios of plasma and platelets, DCR is actually composed of four basic components: permissive hypotension, minimizing crystalloid-based resusci-tation, the immediate release and administration of predefined balanced blood products (red blood cells, plasma, and platelets) in ratios similar to those of whole blood, and the use of hemo-static adjuncts.The shift to DCR began in earnest in 2007 when a retro-spective study of 246 military casualties reported that patients with high plasma:RBC ratio (median 1:1.4) had substantially reduced mortality (19% vs. 65%) compared to patients with low plasma:RBC ratio (median 1:8).114 Subsequent observational studies among civilian and military trauma patients corrobo-rated these findings.115-118 In particular, the prospective, obser-vational, multicenter, major trauma transfusion (PROMMTT) study119 found that hemorrhagic death occurred rapidly (median of 2 to 3 hours after hospital arrival) and that plasma:RBC and platelet:RBC ratios significantly varied during massive trans-fusion. Increased plasma:RBC (adjusted hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.16-0.58) and increased platelet:RBC (adjusted HR 0.55, 95% CI 0.31-0.98) were associated with reduced 6-hour mortality, when risk of hemor-rhagic death was highest. After 6 hours, however, increasing plasma:RBC and platelet:RBC were no longer associated with reduced mortality due to increasing competing risk for non-hemorrhagic death (e.g., traumatic brain injury). The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial120 randomized 680 bleeding trauma patients across 12 highest-level trauma centers to resuscitation with 1:1:1 vs. 1:1:2 plasma to platelets to RBCs. Although there was no significant difference in mortality at 24 hours (13% vs. 17%) or 30 days (22% vs. 26%), the 1:1:1 group had significantly decreased mortality due to hemorrhage at 24 hours (9% vs. 15%) and more patients achieving hemostasis (86% vs. 78%). Despite fears that resuscitation with increased plasma volumes would lead to more inflammatory complications, there were no between-group differences in 23 prespecified secondary outcomes, including acute respiratory distress syndrome, sepsis, multiple organ failure, and venous thromboembolism. A recent system-atic review/meta-analysis and practice management guideline from EAST reported reduced mortality (31% vs. 38%) in 5292 patients receiving high (≥1:1) versus low (<1:2) plasma to RBC, and reduced mortality (28% vs. 43%) in 1607 patients receiving high versus low platelet to RBC.99 The authors therefore recom-mend high and balanced ratio (≥1:1) of plasma and platelet to RBC for resuscitation of severely injured trauma patients.The mechanism for these benefits are unclear. While cor-rection of hypovolemia as well as augmention of the patient’s hemostatic potential with clotting factors and platelets are impor-tant, other plasma proteins likely play key roles as well. Recently, plasma resuscitation has been shown to reverse endothelial injury in animal models of hemorrhagic shock, particularly by repair of the endothelial glycocalyx layer (EGL).121,122 The EGL is the primary determinant of vascular permeability.123 Hemorrhage results in shedding of EGL components and vascular perme-ability. Crystalloid and artificial colloid-based resuscitation increases the hydrostatic pressure without repairing the EGL, which likely contributes to the myriad of edema-related com-plications seen in the pre-DCR era. Plasma, on the other hand, repairs the EGL, limiting extravascular leakage and edema. However, the exact protein moieties that mediate these benefits have yet to be identified and remain an area of investigation. Nevertheless, several studies have reported decreased inflam-matory and edema-related complications with increased plasma and decreased crystalloid utilization. In trauma patients, there are strong correlations between increasing circulating levels of glycocalyx components such as syndecan-1 and trauma severity, coagulopathy, and mortality,124-126 although it remains unclear if these relationships are causative or merely associative. Finally, the use of DCR principles to guide transfusion of substantial nontraumatic hemorrhage is intuitive, although there is little evidence in the literature to support this practice.It is essential that the trauma center has an established mechanism to deliver these products quickly and in the correct amounts to these critically injured patients.99 An example of an adult massive transfusion clinical guideline specifying the early use of component therapy is shown in Table 4-6. Specific rec-ommendations for the administration of component ther-apy during a massive transfusion are shown in Table 4-7.Because only a small percentage of trauma patients require a massive transfusion and because blood products in general are in short supply, there is a need for early prediction models.127 A comparison of results from existing models in both civilian and military studies is shown in Table 4-8.128-132 While compel-ling, many of these models require laboratory data, complicated injury severity scores, or calculated values that are not readily available or feasible to obtain in the urgent setting of bleeding. The Assessment of Blood Consumption (ABC) score is a sim-plified score to predict massive transfusion after trauma using immediately available data (heart rate, blood pressure, FAST exam, mechanism of injury).132 The ABC score has been vali-dated across multiple trauma centers; however, it may be limited in some centers by the variable use of and operator-dependent FAST examination. In using the ABC score as it was intended, less than 5% of patients who will require massive transfusion will be missed; and 85% of all major trauma patients will be correctly identified.Prehospital TransfusionIn bleeding patients, earlier initiation of appropriate therapy improves outcomes. For example, decreased overall blood product use and increased 30-day survival was observed after moving four units of universal donor, ready-to-transfuse plasma from the blood bank to the emergency department and using the plasma as a primary resuscitation fluid.133 A prehospital retrospective study that analyzed 1677 severely injured trauma patients who were transported by helicopter found that in-flight plasma transfusion was associated with less deranged physiol-ogy on admission and reduced early mortality in the most criti-cally ill patients.134 Prehospital RBC transfusion has also been 56Brunicardi_Ch04_p0103-p0130.indd 11929/01/19 11:05 AM 120BASIC CONSIDERATIONSPART ITable 4-6Adult transfusion clinical practice guidelineA. Initial Transfusion of Red Blood Cells (RBCs):1. Notify blood bank immediately of urgent need for RBCs.O negative uncrossmatched (available immediately).As soon as possible, switch to O negative for females and O positive for males.Type-specific uncrossmatched (available in approximately 5–10 min).Completely crossmatched (available in approximately 40 min).2. A blood sample must be sent to blood bank for a type and cross.3. The Emergency Release of Blood form must be completed. If the blood type is not known and blood is needed immediately, O-negative RBCs should be issued.4. RBCs will be transfused in the standard fashion. All patients must be identified (name and number) prior to transfusion.5. Patients who are unstable or receive 1–2 RBCs and do not rapidly respond should be considered candidates for the massive transfusion (MT) guideline.B. Adult Massive Transfusion Guideline:1. The Massive Transfusion Guideline (MTG) should be initiated as soon as it is anticipated that a patient will require massive transfusion. The blood bank should strive to deliver plasma, platelets, and RBCs in a 1:1:1 ratio. To be effective and minimize further dilutional coagulopathy, the 1:1:1 ratio must be initiated early, ideally with the first 2 units of transfused RBCs. Crystalloid infusion should be minimized.2. Once the MTG is activated, the blood bank will have 6 RBCs, 6 FFP, and a 6-pack of platelets packed in a cooler available for rapid transport. If 6 units of thawed FFP are not immediately available, the blood bank will issue units that are ready and notify appropriate personnel when the remainder is thawed. Every attempt should be made to obtain a 1:1:1 ratio of plasma:platelets:RBCs.3. Once initiated, the MT will continue until stopped by the attending physician. MT should be terminated once the patient is no longer actively bleeding.4. No blood components will be issued without a pickup slip with the recipient’s medical record number and name.5. Basic laboratory tests should be drawn immediately on ED arrival and optimally performed on point-of-care devices, facilitating timely delivery of relevant information to the attending clinicians. These tests should be repeated as clinically indicated (e.g., after each cooler of products has been transfused). Suggested laboratory values are:• CBC• INR, fibrinogen• pH and/or base deficit• TEG, where availableCBC = complete blood count; ED = emergency department; FFP = fresh frozen plasma; INR = international normalized ratio; TEG = thromboelastography.Table 4-7Component therapy administration during massive transfusionFresh frozen plasma (FFP)As soon as the need for massive transfusion is recognized.For every 6 red blood cells (RBCs), give 6 FFP (1:1 ratio).PlateletsFor every 6 RBCs and plasma, give one 6-pack of platelets. 6 random-donor platelet packs = 1 apheresis platelet unit.Platelets are in every cooler.Keep platelet counts >100,000.CryoprecipitateAfter first 6 RBCs, check fibrinogen level. If ≤200 mg/dL, give 20 units cryoprecipitate (2 g fibrinogen). Repeat as needed, depending on fibrinogen level, and request appropriate amount of cryoprecipitate.Table 4-8Comparison of massive transfusion prediction studiesAUTHORVARIABLESROC AUC VALUEMcLaughlin et al128SBP, HR, pH, Hct0.839Yücel et al129SBP, HR, BD, Hgb, male, + FAST, long bone/pelvic fracture0.892Moore et al130SBP, pH, ISS >250.804Schreiber et al131Hgb ≤11, INR >1.5, penetrating injury0.80Cotton et al132HR, SBP, FAST, penetrating injury0.83–0.90AUC = area under the curve; BD = base deficit; FAST = focused assessment with sonography for trauma; Hct = hematocrit; Hgb = hemoglobin; HR = heart rate; INR = international normalized ratio; ISS = injury severity score; ROC = receiver operating characteristic; SBP = systolic blood pressure.Brunicardi_Ch04_p0103-p0130.indd 12029/01/19 11:05 AM 121HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4Nonhemolytic Reactions. Febrile, nonhemolytic reactions are defined as an increase in temperature (>1°C) associated with a transfusion and are fairly common (approximately 1% of all transfusions). Preformed cytokines in donated blood and recipi-ent antibodies reacting with donated antibodies are postulated eti-ologies. The incidence of febrile reactions can be greatly reduced by the use of leukocyte-reduced blood products. Pretreatment with acetaminophen reduces the severity of the reaction.Bacterial contamination of infused blood is rare. Gram-negative organisms, which are capable of growth at 4°C, are the most common cause. Most cases, however, are associated with the administration of platelets that are stored at 20°C or, even more commonly, with apheresis platelets stored at room tem-perature. Cases from FFP thawed in contaminated water baths have also been reported.150 Bacterial contamination can result in sepsis and death in up 25% of patients.151 Clinical manifesta-tions includes systemic signs such as fever and chills, tachycar-dia and hypotension, and gastrointestinal symptoms (abdominal cramps, vomiting, and diarrhea). If the diagnosis is suspected, the transfusion should be discontinued and the blood cultured. Emergency treatment includes oxygen, adrenergic blocking agents, and antibiotics.Allergic Reactions. Allergic reactions are relatively frequent, occurring in about 1% of all transfusions. Reactions are usually mild and consist of rash, urticaria, and flushing. In rare instances, anaphylactic shock develops. Allergic reactions are caused by the transfusion of antibodies from hypersensitive donors or the trans-fusion of antigens to which the recipient is hypersensitive. Allergic reactions can occur after the administration of any blood product but are commonly associated with FFP and platelets. Treatment and prophylaxis consist of the administration of antihistamines. In more serious cases, epinephrine or steroids may be indicated.Respiratory Complications. Respiratory compromise may be associated with transfusion-associated circulatory overload (TACO), which is an avoidable complication. It can occur with rapid infusion of blood, plasma expanders, and crystalloids, par-ticularly in older patients with underlying heart disease. Central venous pressure monitoring should be considered whenever large amounts of fluid are administered. Overload is manifested by a rise in venous pressure, dyspnea, and cough. Rales can gen-erally be heard at the lung bases. Treatment consists of diuresis, slowing the rate of blood administration, and minimizing fluids while blood products are being transfused.The syndrome of TRALI is defined as noncardiogenic pulmonary edema related to transfusion.152 It can occur with the administration of any plasma-containing blood product. Symptoms are similar to circulatory overload with dyspnea and associated hypoxemia. However, TRALI is characterized as noncardiogenic and is often accompanied by fever, rigors, and bilateral pulmonary infiltrates on chest X-ray. It most com-monly occurs within 1 to 2 hours after the onset of transfusion but virtually always before 6 hours. Toy et al reported a decrease in the incidence of TRALI with the reduction transfusion of plasma from female donors, due to a combination of reduced transfusion of strong cognate HLA class II antibodies and HNA antibodies in patients with risk factors for acute lung injury.153 TRALI now occurs less than 1 in 10,000 units transfused and is usually self-limited with supportive therapy. Treatment of TRALI entails discontinuation of any transfusion, notification of the transfusion service, and pulmonary support, which may vary from supplemental oxygen to mechanical ventilation.associated with similar findings.135 In the military setting, imple-mentation of prehospital transfusion protocols in conjunction with other measures, including more rapid transport times, was also associated with reduced mortality.136Whole Blood ResuscitationMilitary experience with whole blood for the resuscitation of traumatic hemorrhage is extensive, going back to the American Civil War. In the modern era, more than 10,000 whole blood units were transfused during Operations Enduring Freedom and Iraqi Freedom. One key advantage of whole blood ver-sus component therapy is that platelets are often unavailable in the remote and austere settings. Two retrospective studies of military casualties treated at a combat support hospital and forward surgical teams found that whole blood was associated with improved survival compared to component (plasma and RBC) therapy.137,138 Whole blood has higher hematocrit, clotting factor activity, and platelet count compared to 1:1:1 component therapy due to relatively less diluent volume in whole blood. During the Vietnam War, low anti-A and anti-B titer whole blood was transfused universally with a low incidence of hemo-lytic reactions (1 per 9600 units).139 An in vitro study found that the hemostatic potential of whole blood was preserved for up to 14 days with cold storage.140 Pilot trials have reported success-ful use of crossmatched modified whole blood (leukoreduced and platelet-poor)141 and uncrossmatched low-titer whole blood (leukoreduced, containing platelets)142 in the initial resuscita-tion of civilian trauma patients. In the future, whole blood may return as the therapy of choice for the initial resuscitation of substantial hemorrhage.143Fibrinogen ReplacementFibrinogen is the first coagulation factor to fall to critically low levels during major hemorrhage, and low systemic concentra-tions of fibrinogen are associated with increased severity of injury and coagulopathy and are independently predictive of mortality.144,145 Additionally, fibrinogen levels drop in the pre-hospital phase of injury, suggesting early administration by fibrinogen concentrate (not FDA-approved) or cryoprecipitate is needed.146 Fibrinogen concentrate is stored as a lyophilized powder at room temperature and can be reconstituted quickly allowing for rapid administration without delays for thawing or crossmatching.147 In contrast to plasma, viral inactivation steps are routinely included in the manufacturing process for fibrino-gen concentrate, thus minimizing the risk of viral transmission. A pilot trial of massively transfused trauma patients randomized to a massive transfusion protocol or a massive transfusion pro-tocol with early cryoprecipitate found that early cryoprecipitate delivery was feasible and that these patients had higher fibrino-gen levels at all time points during resuscitation, although there was no mortality difference.148 A randomized control trial in Austria of prehospital fibrinogen concentrate versus placebo has been completed with publication of results pending.149Complications of Transfusion (Table 4-9)Transfusion-related complications are primarily related to blood-induced proinflammatory responses. Transfusion-related149a events are estimated to occur in approximately 10% of all trans-fusions, but less than 0.5% are serious in nature. Transfusionrelated deaths, although exceedingly rare, do occur and are related primarily to transfusion-related acute lung injury (TRALI), ABO hemolytic transfusion reactions, and bacterial contamination of platelets.Brunicardi_Ch04_p0103-p0130.indd 12129/01/19 11:05 AM 122BASIC CONSIDERATIONSPART IHemolytic Reactions. Hemolytic reactions can be classified as either acute or delayed. Acute hemolytic reactions occur with the administration of ABO-incompatible blood and can be fatal in up to 6% of cases. Contributing factors include errors in the laboratory of a technical or clerical nature or the administra-tion of the wrong blood type. Immediate hemolytic reactions are characterized by intravascular destruction of red blood cells and consequent hemoglobinemia and hemoglobinuria. DIC can be initiated by antibody-antigen complexes activating factor XII and complement, leading to activation of the coagulation cas-cade. Finally, acute renal insufficiency results from the toxicity associated with free hemoglobin in the plasma, resulting in tubu-lar necrosis and precipitation of hemoglobin within the tubules.Delayed hemolytic transfusion reactions occur 2 to 10 days after transfusion and are characterized by extravascular hemolysis, mild anemia, and indirect (unconjugated) hyperbili-rubinemia. They occur when an individual has a low antibody titer at the time of transfusion, but the titer increases after trans-fusion as a result of an anamnestic response. Reactions to non-ABO antigens involve immunoglobulin G-mediated clearance by the reticuloendothelial system.If the patient is awake, the most common symptoms of acute transfusion reactions are pain at the site of transfusion, facial flushing, and back and chest pain. Associated symptoms include fever, respiratory distress, hypotension, and tachycardia. In anesthetized patients, diffuse bleeding and hypotension are the hallmarks. A high index of suspicion is needed to make the diag-nosis. The laboratory criteria for a transfusion reaction are hemo-globinuria and serologic criteria that show incompatibility of the donor and recipient blood. A positive Coombs’ test indicates Table 4-9Transfusion-related complicationsABBREVIATIONCOMPLICATIONSIGNS AND SYMPTOMSFREQUENCYMECHANISMPREVENTIONNHTRFebrile, nonhemolytic transfusion reactionFever0.5%–1.5% of transfusionsPreformed cytokinesHost Ab to donor lymphocytesUse leukocyte-reduced bloodStore platelets <5 d Bacterial contaminationHigh fever, chillsHemodynamic changesDICEmesis, diarrheaHemoglobinuria<0.01% of blood<0.05% of plateletsInfusion of contaminated blood  Allergic reactionsRash, hivesItching0.1%–0.3% of unitsSoluble transfusion constituentsProvide antihistamine prophylaxisTACOTransfusion-associated circulatory overloadPulmonary edema1:200–1:10,00 of transfused patientsLarge volume of blood transfused into an older patient with CHFIncrease transfusion timeAdminister diureticsMinimize associated fluidsTRALITransfusion-related acute lung injuryAcute (<6 h) hypoxemiaBilateral infiltrates ± Tachycardia, hypotension Anti-HLA or anti-HNA Ab in transfused blood attacks circulatory and pulmonary leukocytesLimit female donors Hemolytic reaction, acuteFeverHypotensionDICHemoglobinuriaHemoglobinemiaRenal insufficiency1:33,000–1:1,500,000 unitsTransfusion of ABO-incompatible bloodPreformed IgM Ab to ABO AgTransfuse appropriately matched blood Hemolytic reaction, delayed (2–10 d)AnemiaIndirect hyperbilirubinemiaDecreased haptoglobin levelPositive result on direct Coombs’ test IgG mediatedIdentify patient’s Ag to prevent recurrenceAb = antibody; Ag = antigen; CHF = congestive heart failure; DIC = disseminated intravascular coagulation; HLA = human leukocyte antigen; HNA = anti-human neutrophil antigen; IgG = immunoglobulin G; IgM = immunoglobulin M.Brunicardi_Ch04_p0103-p0130.indd 12229/01/19 11:05 AM 123HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4transfused cells coated with patient antibody and is diagnostic. Delayed hemolytic transfusions may also be manifested by fever and recurrent anemia. Jaundice and decreased haptoglobin usu-ally occur, and low-grade hemoglobinemia and hemoglobinuria may be seen. The Coombs’ test is usually positive, and the blood bank must identify the antigen to prevent subsequent reactions.If an immediate hemolytic transfusion reaction is sus-pected, the transfusion should be stopped immediately, and a sample of the recipient’s blood drawn and sent along with the suspected unit to the blood bank for comparison with the pretransfusion samples. Urine output should be monitored and adequate hydration maintained to prevent precipitation of hemo-globin within the tubules. Delayed hemolytic transfusion reac-tions do not usually require specific intervention.Transmission of Disease. Malaria, Chagas’ disease, brucel-losis, and, very rarely, syphilis are among the diseases that have been transmitted by transfusion. Malaria can be transmitted by all blood components. The species most commonly implicated is Plasmodium malariae. The incubation period ranges from 8 to 100 days; the initial manifestations are shaking chills and spiking fever. Cytomegalovirus (CMV) infection resembling infectious mononucleosis also has occurred.Transmission of hepatitis C and HIV-1 has been dra-matically minimized by the introduction of better antibody and nucleic acid screening for these pathogens. The residual risk among allogeneic donations is now estimated to be less than 1 per 1,000,000 donations. The residual risk of hepatitis B is approximately 1 per 300,000 donations.154 Hepatitis A is very rarely transmitted because there is no asymptomatic carrier state. Improved donor selection and testing are responsible for the decreased rates of transmission. Recent concerns about the rare transmission of these and other pathogens, such as West Nile virus, are being addressed by current trials of “pathogen inactivation systems” that reduce infectious levels of all viruses and bacteria known to be transmittable by transfusion. Prion dis-orders (e.g., Creutzfeldt-Jakob disease) also are transmissible by transfusion, but there is currently no information on inactivation of prions in blood products for transfusion.Recently, there is heightened concern of transmission of Zika virus by blood product transfusion. Studies in endemic areas have shown rates of Zika infection detected in donor blood as high as 2.8%.155 Although no such cases have been reported in the United States, transmission of Zika virus via platelet products have been reported in Brazil.156 Zika virus may result in serious birth defects including microcephaly when infection occurs in pregnant women. Because the majority of cases in adults produce nonspecific or no symptoms, Zika screening cannot be accomplished by questionnaires.157 The Centers for Disease Control and Prevention has issued guidelines for screen-ing of Zika virus in donated blood. Although no tests have been FDA-approved, laboratory testing is currently being performed under the FDA’s IND program.TESTS OF HEMOSTASIS AND BLOOD COAGULATIONThe initial approach to assessing hemostatic function is a careful review of the patient’s clinical history (including previous abnor-mal bleeding or bruising), drug use, and basic laboratory testing.Conventional Coagulation Tests. Common screening labo-ratory testing includes platelet count, PT or INR, and aPTT. Platelet dysfunction can occur at either extreme of platelet count. The normal platelet count ranges from 150,000 to 400,000/μL. Whereas a platelet count greater than 1,000,000/μL may be associated with bleeding or thrombotic complications, increased bleeding complications may be observed with major surgical procedures when the platelets are below 50,000/μL and with minor surgical procedures when counts are below 30,000/μL, and spontaneous hemorrhage can occur when the counts fall below 20,000/μL. Despite a lack of evidence supporting their use, platelet transfusions are still recommended in ophthalmo-logic and neurosurgical procedures when the platelet count is less than 100,000/μL.The PT and aPTT are variations of plasma recalcifica-tion times initiated by the addition of a thromboplastic agent. The PT reagent contains thromboplastin and calcium that, when added to plasma, leads to the formation of a fibrin clot. The PT test measures the function of factors I, II, V, VII, and X. Factor VII is part of the extrinsic pathway, and the remaining factors are part of the common pathway. Factor VII has the shortest half-life of the coagulation factors, and its synthesis is vitamin K dependent. The PT test is best suited to detect abnor-mal coagulation caused by vitamin K deficiencies and warfarin therapy.Due to variations in thromboplastin activity, it can be dif-ficult to accurately assess the degree of anticoagulation on the basis of PT alone. To account for these variations, the INR is now the method of choice for reporting PT values. The Interna-tional Sensitivity Index (ISI) is unique to each batch of thrombo-plastin and is furnished by the manufacturer to the hematology laboratory. Human brain thromboplastin has an ISI of 1, and the optimal reagent has an ISI between 1.3 and 1.5.The INR is a calculated number derived from the follow-ing equation:INR = (measured PT/normal PT)ISIThe aPTT reagent contains a phospholipid substitute, acti-vator, and calcium, which in the presence of plasma leads to fibrin clot formation. The aPTT measures function of factors I, II, and V of the common pathway and factors VIII, IX, X, and XII of the intrinsic pathway. Heparin therapy is often monitored by following aPTT values with a therapeutic target range of 1.5 to 2.5 times the control value (approximately 50 to 80 seconds). Low molecular weight heparins are selective Xa inhibitors that may mildly elevate the aPTT, but therapeutic monitoring is not routinely recommended.Additional medications may significantly impair hemo-static function, such as antiplatelet agents (clopidogrel and GP IIb/IIIa inhibitors), anticoagulant agents (hirudin, chondroitin sul-fate, dermatan sulfate), and thrombolytic agents (streptokinase, tPA). If abnormalities in any of the coagulation studies cannot be explained by known medications, congenital abnormalities of coagulation or comorbid disease should be considered.Unfortunately, while conventional coagulation tests (PT, aPTT) capture the classic intrinsic and extrinsic coagulation cas-cade, they do not reflect the complexity of in vivo coagulation.158 Although they are useful to follow warfarin and heparin thera-pies, they poorly reflect the status of actively bleeding patients. This is not surprising given that these tests use only plasma and not whole blood to provide their assessment of the patient’s clot-ting status. To better assess the complex and rapidly changing hemostatic function of an actively bleeding patient, many cen-ters have moved to whole blood viscoelastic testing.Brunicardi_Ch04_p0103-p0130.indd 12329/01/19 11:05 AM 124BASIC CONSIDERATIONSPART IViscoelastic Assays. Viscoelastic assays, such as TEG or rotational thromboelastometry (ROTEM), monitor hemostasis as a dynamic process rather than revealing information from isolated conventional coagulation screens.159 Both tests measure the viscoelastic properties of blood as clotting is induced under a low-shear environment. The patterns of change in shear elas-ticity enable determination of the kinetics of clot formation and growth as well as the strength and stability of the formed clot. The strength and stability provide information about the ability of the clot to perform the work of hemostasis, while the kinet-ics determines the adequacy of quantitative factors available for clot formation.Continuous improvements in this technique have made this test a valuable tool for medical personnel interested in coagulation. A sample of celite-activated whole blood is placed into a prewarmed cuvette, and the clotting process is activated with reagents, such as kaolin for standard TEG, and kaolin plus tissue factor for rapid TEG. Both TEG and ROTEM employ a vertical pin which is lowered into the activated blood sample. In TEG, the cuvette oscillates in an arc around the stationary pin. As the blood clots, fibrin strands and platelet aggregates form between the pin and inner walls of the cuvette. The resulting torque on the pin is measured and converted to an electrical signal. In ROTEM, the cuvette is stationary while the pin oscil-lates within the sample. The extent to which the pin can oscillate is reduced as the blood clots, and this is measured by the angle of deflection of a beam of light directed at the pin.160 In TEGs, the strength of a clot is graphically represented over time as a characteristic cigar-shaped figure (Fig. 4-7).Several parameters are generated from the TEG tracing. The r-value (reaction time) represents the time between the start of the assay and initial clot formation. This reflects clotting fac-tor activity and initial fibrin formation and is increased with fac-tor deficiency or severe hemodilution. The k-time (clot kinetics) is the time needed to reach specified clot strength and repre-sents the interactions of clotting factors and platelets. As such, the k-time is prolonged with hypofibrinogenemia and signifi-cant factor deficiency. Prolonged r-value and k-time are com-monly addressed with plasma transfusions. The alpha or angle (∝) is the slope of the tracing and reflects clot acceleration. The angle reflects the interactions of clotting factors and platelets. The slope is decreased with hypofibrinogenemia and platelet dysfunction. Decreased angles are treated with cryoprecipitate transfusion or fibrinogen administration. The maximal ampli-tude (mA) is the greatest height of the tracing and represents clot strength. Its height is reduced with dysfunction or deficiencies in platelets or fibrinogen. Decreased mA is addressed with platelet transfusion and, in cases where the angle is also decreased, with cryoprecipitate (or fibrinogen) as well. The G-value is a para-metric measure derived from the mA value and reflects overall clot strength or firmness. An increased G-value is associated with hypercoagulability, whereas a decrease is seen with hypo-coagulable states. Finally, the LY30 is the amount of lysis occur-ring in the clot, and the value is the percentage of amplitude reduction at 30 minutes after mA is achieved. The LY30 rep-resents clot stability and when increased fibrinolysis is present.TEG and ROTEM are the only tests measuring all dynamic steps of clot formation until eventual clot lysis or retraction. TEG has also been shown to identify on admission those patients likely to develop thromboembolic complications after injury and postoperatively.161Recent trauma data have shown TEG to be useful in pre-dicting early transfusion of red blood cells, plasma, platelets, and cryoprecipitate.162 TEG can also predict the need for life-saving interventions shortly after arrival, 24-hour and 30-day mortality, and can be used to guide administration of TXA to injured patients with hyperfibrinolysis.163,164 Lastly, some cen-ters have demonstrated that the graphic display options allow for more rapid return of results and may be less expensive than standard coagulation panels. Given the strong association of viscoelastic tests with clinical outcomes, some centers now use TEG rather than conventional coagulation tests to evaluate injured patients in the emergency department.165EVALUATION OF EXCESSIVE INTRAOPERATIVE OR POSTOPERATIVE BLEEDINGExcessive bleeding during or after a surgical procedure may be the result of ineffective hemostasis, blood transfusion, unde-tected hemostatic defect, consumptive coagulopathy, and/or fibrinolysis. Excessive bleeding from the operative field unas-sociated with bleeding from other sites usually suggests inad-equate mechanical hemostasis.Massive blood transfusion is a well-known cause of throm-bocytopenia. Bleeding following massive transfusion can occur because of hypothermia, dilutional coagulopathy, platelet dys-function, fibrinolysis, or hypofibrinogenemia. Another cause of hemostatic failure related to the administration of blood is a hemolytic transfusion reaction. The first sign of a transfusion reaction may be diffuse bleeding. The pathogenesis of this bleed-ing is thought to be related to the release of ADP from hemolyzed red blood cells, resulting in diffuse platelet aggregation, after which the platelet clumps are removed out of the circulation.Transfusion purpura occurs when the donor platelets are of the uncommon HPA-1 group. This is an uncommon cause of thrombocytopenia and associated bleeding after transfusion. The platelets sensitize the recipient, who makes antibody to the foreign platelet antigen. The foreign platelet antigen does not completely disappear from the recipient circulation but attaches to the recipient’s own platelets. The antibody then destroys the recipient’s own platelets. The resultant thrombocytopenia and bleeding may continue for several weeks. This uncommon cause of thrombocytopenia should be considered if bleeding follows transfusion by 5 or 6 days. Platelet transfusions are of little help in the management of this syndrome because the new donor platelets usually are subject to the binding of antigen and dam-age from the antibody. Corticosteroids may be of some help in reducing the bleeding tendency. Posttransfusion purpura is self-limited, and the passage of several weeks inevitably leads to subsidence of the problem.DIC is characterized by systemic activation of the coagu-lation system, which results in the deposition of fibrin clots and microvascular ischemia and may contribute to the development CoagulationLYFibrinolysisRMAKAngleFigure 4-7. Illustration of a thromboelastogram (TEG) tracing. K = clot kinetics; LY = lysis.Brunicardi_Ch04_p0103-p0130.indd 12429/01/19 11:05 AM 125HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4of multiorgan failure. 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This is an important trial that demonstrated forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembo-lism and decreased the risk of major bleeding. It has changed management of these patients. 67. Rechenmacher SJ, Fang JC. Bridging anticoagulation: pri-mum non nocere. J Am Coll Cardiol. 2015;66(12):1392-1403. 68. Besser MW, Klein AA. The coagulopathy of cardiopulmo-nary bypass. Crit Rev Clin Lab Sci. 2011;47(5-6):197-212.Brunicardi_Ch04_p0103-p0130.indd 12629/01/19 11:05 AM 127HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4 69. Simon TL, Akl BF, Murphy W. Controlled trial of routine administration of platelet concentrates in cardiopulmonary bypass surgery. Ann Thorac Surg. 1984;37:359-364. 70. Taneja R, Fernandes P, Marwaha G, Cheng D, Bainbridge D. Perioperative coagulation management and blood conserva-tion in cardiac surgery: a Canadian survey. 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A multicentre, prospec-tive, randomized, controlled trial comparing EVARREST™ fibrin sealant patch to standard of care in controlling bleed-ing following elective hepatectomy: anatomic versus nonanatomic resection. HPB (Oxford). 2016;18(3):221-228. 77. Spinella PC, Reddy HL, Jaffe JS, et al. Fresh whole blood use for hemorrhagic shock: preserving benefit while avoiding complications. Anesth Analg. 2012;115(4):751-758. 78. Zielinski MD, Johnson PM, Jenkins D, et al. Emergency use of prethawed group A plasma in trauma patients. J Trauma Acute Care Surg. 2013;74(1):69-74. 79. Mair B, Benson K. Evaluation of changes in hemoglobin lev-els associated with ABO-incompatible plasma in apheresis platelets. Transfusion. 1998;38:51-55. 80. Eder AF, Dy BA, Perez JM, et al. The residual risk of transfusion-related acute lung injury at the American Red Cross (2008-2011): limitations of a predominantly male-donor plasma mitigation strategy. Transfusion. 2013;53(7):1442-1449. 81. Zielinski MD, Schrager JJ, Johnson P, et al. Multicenter comparison of emergency release group A versus AB plasma in blunt-injured trauma patients. Clin Transl Sci. 2015;8(1):43-47. 81a. McGinity AC, Zhu CS, Greebon L, et al. Prehospital low-titer cold-stored whole blood: Philosophy for ubiquitous utilization of O-positive product for emergency use in hemorrhage due to injury. J Trauma Acute Care Surg. 2018;84(6S Suppl 1): S115-S119. 82. Kiraly LN, Underwood S, Differding JA, Schreiber MA. Transfusion of aged packed red blood cells results in decreased tissue oxygenation in critically injured trauma patients. J Trauma. 2009;67(1):29-32. 83. Matijevic N, Wang YW, Cotton BA, et al. Better hemostatic pro-files of never-frozen liquid plasma compared with thawed fresh frozen plasma. J Trauma Acute Care Surg. 2013;74(1):84-90. 84. Caram-Deelder C, Kreuger AL, Jacobse J, et al. Effect of platelet storage time on platelet measurements: a systematic review and meta-analyses. Vox Sang. 2016;111(4):374-382. 85. Schreiber MA, McCully BH, Holcomb JB, et al. Transfusion of cryopreserved packed red blood cells is safe and effective after trauma. Ann Surg. 2015;262:426-433. 86. Chang AL, Hoehn RS, Jernigan P, et al. Previous cryopreser-vation alter the natural history of the red blood cell storage lesion. Shock. 2016;46(S1):89-95. 87. McAlister FA, Clark HD, Wells PS, Laupacis A. Periop-erative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: a meta-analysis of uncon-founded studies. Br J Surg. 1998;85:171-178. 88. Vamvakas EC, Blajchman MA. Universal WBC reduction: the case for and against. Transfusion. 2001;41:691-712. 89. Hebert PC, Fergusson D, Blajchman MA; Leukoreduction Study Investigators. Clinical outcomes following institution of the Canadian universal leukoreduction program for red blood cell transfusions. JAMA. 2003;289(15):1941-1949. 90. Inaba K, Lustenberger T, Rhee P, et al. The impact of plate-let transfusion in massively transfused trauma patients. J Am Coll Surg. 2010;211(5):573-579. 91. Matijevic N, Wang YW, Cotton BA, et al. Better hemo-static profiles of never-frozen liquid plasma compared with thawed fresh frozen plasma. J Trauma Acute Care Surg. 2013;74(1):84-90. 92. Martinaud C, Civadier C, Ausset S, Verret C, Deshayes AV, Sailliol A. In vitro hemostatic properties of French lyophi-lized plasma. Anesthesiology. 2012;117(2):339-346. 93. Sunde GA, Vikenes B, Strandenes G, et al. Freeze dried plasma and fresh red blood cells for civilian prehospital hemorrhagic shock resuscitation. J Trauma Acute Care Surg. 2015;78 (6 Suppl 1):S26-S30. 94. Martinaud C, Ausset S, Deshayes AV, Cauet A, Demazeau N, Sailliol A. Use of freeze-dried plasma in French intensive care unit in Afghanistan. J Trauma. 2011 Dec;71(6):1761-1764. 95. Glassberg E, Nadler R, Gendler S, et al. Freeze-dried plasma at the point of injury: from concept to doctrine. Shock. 2013;40(6):444-450. 96. Pusateri AE, Given MB, Schreiber MA, et al. Dried plasma: state of the science and recent developments. Transfusion. 2016 Apr;56 Suppl 2:S128-139. Due to challenges in using fresh frozen plasma in emergent and austere conditions, a variety of dried plasma products have been and are being developed. The history, state of the science, use of dried products in other coun-tries, and recent developments are reviewed. 97. CRASH-2 Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haem-orrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. 98. Morrison JJ, Ross JD, Dubose JJ, et al. Association of cryo-precipitate and tranexamic acid with improved survival fol-lowing wartime injury: findings from the MATTERs II study. JAMA Surg. 2013;148(3):218-225. 99. Cannon JW, Khan MA, Raja AS, et al. Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Associa-tion for the Surgery of Trauma. J Trauma Acute Care Surg. 2017;82(3):605-617. This is a structured analysis of existing trauma transfusion data with practical recommendations for bleeding patients. 100. Gerber DR. Transfusion of packed red blood cells in patients with ischemic heart disease. Crit Care Med. 2008;36:1068-1074. 101. Herbert PC, Wells GW, Blajchman MA, et al. A multi-center, randomized, controlled clinical trial of transfu-sion requirement in critical care. N Engl J Med. 1999;340: 409-417. 102. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-2462. 103. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfu-sion. Cochrane Database Syst Rev. 2012;4:CD002042. 104. Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresh-olds and storage. JAMA. 2016;316(19):2025-2035.Brunicardi_Ch04_p0103-p0130.indd 12729/01/19 11:05 AM 128BASIC CONSIDERATIONSPART I 105. Thorson CM, Van Haren RM, Ryan ML. Admission hema-tocrit and transfusion requirements after trauma. J Am Coll Surg. 2013;216(1):65-73.105a. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310. 106. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60(6 Suppl):S3. 107. Niles SE, McLaughlin DF, Perkins J, et al. Increased mortal-ity associated with early coagulopathy after trauma in combat casualties. J Trauma. 2008;64:1459-1463. 108. Macleod J, Lynn M, McKenney MG, Jeroukhimov I, Cohn SM. Predictors of mortality in trauma patients. Am Surg. 2004;70:805-810. 109. Moore LJ, Brenner M, Kozar RA, et al. Implementation of resuscitative endovascular balloon occlusion of the aorta as an alternative to resuscitative thoracotomy for noncom-pressible truncal hemorrhage. J Trauma Acute Care Surg. 2015;79(4):523-532. 110. Savage SA, Sumislawski JJ, Zarzaur BL, Dutton WP, Croce MA, Fabian TC. The new metric to define large-volume hemorrhage: results of a prospective study of the critical administration threshold. J Trauma Acute Care Surg. 2015;78(2):224-229. 111. Cap AP, Spinella PC, Borgman MA, Blackbourne LH, Perkins JG. Timing and location of blood product transfu-sion and outcomes in massively transfused combat casu-alties. J Trauma Acute Care Surg. 2012;73(2 Suppl 1): S89-S94. 112. Carrico CJ, Canizaro PC, Shires GT. Fluid resuscitation fol-lowing injury: rationale for the use of balanced salt solutions. Crit Care Med. 1976;4:46. 113. Harrigan C, Lucas CE, Ledgerwood AM, et al. Serial changes in primary hemostasis after massive transfusion. Surgery. 1985;98:836. 114. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63(4):805-813. 115. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248(3):447-458. 116. Mitra B, Mori A, Cameron PA, et al. Fresh frozen plasma (FFP) use during massive blood transfusion in trauma resus-citation. Injury. 2010;41(1):35-39. 117. Peiniger S, Nienaber U, Lefering R, et al. Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care. 2011;15(1):R68. 118. Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated with a reduction in resuscitation volumes and improvement in survival in 390 damage control laparotomy patients. Ann Surg. 2011;254(4):598-605. 119. Holcomb JB, del Junco DJ, Fox EE, et al. The prospective, obser-vational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148:127-136. 120. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471-482. This is a prospective randomized study at 12 level 1 trauma centers of massively bleeding trauma patients, com-paring two balanced transfusion groups. Fewer patients bled to death in the 1:1:1 group. 121. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289-1295. 122. Potter DR, Baimukanova G, Keating SM, et al. Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascu-lar permeability and inflammation in hemorrhagic shock. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S7-S17. 123. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108(3):384-394. 124. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial gly-cocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194-200. 125. Ostrowski SR, Johansson PI. Endothelial glycocalyx degra-dation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60-66. 126. Rahbar E, Cardenas JC, Baimukanova G, et al. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med. 2015;13:117. 127. Johansson PI, Stensballe J, Oliveri R, Wade CE, Ostrowski SR, Holcomb JB. How I treat patients with massive hemor-rhage. Blood. 2014;124(20):3052-3058. 128. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for massive transfusion in combat casualty patients. J Trauma. 2008;64(2 Suppl):S57. 129. Yücel N, Lefering R, Maegele M, et al. Trauma-Associated Severe Hemorrhage (TASH) score: probability of mass trans-fusion as surrogate for life threatening hemorrhage after mul-tiple trauma. J Trauma. 2006;60:1228. 130. Moore FA, Nelson T, McKinley BA, et al. Massive transfu-sion in trauma patients: tissue hemoglobin oxygen saturation predicts poor outcome. J Trauma. 2008;64:1010. 131. Schreiber MA, Perkins J, Kiraly L, et al. Early predictors of massive transfusion in combat casualties. J Am Coll Surg. 2007;205:541. 132. Cotton BA, Dossett LA, Haut ER, et al. Multicenter valida-tion of a simplified score to predict massive transfusion in trauma. J Trauma. 2010;69(Suppl 1):S33-S39. 133. Radwan ZA, Bai Y, Matijevic N, et al. An emergency depart-ment thawed plasma protocol for severely injured patients. JAMA Surg. 2013;148(2):170-175. 134. Holcomb JB, Donathan DP, Cotton BA, et al. Prehospital transfusion of plasma and red blood cells in trauma patients. Prehosp Emerg Care. 2015;19(1):1-9. 135. Brown JB, Sperry JL, Fombona A, Billiar TR, Peitzman AB, Guyette FX. Pre-trauma center red blood cell transfusion is associated with improved early outcomes in air medical trauma patients. J Am Coll Surg. 2015;220(5):797-808. 136. O’Reilly DJ, Morrison JJ, Jansen JO, Apodaca AN, Rasmus-sen TE, Midwinter MJ. Prehospital blood transfusion in the en route management of severe combat trauma: a matched cohort study. J Trauma Acute Care Surg. 2014;77(3 Suppl 2):S114-S120. 137. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh whole blood is independently asso-ciated with improved survival for patients with combat-related traumatic injuries. J Trauma. 2009;66(4 Suppl):S69-S76. 138. Nessen SC, Eastridge BJ, Cronk D, et al. Fresh whole blood use by forward surgical teams in Afghanistan is associated with improved survival compared to component therapy without platelets. Transfusion 2013;53 Suppl 1:107S-113S. 139. Neel S. Chapter 9: The military blood program. In: Medical Support of the U.S. Army in Vietnam. Washington D.C.: Office Brunicardi_Ch04_p0103-p0130.indd 12829/01/19 11:05 AM 129HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4of the Surgeon General, Department of the Army; 1991; 114-126. Available at: http://history.amedd.army.mil/books-docs/vietnam/medicalsupport/chapter9.html. Accessed June 28, 2016. 140. Strandenes G, Austlid I, Apelseth TO, et al. Coagulation function of stored whole blood is preserved for 14 days in austere conditions: A ROTEM feasibility study during a Norwegian antipiracy mission and comparison to equal ratio reconstituted blood. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S31-38. 141. Cotton BA, Podbielski J, Camp E, et al. A randomized con-trolled pilot trial of modified whole blood versus component therapy in severely injured patients requiring large volume transfusions. Ann Surg. 2013;258(4):527-532. This is the first randomized study of whole blood in trauma patients. This small pilot study showed feasibility and suggested benefit. 142. Yazer MH, Jackson B, Sperry JL, et al. Initial safety and fea-sibility of cold-stored uncrossmatched whole blood transfu-sion in civilian trauma patients. J Trauma Acute Care Surg. 2016;81(1):21-26. 143. Stubbs JR, Zielinski MD, Jenkins D. The state of the science of whole blood: lessons learned at Mayo Clinic. Transfusion. 2016;56(Suppl 2):S173-181. 144. Rourke C, Curry N, Khan S, et al. Fibrinogen levels dur-ing trauma hemorrhage response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10(7):1342-1351. 145. Inaba K, Karamanos E, Lustenberger T, et al. Impact of fibrin-ogen levels on outcomes after injury in patients requiring a massive transfusion. J Am Coll Surg. 2013;216(2):290-297. 146. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43(1):26-32. 147. Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeu-tic target for bleeding: a review of critical levels and replace-ment therapy. Transfusion. 2014 May;54(5):1389-1405. 148. Curry N, Rourke C, Davenport R, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015;115(1):76-83. 149. www.clinical trials.gov. Fibrinogen concentrate in trauma patients presumed to bleed; NCT01475344. Accessed December 28, 2016.149a. Meyer DE, Reynolds JW, Hobbs R, et al. The Incidence of Transfusion-Related Acute Lung Injury at a Large, Urban Tertiary Medical Center: A Decade’s Experience. Anesth Analg. 2018;127(2):444-449. 150. Pandey S, Vyas GN. Adverse-effects of plasma transfusion. Transfusion. 2012;52:65S-79S. 151. Goodnough LT, Brecher ME, Kanter MH. Transfusion medi-cine: blood transfusion. N Engl J Med. 1999;340:438. 152. Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury. Chest. 2004;126:249. 153. Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012;119(7):1757-1767. 154. Zou S, Stramer SL, Dodd RY. Donor testing and risk: cur-rent prevalence, incidence, and residual risk of transfusion-transmissible agents in US allogeneic donations. Transfusion Med Rev. 2012;26(2):119-128. 155. Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19(14). 156. Jimenez A, Shaz BH, Bloch EM. Zika Virus and the blood sup-ply: what do we know? Transfus Med Rev. 2017;31(1):1-10. 157. Bierlaire D, Mauguin S, Broult J, Musso D. Zika virus and blood transfusion: the experience of French Polynesia. Trans-fusion. 2017;57(3pt2):729-733. 158. Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21:1-11. 159. Mallet SV, Cox DJA. Thromboelastography: a review article. Br J Anaesth. 1992;69:307. 160. Jackson GN, Ashpole KJ, Yentis SM. The TEG vs the ROTEM thromboelastography/ thromboelastometry systems. Anaesthe-sia. 2009;64(2):212-215. 161. Cotton BA, Radwan ZA, Matijevic N, et al. Admission rapid thromboelastography (rTEG) predicts development of pulmonary embolism in trauma patients. J Trauma. 2012;72(6):1470-1477. 162. Cotton BA, Faz G, Hatch Q, et al. Rapid thromboelastogra-phy (r-TEG) delivers real-time results that predict transfusion within one hour of admission. J Trauma. 2011;71(2):407-417. 163. Schöchl H, Cotton BA, Inaba K, et al. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265-R271. 164. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinoly-sis on admission is an uncommon but highly lethal event associated with shock and pre-hospital fluid administration. J Trauma. 2012;72(2):365-370. 165. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thromboelastography (r-TEG) can replace conventional coag-ulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256(3): 476-486.Brunicardi_Ch04_p0103-p0130.indd 12929/01/19 11:05 AM

Brunicardi_Ch04_p0103-p0130.indd 13029/01/19 11:05 AMThis page intentionally left blankShockBrian S. Zuckerbraun, Andrew B. Peitzman, and Timothy R. Billiar 5chapter“Shock is the manifestation of the rude unhinging of the machinery of life.”1—Samuel V. Gross, 1872EVOLUTION IN UNDERSTANDING SHOCKOverviewShock, at its most rudimentary definition and regardless of its etiology, is the failure to meet the metabolic needs of the cell and the consequences that ensue. The initial cellular injury that occurs is reversible; however, the injury will become irre-versible if tissue perfusion is prolonged or severe enough such that, at the cellular level, compensation is no longer pos-sible. Our understanding of shock and the disease processes that result in shock made its most significant advances throughout the 20th century as our appreciation for the physiology and pathophysiology of shock matured. Most notably, our compre-hension of the sympathetic and neuroendocrine stress responses on the cardiovascular system has flourished. The clinical mani-festations of these physiologic responses are most often what lead practitioners to the diagnosis of shock as well as guide the management of patients in shock. However, hemodynamic parameters such as blood pressure and heart rate are relatively insensitive measures of shock, and additional considerations must be used to help aid in early diagnosis and treatment of patients in shock. The general approach to the management of patients in shock has been empiric: assuring a secure airway with adequate ventilation, control of hemorrhage in the bleeding patient, and restoration of vascular volume and tissue perfusion.Historical BackgroundIntegral to our understanding of shock is the appreciation that our bodies attempt to maintain a state of homeostasis. Claude Bernard suggested in the mid-19th century that the organism attempts to maintain constancy in the internal environment against external 1forces that attempt to disrupt the milieu interieur.2 Walter B. Cannon carried Bernard’s observations further and introduced the term homeostasis, emphasizing that an organism’s ability to survive was related to maintenance of homeostasis.3 The failure of physiologic systems to buffer the organism against external forces results in organ and cellular dysfunction, what is clini-cally recognized as shock. He first described the “fight or flight response,” generated by elevated levels of catecholamines in the bloodstream. Cannon’s observations on the battlefields of World War I led him to propose that the initiation of shock was due to a disturbance of the nervous system that resulted in vasodilation and hypotension. He proposed that secondary shock, with its attendant capillary permeability leak, was caused by a “toxic factor” released from the tissues.In a series of critical experiments, Alfred Blalock docu-mented that the shock state in hemorrhage was associated with reduced cardiac output due to volume loss, not a “toxic factor.”4 In 1934, Blalock proposed four categories of shock: hypovole-mic, vasogenic, cardiogenic, and neurogenic. Hypovolemic shock, the most common type, results from loss of circulating blood volume. This may result from loss of whole blood (hemorrhagic shock), plasma, interstitial fluid (bowel obstruction), or a combi-nation. Vasogenic shock results from decreased resistance within capacitance vessels, usually seen in sepsis. Neurogenic shock is a form of vasogenic shock in which spinal cord injury or spinal anesthesia causes vasodilation due to acute loss of sympathetic vascular tone. Cardiogenic shock results from failure of the heart as a pump, as in arrhythmias or acute myocardial infarction (MI).This categorization of shock based on etiology persists today (Table 5-1). In recent clinical practice, further classifi-cation has described six types of shock: hypovolemic, septic (vasodilatory), neurogenic, cardiogenic, obstructive, and trau-matic shock. Obstructive shock is a form of cardiogenic shock that results from mechanical impediment to circulation leading to depressed cardiac output rather than primary cardiac failure. Evolution in Understanding Shock 131Overview / 131Historical Background / 131Current Definitions and Challenges/ 133Pathophysiology of Shock 133Neuroendocrine and Organ-Specific Responses to Hemorrhage/ 134Afferent Signals / 134Efferent Signals / 135Circulatory Homeostasis / 136Metabolic Effects 136Cellular Hypoperfusion / 137Immune and Inflammatory Responses 137Cytokines/Chemokines / 138Complement / 140Neutrophils / 140Cell Signaling / 140Forms of Shock 141Hypovolemic/Hemorrhagic / 141Traumatic Shock / 145Septic Shock (Vasodilatory Shock) / 145Cardiogenic Shock / 148Obstructive Shock / 150Neurogenic Shock / 151Endpoints in Resuscitation 152Assessment of Endpoints in Resuscitation / 152Brunicardi_Ch05_p0131-p0156.indd 13129/01/19 11:06 AM 132Table 5-1Classification of shockHypovolemicCardiogenicSeptic (vasogenic)NeurogenicTraumaticObstructiveKey Points1 Shock is defined as a failure to meet the metabolic demands of cells and tissues and the consequences that ensue.2 A central component of shock is decreased tissue perfusion. This may be a direct consequence of the etiology of shock, such as in hypovolemic/hemorrhagic, cardiogenic, or neuro-genic etiologies, or may be secondary to elaborated or released molecules or cellular products that result in endothelial/ cellular activation, such as in septic shock or traumatic shock.3 Physiologic responses to shock are based upon a series of affer-ent (sensing) signals and efferent responses that include neu-roendocrine, metabolic, and immune/inflammatory signaling.4 The mainstay of treatment of hemorrhagic/hypovolemic shock includes volume resuscitation with blood products. In the case of hemorrhagic shock, timely control of bleeding is essential and influences outcome.5 Prevention of hypothermia, acidemia, and coagulopathy are essential in the management of patients in hemorrhagic shock.6 The mainstay of treatment of septic shock is fluid resuscita-tion, initiation of appropriate antibiotic therapy, and control of the source of infection. This includes drainage of infected fluid collections, removal of infected foreign bodies, and debridement of devitalized tissues.7 A combination of physiologic parameters and markers of organ perfusion/tissue oxygenation are used to determine if patients are in shock and to follow the efficacy of resuscitation.This includes etiologies such as pulmonary embolism or tension pneumothorax. In traumatic shock, soft tissue and bony injury lead to the activation of inflammatory cells and the release of circulating factors, such as cytokines and intracellular molecules that modulate the immune response. Recent investigations have revealed that the inflammatory mediators released in response to tissue injury (damage-associated molecular patterns [DAMPs]) are recognized by many of the same cellular receptors (pattern recognition receptors [PRRs]) and activate similar signaling pathways as do bacterial products elaborated in sepsis (pathogen-associated molecular patterns), such as lipopolysaccharide.5 These effects of tissue injury are combined with the effects of hemorrhage, creating a more complex and amplified deviation from homeostasis.In the midto later 20th century, further development of experimental models contributed significantly to the under-standing of the pathophysiology of shock. In 1947, Wiggers developed a sustainable, irreversible model of hemorrhagic shock based on uptake of shed blood into a reservoir to maintain a set level of hypotension.6 G. Tom Shires added further under-standing of hemorrhagic shock with a series of clinical stud-ies demonstrating that a large extracellular fluid deficit, greater than could be attributed to vascular refilling alone, occurred in severe hemorrhagic shock.7,8 The phenomenon of fluid redistri-bution after major trauma involving blood loss was termed third spacing and described the translocation of intravascular volume into the peritoneum, bowel, burned tissues, or crush injury sites. These seminal studies form the scientific basis for the current treatment of hemorrhagic shock with red blood cells and lac-tated Ringer’s solution or isotonic saline.As resuscitation strategies evolved and patients survived the initial consequences of hemorrhage, new challenges of sustained shock became apparent. During the Vietnam War, aggressive fluid resuscitation with red blood cells and crystal-loid solution or plasma resulted in survival of patients who pre-viously would have succumbed to hemorrhagic shock. Renal failure became a less frequent clinical problem; however, a new disease process, acute fulminant pulmonary failure, appeared as an early cause of death after seemingly successful surgery to control hemorrhage. Initially called DaNang lung or shock lung, the clinical problem became recognized as acute respiratory dis-tress syndrome (ARDS). This led to new methods of prolonged mechanical ventilation. Our current concept of ARDS is a com-ponent in the spectrum of multiple organ system failure.Studies and clinical observations over the past two decades have extended the early observations of Canon, that “restoration of blood pressure prior to control of active bleeding may result in loss of blood that is sorely needed,” and challenged the appro-priate endpoints in resuscitation of uncontrolled hemorrhage.9 Core principles in the management of patients in hemorrhagic shock include: (a) control of active hemorrhage must occur promptly (delay in control of bleeding increases mortality and recent battlefield data would suggest that in the young and otherwise healthy population commonly injured in combat, that control of bleeding is the paramount priority); (b) volume resuscitation with blood products (red blood cells, plasma, and platelets) with limited volume of crystalloid must occur while operative control of bleeding is achieved; (c) unrecognized or inadequately corrected hypoperfusion increases morbidity and mortality (i.e., inadequate resuscitation results in avoidable early deaths from shock); and (d) excessive fluid resuscitation may exacerbate bleeding (i.e., uncontrolled resuscitation is harmful). Thus, both inadequate or unrestrained volume resus-citation are harmful.Likewise, observations in the management of septic shock have led to consensus statements and evolving guideline based management.10 Core principles in the management of patients in septic shock include: (a) septic shock is an emergency, and treatment/resuscitation should begin as early as possible; (b) specific anatomic diagnosis of infection requiring emergent source control be identified or excluded as rapidly as possible and that any required source control intervention be imple-mented as soon as medically and logistically practical; (c) ini-tiation of broad spectrum antibiotics within 1 hour of diagnosis; (d) in the resuscitation from sepsis-induced hypoperfusion, at Brunicardi_Ch05_p0131-p0156.indd 13229/01/19 11:06 AM 133SHOCKCHAPTER 5least 30 mL/kg of intravenous crystalloid fluid be given within the first 3 hours, and additional fluids be guided by frequent reassessment of hemodynamic status; (e) vasopressors (norepi-nephrine) should be added to achieve a mean arterial pressure of 65 mmHg if fluid resuscitation is inadequate.Current Definitions and ChallengesA modern definition and approach to shock acknowledges that shock consists of inadequate tissue perfusion marked by decreased delivery of required metabolic substrates and inade-quate removal of cellular waste products. This involves failure of oxidative metabolism that can involve defects of oxygen (O2) delivery, transport, and/or utilization. Current challenges include moving beyond fluid resuscitation based upon endpoints of tissue oxygenation and using therapeutic strategies at the cellular and molecular level. This approach will help to identify compensated patients or patients early in the course of their disease, initiate appropriate treatment, and allow for con-tinued evaluation for the efficacy of resuscitation and adjuncts.Current investigations focus on determining the cellular events that often occur in parallel to result in organ dysfunc-tion, shock irreversibility, and death. This chapter will review our current understanding of the pathophysiology and cellular responses of shock states. Current and experimental diagnostic and therapeutic modalities for the different categories of shock are reviewed, with a focus on hemorrhagic/hypovolemic shock and septic shock.PATHOPHYSIOLOGY OF SHOCKRegardless of etiology, the initial physiologic responses in shock are driven by tissue hypoperfusion and the developing cellular energy deficit. This imbalance between cellular supply and demand leads to neuroendocrine and inflammatory responses, the magnitude of which is usually proportional to the degree and duration of shock. The specific responses will differ based on the etiology of shock, as certain physiologic responses may be limited by the inciting pathology. For exam-ple, the cardiovascular response driven by the sympathetic ner-vous system is markedly blunted in neurogenic or septic shock. Additionally, decreased perfusion may occur as a consequence of cellular activation and dysfunction, such as in septic shock and to a lesser extent traumatic shock (Fig. 5-1). Many of the organ-specific responses are aimed at maintaining perfusion in the cerebral and coronary circulation. These are regulated at multiple levels including (a) stretch receptors and baroreceptors in the heart and vasculature (carotid sinus and aortic arch), (b) chemoreceptors, (c) cerebral ischemia responses, (d) release of endogenous vasoconstrictors, (e) shifting of fluid into the intra-vascular space, and (f) renal reabsorption and conservation of salt and water.Furthermore, the pathophysiologic responses vary with time and in response to resuscitation. In hemorrhagic shock, the body can compensate for the initial loss of blood volume primar-ily through the neuroendocrine response to maintain hemody-namics. This represents the compensated phase of shock. With continued hypoperfusion, which may be unrecognized, cellular death and injury are ongoing, and the decompensation phase of shock ensues. Microcirculatory dysfunction, parenchymal tissue damage, and inflammatory cell activation can perpetuate hypo-perfusion. Ischemia/reperfusion injury will often exacerbate the initial insult. These effects at the cellular level, if untreated, will lead to compromise of function at the organ system level, thus leading to the “vicious cycle” of shock (Fig. 5-2). Persis-tent hypoperfusion results in further hemodynamic derange-ments and cardiovascular collapse. This has been termed the irreversible phase of shock and can develop quite insidiously and may only be obvious in retrospect. At this point, there has occurred extensive enough parenchymal and microvascular injury such that volume resuscitation fails to reverse the pro-cess, leading to death of the patient. In experimental animal models of hemorrhagic shock (modified Wiggers model), this is 23Figure 5-1. Pathways leading to decreased tissue perfusion and shock. Decreased tissue perfusion can result directly from hemorrhage/hypovolemia, cardiac failure, or neurologic injury. Decreased tissue perfusion and cellu-lar injury can then result in immune and inflammatory responses. Alternatively, elaboration of microbial products during infection or release of endogenous cellular products from tissue injury can result in cellular activation to subsequently influ-ence tissue perfusion and the develop-ment of shock. HMGB1 = high mobility group box 1; LPS = lipopolysaccharide; RAGE = receptor for advanced glycation end products.Bacterial products(i.e., LPS)Direct effectPattern recognition receptor activation(Toll-like receptors, RAGE)TissueinjuryDamage associatedmolecular patterns(i.e., HMGB1, heparan sulfate)Released/elaboratedmediators ofinflammationCellular activationDecreased tissue perfusionCellular hypoxia/ischemiaShockDisruptionhost-microbeequilibriumAcute heart failureNeurogenicHemorrhageTraumaCellular effectBrunicardi_Ch05_p0131-p0156.indd 13329/01/19 11:06 AM 134BASIC CONSIDERATIONSPART Irepresented by the “uptake phase” or “compensation endpoint” when shed blood must be returned to the animal to sustain the hypotension at the set level to prevent further hypotension and death.11 If shed blood volume is slowly returned to maintain the set level of hypotension, eventually the injury progresses to irreversible shock, where further volume will not reverse the process and the animal dies (Fig. 5-3).Neuroendocrine and Organ-Specific Responses to HemorrhageThe goal of the neuroendocrine response to hemorrhage is to maintain perfusion to the heart and the brain, even at the expense of other organ systems. Peripheral vasoconstriction occurs, and fluid excretion is inhibited. The mechanisms include autonomic control of peripheral vascular tone and cardiac contractility, hormonal response to stress and volume depletion, and local microcirculatory mechanisms that are organ specific and regu-late regional blood flow. The initial stimulus is loss of circulat-ing blood volume in hemorrhagic shock. The magnitude of the neuroendocrine response is based on both the volume of blood lost and the rate at which it is lost.Afferent SignalsAfferent impulses transmitted from the periphery are processed within the central nervous system (CNS) and activate the reflexive effector responses or efferent impulses. These effec-tor responses are designed to expand plasma volume, maintain peripheral perfusion and tissue O2 delivery, and restore homeo-stasis. The afferent impulses that initiate the body’s intrinsic adaptive responses and converge in the CNS originate from a variety of sources. The initial inciting event usually is loss of circulating blood volume. Other stimuli that can produce the neuroendocrine response include pain, hypoxemia, hypercarbia, acidosis, infection, change in temperature, emotional arousal, or hypoglycemia. The sensation of pain from injured tissue is trans-mitted via the spinothalamic tracts, resulting in activation of the hypothalamic-pituitary-adrenal axis, as well as activation of the autonomic nervous system (ANS) to induce direct sympathetic stimulation of the adrenal medulla to release catecholamines.Baroreceptors also are an important afferent pathway in initiation of adaptive responses to shock. Volume receptors, sensitive to changes in both chamber pressure and wall stretch, are present within the atria of the heart. They become activated with low volume hemorrhage or mild reductions in right atrial pressure. Receptors in the aortic arch and carotid bodies respond to alterations in pressure or stretch of the arterial wall, respond-ing to larger reductions in intravascular volume or pressure. These receptors normally inhibit induction of the ANS. When activated, these baroreceptors diminish their output, thus dis-inhibiting the effect of the ANS. The ANS then increases its output, principally via sympathetic activation at the vasomotor centers of the brain stem, producing centrally mediated constric-tion of peripheral vessels.Chemoreceptors in the aorta and carotid bodies are sensi-tive to changes in O2 tension, H+ ion concentration, and car-bon dioxide (CO2) levels. Stimulation of the chemoreceptors results in vasodilation of the coronary arteries, slowing of the heart rate, and vasoconstriction of the splanchnic and skeletal circulation. In addition, a variety of protein and nonprotein mediators are produced at the site of injury as part of the inflam-matory response, and they act as afferent impulses to induce a host response. These mediators include histamine, cytokines, Decreased cardiac outputDecreased tissue perfusion˜ Venousreturn˜ CoronaryperfusionMetabolicacidosisCellularhypoxiaParenchymal cell injuryEndothelial activation/microcirculatory damageCellularaggregationIntracellularfluid lossFigure 5-2. The “vicious cycle of shock.” Regardless of the etiol-ogy, decreased tissue perfusion and shock results in a feed-forward loop that can exacerbate cellular injury and tissue dysfunction.Figure 5-3. Rat model of hemorrhagic shock through the phases of compensa-tion, decompensation, and irreversibility. The percentages shown above the curve represent survival rates. (Reproduced with permission from Shah NS, Kelly E, Billiar TR, et al. Utility of clinical param-eters of tissue oxygenation in a quantita-tive model of irreversible hemorrhagic shock, Shock. 1998 Nov;10(5):343-346.)Rat hemorrhagic shock model24-hour survival following resuscitationMean arterial pressureCompensatedDecompensatedIrreversible% Shedblood returnTransition to acute irreversible shockTransition to subacute lethal shockABDeath100%90%50%30%10%0%10%20%30%40%50%0%Compensation endpoint8040ABBrunicardi_Ch05_p0131-p0156.indd 13429/01/19 11:06 AM 135SHOCKCHAPTER 5eicosanoids, and endothelins, among others that are discussed in greater detail later in this chapter in the “Immune and Inflam-matory Responses” section.Efferent SignalsCardiovascular Response. Changes in cardiovascular func-tion are a result of the neuroendocrine response and ANS response to shock, and they constitute a prominent feature of both the body’s adaptive response mechanism and the clinical signs and symptoms of the patient in shock. Hemorrhage results in diminished venous return to the heart and decreased cardiac output. This is compensated by increased cardiac heart rate and contractility, as well as venous and arterial vasoconstriction. Stimulation of sympathetic fibers innervating the heart leads to activation of β1-adrenergic receptors that increase heart rate and contractility in this attempt to increase cardiac output. Increased myocardial O2 consumption occurs as a result of the increased workload; thus, myocardial O2 supply must be maintained, or myocardial dysfunction will develop. The car-diovascular response in hemorrhage/hypovolemia differs from the responses elicited with the other etiologies of shock. These are compared in Table 5-2.Direct sympathetic stimulation of the peripheral circula-tion via the activation of α1-adrenergic receptors on arterioles induces vasoconstriction and causes a compensatory increase in systemic vascular resistance and blood pressure. The arte-rial vasoconstriction is not uniform; marked redistribution of blood flow results. Selective perfusion to tissues occurs due to regional variations in arteriolar resistance, with blood shunted away from less essential organ beds such as the intestine, kidney, and skin. In contrast, the brain and heart have autoreg-ulatory mechanisms that attempt to preserve their blood flow despite a global decrease in cardiac output. Direct sympathetic stimulation also induces constriction of venous vessels, decreas-ing the capacitance of the circulatory system and accelerating blood return to the central circulation.Increased sympathetic output induces catecholamine release from the adrenal medulla. Catecholamine levels peak within 24 to 48 hours of injury and then return to baseline. Persis-tent elevation of catecholamine levels beyond this time suggests ongoing noxious afferent stimuli. The majority of the circulating epinephrine is produced by the adrenal medulla, while norepi-nephrine is derived from synapses of the sympathetic nervous system. Catecholamine effects on peripheral tissues include stimulation of hepatic glycogenolysis and gluconeogenesis to increase circulating glucose availability to peripheral tissues, an increase in skeletal muscle glycogenolysis, suppression of insulin release, and increased glucagon release.Hormonal Response. The stress response includes activation of the ANS as discussed previously in the “Afferent Signals” section, as well as activation of the hypothalamic-pituitary-adrenal axis. Shock stimulates the hypothalamus to release corticotropin-releasing hormone, which results in the release of adrenocorticotropic hormone (ACTH) by the pituitary. ACTH subsequently stimulates the adrenal cortex to release cortisol. Cortisol acts synergistically with epinephrine and glucagon to induce a catabolic state. Cortisol stimulates gluconeogenesis and insulin resistance, resulting in hyperglycemia as well as muscle cell protein breakdown and lipolysis to provide sub-strates for hepatic gluconeogenesis. Cortisol causes retention of sodium and water by the nephrons of the kidney. In the setting of severe hypovolemia, ACTH secretion occurs independently of cortisol negative feedback inhibition.The renin-angiotensin system is activated in shock. Decreased renal artery perfusion, β-adrenergic stimulation, and increased renal tubular sodium concentration cause the release of renin from the juxtaglomerular cells. Renin catalyzes the conversion of angiotensinogen (produced by the liver) to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) produced in the lung. While angiotensin I has no significant functional activity, angiotensin II is a potent vasoconstrictor of both splanchnic and peripheral vascular beds, and also stimulates the secretion of aldosterone, ACTH, and antidiuretic hormone (ADH). Aldo-sterone, a mineralocorticoid, acts on the nephron to promote reabsorption of sodium, and as a consequence, water. Potassium and hydrogen ions are lost in the urine in exchange for sodium.The pituitary also releases vasopressin or ADH in response to hypovolemia, changes in circulating blood volume sensed by baroreceptors and left atrial stretch receptors, and increased plasma osmolality detected by hypothalamic osmo-receptors. Epinephrine, angiotensin II, pain, and hyperglycemia increase production of ADH. ADH levels remain elevated for about 1 week after the initial insult, depending on the sever-ity and persistence of the hemodynamic abnormalities. ADH acts on the distal tubule and collecting duct of the nephron to increase water permeability, decrease water and sodium losses, and preserve intravascular volume. Also known as arginine vasopressin, ADH acts as a potent mesenteric vasoconstrictor, shunting circulating blood away from the splanchnic organs during hypovolemia.12 This may contribute to intestinal isch-emia and predispose to intestinal mucosal barrier dysfunction in Table 5-2Hemodynamic responses to different types of shockTYPE OF SHOCKCARDIAC INDEXSVRVENOUS CAPACITANCECVP/PCWPSvo2CELLULAR/METABOLIC EFFECTSHypovolemic↓↑↓↓↓EffectSeptic↑↑↓↑↑↓↑↓CauseCardiogenic↓↓↑↑→↑↓EffectNeurogenic↑↓→↓↓EffectThe hemodynamic responses are indicated by arrows to show an increase (↑), severe increase (↑↑), decrease (↓), severe decrease (↓↓), varied response (↑↓), or little effect →). CVP = central venous pressure; PCWP = pulmonary capillary wedge pressure; Svo2 = mixed venous oxygen saturation; SVR = systemic vascular resistance.Brunicardi_Ch05_p0131-p0156.indd 13529/01/19 11:06 AM 136BASIC CONSIDERATIONSPART Ishock states. Vasopressin also increases hepatic gluconeogen-esis and increases hepatic glycolysis.In septic states, endotoxin directly stimulates arginine vasopressin secretion independently of blood pressure, osmotic, or intravascular volume changes. Proinflammatory cytokines also contribute to arginine vasopressin release. Interestingly, patients on chronic therapy with ACE inhibitors are more at risk of developing hypotension and vasodilatory shock with open heart surgery. Low plasma levels of arginine vasopressin were confirmed in these patients.13Circulatory HomeostasisPreload. At rest, the majority of the blood volume is within the venous system. Venous return to the heart generates ventricular end-diastolic wall tension, a major determinant of cardiac out-put. Gravitational shifts in blood volume distribution are quickly corrected by alterations in venous capacity. With decreased arte-riolar inflow, there is active contraction of the venous smooth muscle and passive elastic recoil in the thin-walled systemic veins. This increases venous return to the heart, thus maintain-ing ventricular filling.Most alterations in cardiac output in the normal heart are related to changes in preload. Increases in sympathetic tone have a minor effect on skeletal muscle beds but produce a dra-matic reduction in splanchnic blood volume, which normally holds 20% of the blood volume.The normal circulating blood volume is maintained within narrow limits by the kidney’s ability to manage salt and water balance with external losses via systemic and local hemody-namic changes and hormonal effects of renin, angiotensin, and ADH. These relatively slow responses maintain preload by altering circulating blood volume. Acute responses to intravas-cular volume include changes in venous tone, systemic vascular resistance, and intrathoracic pressure, with the slower hormonal changes less important in the early response to volume loss. Furthermore, the net effect of preload on cardiac output is influ-enced by cardiac determinants of ventricular function, which include coordinated atrial activity and tachycardia.Ventricular Contraction. The Frank-Starling curve describes the force of ventricular contraction as a function of its preload. This relationship is based on force of contraction being deter-mined by initial muscle length. Intrinsic cardiac disease will shift the Frank-Starling curve and alter mechanical performance of the heart. In addition, cardiac dysfunction has been demon-strated experimentally in burns and in hemorrhagic, traumatic, and septic shock.Afterload. Afterload is the force that resists myocardial work during contraction. Arterial pressure is the major component of afterload influencing the ejection fraction. This vascular resistance is determined by precapillary smooth muscle sphinc-ters. Blood viscosity also will increase vascular resistance. As afterload increases in the normal heart, stroke volume can be maintained by increases in preload. In shock, with decreased circulating volume and therefore diminished preload, this com-pensatory mechanism to sustain cardiac output is impeded. The stress response with acute release of catecholamines and sym-pathetic nerve activity in the heart increases contractility and heart rate.Microcirculation. The microvascular circulation plays an integral role in regulating cellular perfusion and is significantly influenced in response to shock. The microvascular bed is innervated by the sympathetic nervous system and has a pro-found effect on the larger arterioles. Following hemorrhage, larger arterioles vasoconstrict; however, in the setting of sep-sis or neurogenic shock, these vessels vasodilate. Addition-ally, a host of other vasoactive proteins, including vasopressin, angiotensin II, and endothelin-1, also lead to vasoconstriction to limit organ perfusion to organs such as skin, skeletal muscle, kidneys, and the GI tract to preserve perfusion of the myocar-dium and CNS.Flow in the capillary bed is heterogeneous in shock states, which likely is secondary to multiple local mechanisms, including endothelial cell swelling, dysfunction, and activa-tion marked by the recruitment of leukocytes and platelets.14 Together, these mechanisms lead to diminished capillary perfu-sion that may persist after resuscitation. In hemorrhagic shock, correction of hemodynamic parameters and restoration of O2 delivery generally leads to restoration of tissue O2 consumption and tissue O2 levels. In contrast, regional tissue dysoxia often persists in sepsis, despite similar restoration of hemodynamics and O2 delivery. Whether this defect in O2 extraction in sepsis is the result of heterogeneous impairment of the microcirculation (intraparenchymal shunting) or impaired tissue parenchymal cell oxidative phosphorylation and O2 consumption by the mito-chondria is not resolved.15 Interesting data suggest that in sepsis the response to limit O2 consumption by the tissue parenchymal cells is an adaptive response to the inflammatory signaling and decreased perfusion.16An additional pathophysiologic response of the microcir-culation to shock is failure of the integrity of the endothelium of the microcirculation and development of capillary leak, intracellular swelling, and the development of an extracellu-lar fluid deficit. Seminal work by Shires helped to define this phenomenon.8,17 There is decreased capillary hydrostatic pres-sure secondary to changes in blood flow and increased cellular uptake of fluid. The result is a loss of extracellular fluid vol-ume. The cause of intracellular swelling is multifactorial, but dysfunction of energy-dependent mechanisms, such as active transport by the sodium-potassium pump contributes to loss of membrane integrity.Capillary dysfunction also occurs secondary to activation of endothelial cells by circulating inflammatory mediators gen-erated in septic or traumatic shock. This exacerbates endothelial cell swelling and capillary leak, as well as increases leukocyte adherence. This results in capillary occlusion, which may persist after resuscitation, and is termed no-reflow. Further ischemic injury ensues as well as release of inflammatory cytokines to compound tissue injury. Experimental models have shown that neutrophil depletion in animals subjected to hemorrhagic shock produces fewer capillaries with no-reflow and lower mortality.14METABOLIC EFFECTSCellular metabolism is based primarily on the hydrolysis of adenosine triphosphate (ATP). The splitting of the phosphoan-hydride bond of the terminal or g-phosphate from ATP is the source of energy for most processes within the cell under nor-mal conditions. The majority of ATP is generated in our bodies through aerobic metabolism in the process of oxidative phos-phorylation in the mitochondria. This process is dependent on the availability of O2 as a final electron acceptor in the electron transport chain. As O2 tension within a cell decreases, there is a decrease in oxidative phosphorylation, and the generation Brunicardi_Ch05_p0131-p0156.indd 13629/01/19 11:06 AM 137SHOCKCHAPTER 5of ATP slows. When O2 delivery is so severely impaired such that oxidative phosphorylation cannot be sustained, the state is termed dysoxia.18 When oxidative phosphorylation is insuffi-cient, the cells shift to anaerobic metabolism and glycolysis to generate ATP. This occurs via the breakdown of cellular glyco-gen stores to pyruvate. Although glycolysis is a rapid process, it is not efficient, allowing for the production of only 2 mol of ATP from 1 mol of glucose. This is compared to complete oxidation of 1 mol of glucose that produces 38 mol of ATP. Additionally, under hypoxic conditions in anaerobic metabo-lism, pyruvate is converted into lactate, leading to an intracel-lular metabolic acidosis.There are numerous consequences secondary to these met-abolic changes. The depletion of ATP potentially influences all ATP-dependent cellular processes. This includes maintenance of cellular membrane potential, synthesis of enzymes and pro-teins, cell signaling, and DNA repair mechanisms. Decreased intracellular pH also influences vital cellular functions such as normal enzyme activity, cell membrane ion exchange, and cellular metabolic signaling.19 These changes also will lead to changes in gene expression within the cell. Furthermore, acido-sis leads to changes in calcium metabolism and calcium signal-ing. Compounded, these changes may lead to irreversible cell injury and death.Epinephrine and norepinephrine have a profound impact on cellular metabolism. Hepatic glycogenolysis, gluconeogen-esis, ketogenesis, skeletal muscle protein breakdown, and adi-pose tissue lipolysis are increased by catecholamines. Cortisol, glucagon, and ADH also contribute to the catabolism during shock. Epinephrine induces further release of glucagon, while inhibiting the pancreatic β-cell release of insulin. The result is a catabolic state with glucose mobilization, hyperglycemia, pro-tein breakdown, negative nitrogen balance, lipolysis, and insulin resistance during shock and injury. The relative underuse of glu-cose by peripheral tissues preserves it for the glucose-dependent organs such as the heart and brain.Cellular HypoperfusionHypoperfused cells and tissues experience what has been termed oxygen debt, a concept first proposed by Crowell in 1961.20 The O2 debt is the deficit in tissue oxygenation over time that occurs during shock. When O2 delivery is limited, O2 consumption can be inadequate to match the metabolic needs of cellular respira-tion, creating a deficit in O2 requirements at the cellular level. The measurement of O2 deficit uses calculation of the difference between the estimated O2 demand and the actual value obtained for O2 consumption. Under normal circumstances, cells can “repay” the O2 debt during reperfusion. The magnitude of the O2 debt correlates with the severity and duration of hypoperfusion. Surrogate values for measuring O2 debt include base deficit and lactate levels and are discussed later in the “Hypovolemic/ Hemorrhagic” section.In addition to induction of changes in cellular metabolic pathways, shock also induces changes in cellular gene expres-sion. The DNA binding activity of a number of nuclear tran-scription factors is altered by hypoxia and the production of O2 radicals or nitrogen radicals that are produced at the cellular level by shock. Expression of other gene products such as heat shock proteins, vascular endothelial growth factor, inducible nitric oxide synthase (iNOS), heme oxygenase-1, and cytokines also are clearly increased by shock.21 Many of these shock-induced gene products, such as cytokines, have the ability to subsequently alter gene expression in specific target cells and tissues. The involvement of multiple pathways emphasizes the complex, integrated, and overlapping nature of the response to shock.IMMUNE AND INFLAMMATORY RESPONSESThe inflammatory and immune responses are a complex set of interactions between circulating soluble factors and cells that can arise in response to trauma, infection, ischemia, toxic, or autoimmune stimuli.21 The processes are well regulated and can be conceptualized as an ongoing surveillance and response sys-tem that undergoes a coordinated escalation following injury to heal disrupted tissue or restore host-microbe equilibrium, as well as active suppression back to baseline levels. Failure to adequately control the activation, escalation, or suppression of the inflammatory response can lead to systemic inflammatory response syndrome and potentiate multiple organ failure.Both the innate and adaptive branches of the immune system work in concert to rapidly respond in a specific and effective manner to challenges that threaten an organism’s well-being. Each arm of the immune system has its own set of func-tions, defined primarily by distinct classes of effector cells and their unique cell membrane receptor families. Alterations in the activity of the innate host immune system can be responsible for both the development of shock (i.e., septic shock follow-ing severe infection and traumatic shock following tissue injury with hemorrhage) and the pathophysiologic sequelae of shock such as the proinflammatory changes seen following hypoperfu-sion (see Fig. 5-1). When the predominantly paracrine mediators gain access to the systemic circulation, they can induce a variety of metabolic changes that are collectively referred to as the host inflammatory response. Understanding of the intricate, redun-dant, and interrelated pathways that comprise the inflammatory response to shock continues to expand. Despite limited under-standing of how our current therapeutic interventions impact the host response to illness, inappropriate or excessive inflam-mation appears to be an essential event in the development of ARDS, multiple organ dysfunction syndrome (MODS), and posttraumatic immunosuppression that can prolong recovery.22Following direct tissue injury or infection, there are several mechanisms that lead to the activation of the active inflamma-tory and immune responses. These include release of bioactive peptides by neurons in response to pain and the release of intra-cellular molecules by broken cells, such as heat shock proteins, mitochondrial products, heparan sulfate, high mobility group box 1, and RNA. Only recently has it been realized that the release of intracellular products from damaged and injured cells can have paracrine and endocrine-like effects on distant tissues to activate the inflammatory and immune responses.23 This hypothesis, which was first proposed by Matzinger, is known as danger signaling. Under this novel paradigm of immune function, endogenous molecules are capable of signaling the presence of danger to surrounding cells and tissues. These molecules that are released from cells are known as damage associated molecular patterns (DAMPs, Table 5-3). DAMPs are recognized by cell surface receptors to effect intracellular signaling that primes and amplifies the immune response. These receptors are known as pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs) and the receptor for advanced glycation end products. Interestingly, TLRs and PRRs were first recognized for their role in signaling as part of the immune response to the Brunicardi_Ch05_p0131-p0156.indd 13729/01/19 11:06 AM 138BASIC CONSIDERATIONSPART Ientry of microbes and their secreted products into a normally sterile environment. These bacterial products, including lipo-polysaccharide, are known as pathogen-associated molecular patterns. The salutary consequences of PRR activation most likely relate to the initiation of the repair process and the mobi-lization of antimicrobial defenses at the site of tissue disruption. However, in the setting of excessive tissue damage, the inflam-mation itself may lead to further tissue damage, amplifying the response both at the local and systemic level.21 PRR activation leads to intracellular signaling and release of cellular products, including cytokines (Fig. 5-4).Before the recruitment of leukocytes into sites of injury, tissue-based macrophages or mast cells act as sentinel respond-ers, releasing histamines, eicosanoids, tryptases, and cytokines (Fig. 5-5). Together these signals amplify the immune response by further activation of neurons and mast cells, as well as increasing the expression of adhesion molecules on the endothe-lium. Furthermore, these mediators cause leukocytes to release platelet-activating factor, further increasing the stickiness of the endothelium. Additionally, the coagulation and kinin cascades impact the interaction of endothelium and leukocytes.Cytokines/ChemokinesThe immune response to shock encompasses the elaboration of mediators with both proinflammatory and anti-inflammatory properties (Table 5-4). Furthermore, new mediators, new rela-tionships between mediators, and new functions of known mediators are continually being identified. As new pathways are uncovered, understanding of the immune response to injury and the potential for therapeutic intervention by manipulating the immune response following shock will expand. What seems clear at present, however, is that the innate immune response can help restore homeostasis, or if it is excessive, promote cel-lular and organ dysfunction.Multiple mediators have been implicated in the host immune response to shock. It is likely that some of the most important mediators have yet to be discovered and the roles of many known mediators have not been defined. A compre-hensive description of all of the mediators and their complex interactions is beyond the scope of this chapter. For a general overview, a brief description of the more extensively studied mediators, as well as some of the known effects of these sub-stances, see the following discussion. A more comprehensive review can be found in Chapter 2, “Systemic Response to Injury and Metabolic Support.”Tumor necrosis factor alpha (TNF-a) was one of the first cytokines to be described, and it is one of the earliest cytokines released in response to injurious stimuli. Monocytes, macro-phages, and T cells release this potent proinflammatory cyto-kine. TNF-a levels peak within 90 minutes of stimulation and return frequently to baseline levels within 4 hours. Release of TNF-a may be induced by bacteria or endotoxin and leads to the development of shock and hypoperfusion, most commonly observed in septic shock. Production of TNF-a also may be induced following other insults, such as hemorrhage and isch-emia. TNF-a levels correlate with mortality in animal models of hemorrhage.24 In contrast, the increase in serum TNF-a levels reported in trauma patients is far less than that seen in septic patients.25 Once released, TNF-a can produce peripheral vaso-dilation, activate the release of other cytokines, induce proco-agulant activity, and stimulate a wide array of cellular metabolic changes. During the stress response, TNF-a contributes to the muscle protein breakdown and cachexia.Interleukin-1 (IL-1) has actions similar to those of TNF-a. IL-1 has a very short half-life (6 minutes) and primarily acts in a paracrine fashion to modulate local cellular responses. Sys-temically, IL-1 produces a febrile response to injury by activat-ing prostaglandins in the posterior hypothalamus, and causes anorexia by activating the satiety center. This cytokine also aug-ments the secretion of ACTH, glucorticoids, and β-endorphins. In conjunction with TNF-a, IL-1 can stimulate the release of other cytokines such as IL-2, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and interferon-g.IL-2 is produced by activated T cells in response to a vari-ety of stimuli and activates other lymphocyte subpopulations and natural killer cells. The lack of clarity regarding the role of IL-2 in the response to shock is intimately associated with that of understanding immune function after injury. Some investigators have postulated that increased IL-2 secretion promotes shock-induced tissue injury and the development of shock. Others have demonstrated that depressed IL-2 production is associated with, Table 5-3Endogenous damage-associated molecular pattern moleculesMitochondrial DNAHyaluronan oligomersHeparan sulfateExtra domain A of fibronectinHeat shock proteins 60, 70, Gp96Surfactant Protein Aβ-Defensin 2FibrinogenBiglycanHigh mobility group box 1Uric acidInterleukin-1αS-100sNucleolinNeuropeptidesTissue-based macrophages/mast cells Histamines,leukotrienes,chemokines,TNF TraumaDAMPs (HMGB1,heparan sulfate,uric acid)Macrophages Bacteria andbacterialproductsComplementNeutrophilsDegranulationChemokines,TNFDefensinsTNF,Interferon-LymphocytesAntigenStimulation/activationProductionFigure 5-4. A schema of information flow between immune cells in early inflammation following tissue injury and infection. Cells require multiple inputs and stimuli before activation of a full response. DAMPs = damage associated molecular patterns; HMGB1 = high mobility group box 1; TNF = tumor necrosis factor.Brunicardi_Ch05_p0131-p0156.indd 13829/01/19 11:06 AM 139SHOCKCHAPTER 5and perhaps contributes to, the depression in immune func-tion after hemorrhage that may increase the susceptibility of patients who develop shock to suffer infections.26,27 It has been postulated that overly exuberant proinflammatory activation promotes tissue injury, organ dysfunction, and the subsequent immune dysfunction/suppression that may be evident later.22 Emphasizing the importance of temporal changes in the produc-tion of mediators, both the initial excessive production of IL-2 and later depressed IL-2 production are probably important in the progression of shock.MKK3p 38MKK 7JNKDAMPLPS signalingHemorrhagic shockIschemia/reperfusionTissue traumaToxic exposureDanger signalingInjuryNecrosisCD14HMGB-1HMGB-1LPSActivatedTLR4TRAMTRIFIRF 3MyD88-dependentpathwayMyD88-independentpathwayNuclear membraneOtherco-receptorsSecretion fromstressed cellsBreakdownof matrixMyD88MALIRAK 4IRAK 1TRAF 6TAK 1IKK 1IKK 2IRF 3MD-2NEMOI˜Bp 50p 65NF-˜Bp 50p 65TBK 1Cell membraneCell membraneTLR4TLR4TLR4MD-2LBPFigure 5-5. Signaling via the pattern recognition receptor TLR4. LPS signaling via TLR4 requires the cofactors LPS binding protein (LBP), MD-2, and CD14. Endogenous danger signals released from a variety of sources also signal in a TLR4-dependent fashion, although it is as yet unknown what cofactors may be required for this activity. Once TLR4 is activated, an intracellular signaling cascade is initiated that involves both a MyD88-dependent and independent pathway. DAMP = damage associated molecular pattern; LPS = lipopolysaccharide; MD-2 = myeloid differentiation factor-2; MyD88 = myeloid differentiation primary response gene 88; NF-kB = nuclear factor kB; TLR4 = Toll-like receptor-4. (Reproduced with permission from Mollen KP, Levy RM, Prince JM, et al. Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells, J Leukoc Biol. 2008 Jan;83(1):80-88.)Brunicardi_Ch05_p0131-p0156.indd 13929/01/19 11:06 AM 140BASIC CONSIDERATIONSPART IIL-6 is elevated in response to hemorrhagic shock, major operative procedures, or trauma. Elevated IL-6 levels correlate with mortality in shock states. IL-6 contributes to lung, liver, and gut injury after hemorrhagic shock.28 Thus, IL-6 may play a role in the development of diffuse alveolar damage and ARDS. IL-6 and IL-1 are mediators of the hepatic acute phase response to injury, and enhance the expression and activity of comple-ment, C-reactive protein, fibrinogen, haptoglobin, amyloid A, and alpha1-antitrypsin, and promote neutrophil activation.29IL-10 is considered an anti-inflammatory cytokine that may have immunosuppressive properties. Its production is increased after shock and trauma, and it has been associated with depressed immune function clinically, as well as an increased susceptibility to infection.30 IL-10 is secreted by T cells, mono-cytes, and macrophages, and inhibits proinflammatory cytokine secretion, O2 radical production by phagocytes, adhesion mol-ecule expression, and lymphocyte activation.30,31 Administra-tion of IL-10 depresses cytokine production and improves some aspects of immune function in experimental models of shock and sepsis.32,33Recent studies point to the importance of chemokines, a specific set of cytokines, that have the ability to induce che-motaxis of leukocytes. Chemokines bind to specific chemokine receptors and transduce chemotactic signals to leukocytes. The significance of this large family of chemoattractant cytokines in immunology is difficult to understate, as almost every facet of the immune system is influenced by chemokines, including immune system development, immune surveillance, immune priming, effector responses, and immune regulation.34ComplementThe complement cascade can be activated by injury, shock, and severe infection, and contributes to host defense and pro-inflammatory activation. Significant complement consumption occurs after hemorrhagic shock.35 In trauma patients, the degree of complement activation is proportional to the magnitude of injury and may serve as a marker for severity of injury. Patients in septic shock also demonstrate activation of the complement pathway, with elevations of the activated complement proteins C3a and C5a. Activation of the complement cascade can con-tribute to the development of organ dysfunction. Activated complement factors C3a, C4a, and C5a are potent mediators of increased vascular permeability, smooth muscle cell contraction, histamine and arachidonic acid by-product release, and adher-ence of neutrophils to vascular endothelium. Activated comple-ment acts synergistically with endotoxin to induce the release of TNF-a and IL-1. The development of ARDS and MODS in trauma patients correlates with the intensity of complement activation.36 Complement and neutrophil activation may corre-late with mortality in multiply injured patients.NeutrophilsNeutrophil activation is an early event in the upregulation of the inflammatory response; neutrophils are the first cells to be recruited to the site of injury. Polymorphonuclear leuko-cytes (PMNs) remove infectious agents, foreign substances that have penetrated host barrier defenses, and nonviable tis-sue through phagocytosis. However, activated PMNs and their products may also produce cell injury and organ dysfunction. Activated PMNs generate and release a number of substances that may induce cell or tissue injury, such as reactive O2 spe-cies, lipid-peroxidation products, proteolytic enzymes (elastase, cathepsin G), and vasoactive mediators (leukotrienes, eico-sanoids, and platelet-activating factor). Oxygen-free radicals, such as superoxide anion, hydrogen peroxide, and hydroxyl radical, are released and induce lipid peroxidation, inactivate enzymes, and consume antioxidants (such as glutathione and tocopherol). Ischemia-reperfusion activates PMNs and causes PMN-induced organ injury. In animal models of hemorrhagic shock, activation of PMNs correlates with irreversibility of shock and mortality, and neutrophil depletion prevents the pathophysiologic sequelae of hemorrhagic and septic shock. Human data corroborate the activation of neutrophils in trauma and shock and suggest a role in the development of MODS.37 Plasma markers of PMN activation, such as elastase, correlate with severity of injury in humans.Interactions between endothelial cells and leukocytes are important in the inflammatory process. The vascular endothe-lium contributes to regulation of blood flow, leukocyte adher-ence, and the coagulation cascade. Extracellular ligands such as intercellular adhesion molecules, vascular cell adhesion mol-ecules, and the selectins (E-selectin, P-selectin) are expressed on the surface of endothelial cells, and are responsible for leuko-cyte adhesion to the endothelium. This interaction allows acti-vated neutrophils to migrate into the tissues to combat infection, but also can lead to PMN-mediated cytotoxicity and microvas-cular and tissue injury.Cell SignalingA host of cellular changes occur following shock. Although many of the intracellular and intercellular pathways that are important in shock are being elucidated, undoubtedly there are many more that have yet to be identified. Many of the media-tors produced during shock interact with cell surface receptors on target cells to alter target cell metabolism. These signaling pathways may be altered by changes in cellular oxygenation, redox state, high-energy phosphate concentration, gene expres-sion, or intracellular electrolyte concentration induced by shock. Cells communicate with their external environment through the use of cell surface membrane receptors, which, once bound by a ligand, transmit their information to the interior of the cell through a variety of signaling cascades. These signaling path-ways may subsequently alter the activity of specific enzymes, the expression or breakdown of important proteins, or affect intracellular energy metabolism. Intracellular calcium (Ca2+) homeostasis and regulation represents one such pathway. Intra-cellular Ca2+ concentrations regulate many aspects of cellular metabolism; many important enzyme systems require Ca2+ for Table 5-4Inflammatory mediators of shockPROINFLAMMATORYANTI-INFLAMMATORYInterleukin-1α/βInterleukin-4Interleukin-2Interleukin-10Interleukin-6Interleukin-13Interleukin-8Prostaglandin E2InterferonTGFβTNF PAF PAF = platelet activating factor; TGFβ = transforming growth factor β; TNF = tumor necrosis factor.Brunicardi_Ch05_p0131-p0156.indd 14029/01/19 11:06 AM 141SHOCKCHAPTER 5full activity. Profound changes in intracellular Ca2+ levels and Ca2+ transport are seen in models of shock.38 Alterations in Ca2+ regulation may lead to direct cell injury, changes in transcription factor activation, alterations in the expression of genes impor-tant in homeostasis, and the modulation of the activation of cells by other shock-induced hormones or mediators.39,40A proximal portion of the intracellular signaling cascade consists of a series of kinases that transmit and amplify the sig-nal through the phosphorylation of target proteins. The O2 radi-cals produced during shock and the intracellular redox state are known to influence the activity of components of this cascade, such as protein tyrosine kinases, mitogen activated kinases, and protein kinase C.41-43 Either through changes in these sig-naling pathways, changes in the activation of enzyme systems through Ca2+-mediated events, or direct conformational changes to oxygen-sensitive proteins, O2 radicals also regulate the activ-ity of a number of transcription factors that are important in gene expression, such as nuclear factor kB, APETALA1, and hypoxia-inducible factor 1.44,45 It is therefore becoming increas-ingly clear that oxidant-mediated direct cell injury is merely one consequence of the production of O2 radicals during shock.The study of the effects of shock on the regulation of gene expression as an important biologic effect was stimulated by the work of Buchman and colleagues.46 The effects of shock on the expression and regulation of numerous genes and gene products has been studied in both experimental animal models and human patients. These studies include investigations into single genes of interest as well as large-scale genomic and proteomic analysis.47-49 Changes in gene expression are critical for adaptive and survival cell signaling. Polymorphisms in gene promoters that lead to a differential level of expression of gene products are also likely to contribute significantly to varied responses to similar insults.50,51 In a recent study, the genetic responses to traumatic injury in humans or endotoxin delivery to healthy human volunteers demonstrated that severe stresses produce a global reprioritiza-tion affecting >80% of the cellular functions and pathways.52 The similarities in genomic responses among different injuries revealed a fundamental human response to stressors involving dysregulated immune responses (Fig. 5-6). Furthermore, in trau-matic injury patients, complications like nosocomial infections and organ failure were not associated with any genomic evi-dence of a second hit and differed only in the magnitude and duration of this genomic reprioritization.FORMS OF SHOCKHypovolemic/HemorrhagicThe most common cause of shock in the surgical or trauma patient is loss of circulating volume from hemorrhage. Acute blood loss results in reflexive decreased baroreceptor stimu-lation from stretch receptors in the large arteries, resulting in decreased inhibition of vasoconstrictor centers in the brain stem, increased chemoreceptor stimulation of vasomotor centers, and diminished output from atrial stretch receptors. These changes increase vasoconstriction and peripheral arterial resistance. Hypovolemia also induces sympathetic stimulation, leading to epinephrine and norepinephrine release, activation of the renin-angiotensin cascade, and increased vasopressin release. Periph-eral vasoconstriction is prominent, while lack of sympathetic effects on cerebral and coronary vessels and local autoregula-tion promote maintenance of cardiac and CNS blood flow.Diagnosis. Treatment of shock is initially empiric. A secure airway must be confirmed or established in obtunded patients. The priority is the initiation of volume infusion while the search for the cause of the hypotension is pursued. Shock in a trauma patient or postoperative patient should be presumed to be due to hemorrhage until proven otherwise. The clinical signs of shock may be evidenced by agitation, cool clammy extremities, tachy-cardia, weak or absent peripheral pulses, and hypotension. Such apparent clinical shock results from at least 25% to 30% loss of the blood volume. However, substantial volumes of blood may be lost before the classic clinical manifestations of shock are evident. Thus, when a patient is significantly tachycardic or hypotensive, this represents both significant blood loss and physiologic decompensation. The clinical and physiologic response to hemorrhage has been classified according to the magnitude of volume loss. Loss of up to 15% of the circulat-ing volume (700 to 750 mL for a 70-kg patient) may produce little in terms of obvious symptoms, while loss of up to 30% of the circulating volume (1.5 L) may result in mild tachycar-dia, tachypnea, and anxiety. Hypotension, marked tachycardia (i.e., pulse greater than 110 to 120 bpm), and confusion may not be evident until more than 30% of the blood volume has been lost; loss of 40% of circulating volume (2 L) is immedi-ately life threatening and generally requires operative control of bleeding (Table 5-5). Young healthy patients with vigor-ous compensatory mechanisms may tolerate larger volumes of blood loss while manifesting fewer clinical signs despite the presence of significant peripheral hypoperfusion. These patients may maintain a near-normal blood pressure until a precipitous cardiovascular collapse occurs. Elderly patients may be tak-ing medications that either promote bleeding (e.g., warfarin or aspirin), or mask the compensatory responses to bleeding (e.g., β-blockers). In addition, atherosclerotic vascular disease, diminishing cardiac compliance with age, inability to elevate heart rate or cardiac contractility in response to hemorrhage, and overall decline in physiologic reserve decrease the elderly Dysregulated adaptive immune responseMagnitude of responseMagnitude of responseUncomplicated outcomeComplicated outcomeDysregulated innate immune responseFigure 5-6. The concurrent dysregulated innate immune responses that promote inflammation and dysregulated adaptive immune responses that result in immunosuppression occur in patients follow-ing traumatic injury. However, these genetic responses can result in complicated outcomes in trauma patients if the magnitude or dura-tion of these responses are pronounced. (Reproduced with permission from Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in criti-cally injured humans, J Exp Med. 2011 Dec 19;208(13):2581-2590.)Brunicardi_Ch05_p0131-p0156.indd 14129/01/19 11:06 AM 142BASIC CONSIDERATIONSPART Ipatient’s ability to tolerate hemorrhage. Recent data in trauma patients suggest that a systolic blood pressure (SBP) of less than 110 mmHg is a clinically relevant definition of hypotension and hypoperfusion based upon an increasing rate of mortality below this pressure (Fig. 5-7).53In addressing the sensitivity of vital signs and identifying major thoracoabdominal hemorrhage, a study retrospectively identified patients with injury to the trunk and an abbreviated injury score of 3 or greater who required immediate surgical intervention and transfusion of at least 5 units of blood within the first 24 hours. Ninety-five percent of patients had a heart rate greater than 80 bpm at some point during their postinjury course. However, only 59% of patients achieved a heart rate greater than 120 bpm. Ninety-nine percent of all patients had a recorded blood pressure of less than 120 mmHg at some point. Ninety-three percent of all patients had a recorded SBP of less than 100 mmHg.54 A more recent study corroborated that tachy-cardia was not a reliable sign of hemorrhage following trauma and was present in only 65% of hypotensive patients.55Serum lactate and base deficit are measurements that are helpful to both estimate and monitor the extent of bleeding and shock. The amount of lactate that is produced by anaerobic res-piration is an indirect marker of tissue hypoperfusion, cellular O2 debt, and the severity of hemorrhagic shock. Several stud-ies have demonstrated that the initial serum lactate and serial lactate levels are reliable predictors of morbidity and mortality with hemorrhage following trauma (Fig. 5-8).56 Similarly, base deficit values derived from arterial blood gas analysis provide clinicians with an indirect estimation of tissue acidosis from hypoperfusion. Davis and colleagues stratified the extent of base deficit into mild (–3 to –5 mmol/L), moderate (–6 to –9 mmol/L), and severe (less than –10 mmol/L), and from this established a correlation between base deficit upon admission with transfu-sion requirements, the development of multiple organ failure, and death (Fig. 5-9).57 Both base deficit and lactate correlate with the extent of shock and patient outcome, but interestingly do not firmly correlate with each other.58-60 Evaluation of both values may be useful in trauma patients with hemorrhage.Although hematocrit changes may not rapidly reflect the total volume of blood loss, admission hematocrit has been shown to be associated with 24 hour fluid and transfusion requirements and more strongly associated with PRBC transfu-sion than either tachycardia, hypotension, or acidosis.61 It must be noted that lack of a depression in the initial hematocrit does not rule out substantial blood loss or ongoing bleeding.In management of trauma patients, understanding the pat-terns of injury of the patient in shock will help direct the evalu-ation and management. Identifying the sources of blood loss in patients with penetrating wounds is relatively simple because potential bleeding sources will be located along the known or suspected path of the wounding object. Patients with penetrating injuries who are in shock usually require operative intervention. Patients who suffer multisystem injuries from blunt trauma have multiple sources of potential hemorrhage. Blood loss sufficient to cause shock is generally of a large volume, and there are a limited number of sites that can harbor sufficient extravascular blood volume to induce hypotension (e.g., external, intratho-racic, intra-abdominal, retroperitoneal, and long bone fractures). In the nontrauma patient, the GI tract must always be considered as a site for blood loss. Substantial blood loss externally may be suspected from prehospital medical reports documenting a sub-stantial blood loss at the scene of an accident, history of massive Table 5-5Classification of hemorrhage CLASSPARAMETERIIIIIIIVBlood loss (mL)<750750–15001500–2000>2000Blood loss (%)<1515–3030–40>40Heart rate (bpm)<100>100>120>140Blood pressureNormalOrthostaticHypotensionSevere hypotensionCNS symptomsNormalAnxiousConfusedObtundedbpm = beats per minute; CNS = central nervous system.3025201510506065707580859095100105Systolic BP in the ED110115120125130135140145150155160121086420% MortalityBase deficit% MortalityBDFigure 5-7. The relationship between systolic blood pressure and mortality in trauma patients with hemorrhage. These data suggest that a systolic blood pressure of less than 110 mmHg is a clinically relevant definition of hypotension and hypoperfusion based upon an increasing rate of mortal-ity below this pressure. Base deficit (BD) is also shown on this graph. ED = emergency department. (Reproduced with permission from Eastridge BJ, Salinas J, McManus JG, et al. Hypotension begins at 110 mm Hg: redefining “hypotension” with data, J Trauma. 2007 Aug;63(2):291-297.)Brunicardi_Ch05_p0131-p0156.indd 14229/01/19 11:06 AM 143SHOCKCHAPTER 5blood loss from wounds, visible brisk bleeding, or presence of a large hematoma adjacent to an open wound. Injuries to major arteries or veins with associated open wounds may cause massive blood loss rapidly. Direct pressure must be applied and sustained to minimize ongoing blood loss. Tourniquets should be used for extremity bleeding stopped by direct pressure and applied in the prehospital setting as needed.62,63 Persistent bleeding from uncontrolled smaller vessels can, over time, precipitate shock if inadequately treated.When major blood loss is not immediately visible in the setting of trauma, internal (intracavitary) blood loss should be suspected. Each pleural cavity can hold 2 to 3 L of blood and can therefore be a site of significant blood loss. Diagnostic and therapeutic tube thoracostomy may be indicated in unstable patients based on clinical findings and clinical suspicion. In a more stable patient, a chest radiograph may be obtained to look for evidence of hemothorax. Major retroperitoneal hem-orrhage typically occurs in association with pelvic fractures, which is confirmed by pelvic radiography in the resuscitation bay. Intraperitoneal hemorrhage is probably the most common source of blood loss that induces shock. The physical exam for detection of substantial blood loss or injury is insensitive and unreliable; large volumes of intraperitoneal blood may be present before physical examination findings are apparent. Findings with intra-abdominal hemorrhage include abdominal distension, abdominal tenderness, or visible abdominal wounds. Hemodynamic abnormalities generally stimulate a search for blood loss before the appearance of obvious abdominal findings. Adjunctive tests are essential in the diagnosis of intraperitoneal bleeding; intraperitoneal blood may be rapidly identified by diagnostic ultrasound or diagnostic peritoneal lavage. Further-more, patients that have sustained high-energy blunt trauma that are hemodynamically stable or that have normalized their vital signs in response to initial volume resuscitation should undergo computed tomography scans to assess for head, chest, and/or abdominal bleeding.Treatment. Control of ongoing hemorrhage is an essential component of the resuscitation of the patient in shock. As mentioned in the previous “Diagnosis” section, treatment of hemorrhagic shock is instituted concurrently with diagnostic evaluation to identify a source. Patients who fail to respond to initial resuscitative efforts should be assumed to have ongo-ing active hemorrhage from large vessels and require prompt operative intervention. Based on trauma literature, patients with ongoing hemorrhage demonstrate increased survival if the elapsed time between the injury and control of bleeding is decreased. Although there are no randomized controlled trials, retrospective studies provide compelling evidence in this regard. To this end, Clarke and colleagues64 demonstrated that trauma Serum lactateMuscle lactateLiver lactateTime (hours)Serum lactate (mg/100 ml)Tissue lactate (M/gm tissue)012345510152025306090120150Figure 5-8. Progressive increases in serum lactate, muscle lactate, and liver lactate in a baboon model of hemorrhagic shock. (Repro-duced with permission from Peitzman AB, Corbett WA, Shires GT, et al: Cellular function in liver and muscle during hemorrhagic shock in primates, Surg Gynecol Obstet. 1985 Nov;161(5):419-424.)Extracellular BEA, mmol/L10059590858075706560555045403530252015100102–6–14–22–38% MortalityBase excess = –11.8LD50% Mortality = e˜1 + e˜x 10010090807060504030201001020% Predicted death on the basis of linear logistic model from BEAECF% Observed death0–0.19–0.17–4.5–7.4–9.7–11.8–14–16.4–19.2–23.530405060708090100Figure 5-9. The relationship between base deficit (negative base excess) and mortality in trauma patients. BEA = base excess arterial; ECF = extracellular fluid. (Reproduced with permission from Siegel JH, Rivkind AI, Dalal S, et al: Early physiologic predictors of injury severity and death in blunt multiple trauma, Arch Surg. 1990 Apr;125(4):498-508.)Brunicardi_Ch05_p0131-p0156.indd 14329/01/19 11:06 AM 144BASIC CONSIDERATIONSPART Ipatients with major injuries isolated to the abdomen requiring emergency laparotomy had an increased probability of death with increasing length of time in the emergency department for patients who were in the emergency department for 90 minutes or less. This probability increased approximately 1% for each 3 minutes in the emergency department.The appropriate priorities in these patients are as follows: (a) control the source of blood loss, (b) perform IV volume resuscitation with blood products in the hypotensive patient, and (c) secure the airway. In trauma, identifying the body cavity har-boring active hemorrhage will help focus operative efforts; how-ever, because time is of the essence, rapid treatment is essential, and diagnostic laparotomy or thoracotomy may be indicated. The actively bleeding patient cannot be resuscitated until control of ongoing hemorrhage is achieved. Our current understanding has led to the management strategy known as damage control resuscitation.65 This strategy begins in the emergency depart-ment, continues into the operating room, and into the intensive care unit (ICU). Initial resuscitation is limited to keep SBP around 80 to 90 mmHg. This prevents renewed bleeding from recently clotted vessels. Resuscitation and intravascular volume resuscitation is accomplished with blood products and lim-ited crystalloids, which is addressed further later in this section. Too little volume allowing persistent severe hypoten-sion and hypoperfusion is dangerous, yet too vigorous of a vol-ume resuscitation may be just as deleterious. Control of hemorrhage is achieved in the operating room (or angiography suite once surgical causes of hemorrhage have been ruled out), and efforts to warm patients and to prevent coagulopathy using multiple blood products and pharmacologic agents are used in both the operating room and ICU.Cannon and colleagues first made the observation that attempts to increase blood pressure in soldiers with uncontrolled sources of hemorrhage is counterproductive, with increased bleeding and higher mortality.3 This work was the foundation for the “hypotensive resuscitation” strategies. Several laboratory studies confirmed the observation that attempts to restore normal blood pressure with fluid infusion or vasopressors was rarely achievable and resulted in more bleeding and higher mortality.66 A prospective, randomized clinical study compared delayed fluid resuscitation (upon arrival in the operating room) with standard fluid resuscitation (with arrival by the paramedics) in hypotensive patients with penetrating torso injury.67 The authors reported that delayed fluid resuscitation resulted in lower patient mortality. Further laboratory studies demonstrated that fluid restriction in the setting of profound hypotension resulted in early deaths from severe hypoperfusion. These studies also showed that aggressive crystalloid resuscitation attempting to normalize blood pressure resulted in marked hemodilution, with hematocrits of 5%.66 Reasonable conclusions in the setting of uncontrolled hemorrhage include (a) any delay in surgery for control of hemorrhage increases mortality; (b) with uncontrolled hemorrhage, attempting to achieve normal blood pressure may increase mortality, particularly with penetrating injuries and short transport times; (c) a goal of SBP of 80 to 90 mmHg may be adequate in the patient with penetrating injury; and (d) profound hemodilution should be avoided by early transfusion of red blood cells. For the patient with blunt injury, where the major cause of death is a closed head injury, the increase in mortality with hypotension in the setting of brain injury must be avoided. In this setting, a SBP of 110 mmHg would seem to be more appropriate.Patients who respond to initial resuscitative effort but then deteriorate hemodynamically frequently have injuries that require operative intervention. The magnitude and duration of their response will dictate whether diagnostic maneuvers can be performed to identify the site of bleeding. However, hemo-dynamic deterioration generally denotes ongoing bleeding for which some form of intervention (i.e., operation or interven-tional radiology) is required. Patients who have lost significant intravascular volume, but whose hemorrhage is controlled or has abated, often will respond to resuscitative efforts if the depth and duration of shock have been limited.A subset of patients exists who fail to respond to resuscita-tive efforts despite adequate control of ongoing hemorrhage. These patients have ongoing fluid requirements despite ade-quate control of hemorrhage, have persistent hypotension despite restoration of intravascular volume necessitating vasopressor support, and may exhibit a futile cycle of uncorrectable hypothermia, hypoperfusion, acidosis, and coagulopathy that cannot be interrupted despite maximum ther-apy. These patients have deteriorated to decompensated or irre-versible shock with peripheral vasodilation and resistance to vasopressor infusion. Mortality is almost inevitable once the patient manifests shock in its terminal stages. Unfortunately, this is often diagnosed in retrospect.Fluid resuscitation is a major adjunct to physically con-trolling hemorrhage in patients with shock. The ideal type of fluid to be used continues to be debated; however, crystalloids continue to be the mainstay fluid of choice. Several studies have demonstrated increased risk of death in bleeding trauma patients treated with colloid compared to patients treated with crystalloid.68 In patients with severe hemorrhage, restoration of intravascular volume should be achieved with blood products.69Ongoing studies continue to evaluate the use of hypertonic saline as a resuscitative adjunct in bleeding patients.70 The ben-efit of hypertonic saline solutions may be immunomodulatory. Specifically, these effects have been attributed to pharmacologic effects resulting in decreased reperfusion-mediated injury with decreased O2 radical formation, less impairment of immune function compared to standard crystalloid solution, and less brain swelling in the multi-injured patient. The reduction of total volume used for resuscitation makes this approach appealing as a resuscitation agent for combat injuries and may contribute to a decrease in the incidence of ARDS and multiple organ failure.Transfusion of packed red blood cells and other blood products is essential in the treatment of patients in hemorrhagic shock. Current recommendations in stable ICU patients aim for a target hemoglobin of 7 to 9 g/dL71,72; however, no prospective randomized trials have compared restrictive and liberal transfu-sion regimens in trauma patients with hemorrhagic shock. The current standard in severely injured patients is termed dam-age control resuscitation and consists of transfusion with red blood cells, fresh frozen plasma (FFP), and platelet units given in equal number.73 Civilian and military trauma data show that the development of coagulopathy of trauma is predictive of mortality.74 Data collected from a U.S. Army combat support hospital helped to propagate this practice, showing in patients that received massive transfusion of packed red blood cells (>10 units in 24 hours) that a high plasma to RBC ratio (1:1.4 units) was independently associated with improved survival.75 A number of civilian studies have demonstrated similar results.76 Similarly, platelet transfusion is important. The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) 45Brunicardi_Ch05_p0131-p0156.indd 14429/01/19 11:06 AM 145SHOCKCHAPTER 5trial has demonstrated that damage-control resuscitation, a massive transfusion strategy targeting a balanced delivery of plasma-platelet-red blood cell in a ratio of 1:1:1, results in improved survival at 3 hours and a reduction in deaths caused by exsanguination in the first 24 hours.77 Studies have demon-strated that low platelet counts in trauma patients was associ-ated with increased mortality78 and that increased platelet use appears to improve outcome.79,80 The benefit of platelet trans-fusion may be most pronounced in trauma patients with brain injury.81 It has been suggested that platelets should be transfused in the bleeding patient to maintain counts above 50 × 109/L. In addition, transfusion of whole blood is gaining in popularity, and ongoing studies are evaluating the benefit of this approach.There is a potential role for other coagulation factor based products, such as fibrinogen concentrates and prothrombin complex concentrates. Use of these agents may be guided by a drop in fibrinogen levels to less than 1 g/L, or less specifically by thromboelastogram findings to suggest hyperfibrinolysis. Data also support the use of antifibrinolytic agents in bleeding trauma patients, specifically tranexamic acid (a synthetic lysine analogues that acts as a competitive inhibitor of plasmin and plasminogen). The multinational Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-2) trial suggested that early use of tranexamic acid limits rebleeding and reduces mortality82 (Fig 5-10). In the past, coagulopathy associated with the bleeding patient was presumed to be due solely to dilution and depletion of clotting factors and plate-lets. We now understand that an acute coagulopathy of trauma occurs as an immediate consequence of injury, with abnormal admission coagulation as a predictor of high mortality.83 Tradi-tional measurement of platelets, INR, and PTT may not reflect the coagulopathy of trauma or response to therapy effectively. Recently, viscoelastic functional testing such as thromboelas-tography (TEG) has been utilized as a quicker, more compre-hensive determination of coagulopathy and fibrinolysis in the injured patient. Holcomb et al recently reported that TEG pre-dicted patients with substantial bleeding and red cell transfusion better than conventional coagulopathy tests, and it also predicted the need for platelet transfusion better than platelet count and the need for plasma transfusion better than fibrinogen levels.84OR (95% CI) of tranexamic acidTime to treatment (h)0.58765432101.01.52.02.53.0Figure 5-10. Early treatment (within 3 hours) of trauma patients with tranexamic acid reduces mortality. However, later treatment exacerbated outcome. (Reproduced with permission from Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial, Lancet. 2011 Mar 26;377(9771):1096-1101.)Additional resuscitative adjuncts in patients with hemor-rhagic shock include minimization of heat loss and maintaining normothermia. The development of hypothermia in the bleeding patient is associated with acidosis, hypotension, and coagulopa-thy. Hypothermia in bleeding trauma patients is an independent risk factor for bleeding and death. This likely is secondary to impaired platelet function and impairments in the coagulation cascade. Several studies have investigated the induction of con-trolled hypothermia in patients with severe shock based on the hypothesis of limiting metabolic activity and energy require-ments, creating a state of “suspended animation.” These studies are promising and continue to be evaluated in large trials.Traumatic ShockThe systemic response after trauma, combining the effects of soft tissue injury, long bone fractures, and blood loss, is clearly a different physiologic insult than simple hemorrhagic shock. Multiple organ failure, including acute respiratory distress syn-drome (ARDS), develops relatively often in the blunt trauma patient, but rarely after pure hemorrhagic shock (such as a GI bleed). The hypoperfusion deficit in traumatic shock is magnified by the proinflammatory activation that occurs following the induc-tion of shock. In addition to ischemia or ischemia-reperfusion, accumulating evidence demonstrates that even simple hemor-rhage induces proinflammatory activation that results in many of the cellular changes typically ascribed only to septic shock.85,86 At the cellular level, this may be attributable to the release of cellular products termed damage associated molecu-lar patterns (DAMPs, i.e., riboxynucleic acid, uric acid, and high mobility group box 1) that activate the same set of cell surface receptors as bacterial products, initiating similar cell signaling.5,87 These receptors are termed pattern recognition receptors (PRRs) and include the TLR family of proteins. Examples of traumatic shock include small volume hemorrhage accompanied by soft tissue injury (femur fracture, crush injury), or any combination of hypovolemic, neurogenic, cardiogenic, and obstructive shock that precipitate rapidly progressive proin-flammatory activation. In laboratory models of traumatic shock, the addition of a soft tissue or long bone injury to hemorrhage produces lethality with significantly less blood loss when the animals are stressed by hemorrhage. Treatment of traumatic shock is focused on correction of the individual elements to diminish the cascade of proinflammatory activation, and includes prompt control of hemorrhage, adequate volume resus-citation to correct O2 debt, debridement of nonviable tissue, stabilization of bony injuries, and appropriate treatment of soft tissue injuries.Septic Shock (Vasodilatory Shock)In the peripheral circulation, profound vasoconstriction is the typical physiologic response to the decreased arterial pressure and tissue perfusion with hemorrhage, hypovolemia, or acute heart failure. This is not the characteristic response in vasodila-tory shock. Vasodilatory shock is the result of dysfunction of the endothelium and vasculature secondary to circulating inflam-matory mediators and cells or as a response to prolonged and severe hypoperfusion. Thus, in vasodilatory shock, hypotension results from failure of the vascular smooth muscle to constrict appropriately. Vasodilatory shock is characterized by peripheral vasodilation with resultant hypotension and resistance to treat-ment with vasopressors. Despite the hypotension, plasma cate-cholamine levels are elevated, and the renin-angiotensin system 6Brunicardi_Ch05_p0131-p0156.indd 14529/01/19 11:06 AM 146BASIC CONSIDERATIONSPART Iis activated in vasodilatory shock. The most frequently encoun-tered form of vasodilatory shock is septic shock. Other causes of vasodilatory shock include hypoxic lactic acidosis, carbon monoxide poisoning, decompensated and irreversible hemor-rhagic shock, terminal cardiogenic shock, and postcardiotomy shock (Table 5-6). Thus, vasodilatory shock seems to represent the final common pathway for profound and prolonged shock of any etiology.88Despite advances in intensive care, the mortality rate for severe sepsis remains at 30% to 50%. In the United States, 750,000 cases of sepsis occur annually, one-third of which are fatal.89 Sepsis accounts for 9.3% of deaths in the United States, as many yearly as MI. Septic shock is a by-product of the body’s response to disruption of the host-microbe equilibrium, result-ing in invasive or severe localized infection.In the attempt to eradicate the pathogens, the immune and other cell types (e.g., endothelial cells) elaborate soluble medi-ators that enhance macrophage and neutrophil killing effec-tor mechanisms, increase procoagulant activity and fibroblast activity to localize the invaders, and increase microvascular blood flow to enhance delivery of killing forces to the area of invasion. When this response is overly exuberant or becomes systemic rather than localized, manifestations of sepsis may be evident. These findings include enhanced cardiac output, peripheral vasodilation, fever, leukocytosis, hyperglycemia, and tachycardia. In septic shock, the vasodilatory effects are due, in part, to the upregulation of the inducible isoform of nitric oxide synthase (iNOS or NOS 2) in the vessel wall. iNOS produces large quantities of nitric oxide for sustained periods of time. This potent vasodilator suppresses vascular tone and renders the vasculature resistant to the effects of vasoconstricting agents. Additionally, endothelial activation or injury likely contributes to some degree of vascular dysfunction.Diagnosis. Attempts to standardize terminology have led to the establishment of criteria for the diagnosis of sepsis in the hospitalized adult. These criteria include manifestations of the host response to infection in addition to identification of an offending organism. The terms sepsis and septic shock are used to quantify the magnitude of the systemic inflammatory reac-tion. Patients with sepsis have evidence of an infection, as well as systemic signs of inflammation (e.g., fever, leukocytosis, and tachycardia). Hypoperfusion with signs of organ dysfunction is termed severe sepsis. Septic shock requires the presence of the aforementioned signs, associated with more significant evidence of tissue hypoperfusion and systemic hypotension. Beyond the hypotension, maldistribution of blood flow and shunting in the microcirculation further compromise delivery of nutrients to the tissue beds.90,91 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) have refined the defi-nitions and utilize a Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score to help determine signs of organ dys-function and to guide management.92Recognizing septic shock begins with defining the patient at risk. The clinical manifestations of septic shock will usually become evident and prompt the initiation of treatment before bacteriologic confirmation of an organism or the source of an organism is identified. In addition to fever, tachycardia, and tachypnea, signs of hypoperfusion such as confusion, malaise, oliguria, or hypotension may be present. These should prompt an aggressive search for infection, including a thorough physical examination, inspection of all wounds, evaluation of intravas-cular catheters or other foreign bodies, obtaining appropriate cultures, and adjunctive imaging studies, as needed.Treatment. Evaluation of the patient in septic shock begins with an assessment of the adequacy of their airway and ven-tilation. Severely obtunded patients and patients whose work of breathing is excessive require intubation and ventilation to prevent respiratory collapse. Because vasodilation and decrease in total peripheral resistance may produce hypotension, fluid resuscitation and restoration of circulatory volume with bal-anced salt solutions is essential. The Surviving Sepsis Campaign has updated treatment recommendations and care bundles with a most recent goal for care within the first hour93,94 (Table 5-7). Serum lactate should be measured as a marker of shock. Fluid resuscitation should begin within the first hour and should be at least 30 mL/kg for hypotensive patients. Incremental fluid boluses should be continued based upon endpoint of resuscita-tion, including clearance of lactate. Starch-based colloid solu-tions should be avoided as recent evidence suggests that these fluids may be deleterious in the setting of sepsis.90,95,96 Blood cultures should be obtained. Empiric antibiotics must be chosen carefully based on the most likely pathogens (gram-negative rods, gram-positive cocci, and anaerobes) because the portal of entry of the offending organism and its identity may not be evi-dent until culture data return or imaging studies are completed. Knowledge of the bacteriologic profile of infections in an indi-vidual unit can be obtained from most hospital infection control departments and will suggest potential responsible organisms. Antibiotics should be tailored to cover the responsible organ-isms once culture data are available, and if appropriate, the Table 5-6Causes of septic and vasodilatory shockSystemic response to infectionNoninfectious systemic inflammation Pancreatitis BurnsAnaphylaxisAcute adrenal insufficiencyProlonged, severe hypotension Hemorrhagic shock Cardiogenic shock Cardiopulmonary bypassMetabolic Hypoxic lactic acidosis Carbon monoxide poisoningTable 5-7Surviving Sepsis Campaign bundles of care to be initiated within the first hour after presentation in the patient with sepsis93,94Measure serum lactate level. Remeasure if the initial lactate is >2 mmol/LObtain blood culture prior to administration of antibioticsAdminister broad spectrum antibioticsRapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/LUse vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain a mean arterial pressure ≥65 mmHgBrunicardi_Ch05_p0131-p0156.indd 14629/01/19 11:06 AM 147SHOCKCHAPTER 5spectrum of coverage narrowed. Long-term, empiric, broad-spectrum antibiotic use should be minimized to reduce the development of resistant organisms and to avoid the potential complications of fungal overgrowth and antibiotic-associated colitis from overgrowth of Clostridium difficile. IV antibiotics will be insufficient to adequately treat the infectious episode in the settings of infected fluid collections, infected foreign bodies, and devitalized tissue. These situations require source control and involve percutaneous drainage and operative management to target a focus of infection. These situations may require mul-tiple operations to ensure proper wound hygiene and healing.After first-line therapy of the septic patient with antibiot-ics, IV fluids, and intubation if necessary, vasopressors may be necessary to treat patients with septic shock. Catecholamines are the vasopressors used most often, with norepinephrine being the first-line agent followed by epinephrine. Occasionally, patients with septic shock will develop arterial resistance to catechol-amines. Arginine vasopressin, a potent vasoconstrictor, is often efficacious in this setting and is often added to norepinephrine.The majority of septic patients have hyperdynamic physi-ology with supranormal cardiac output and low systemic vas-cular resistance. On occasion, septic patients may have low cardiac output despite volume resuscitation and even vasopres-sor support. Dobutamine therapy is recommended for patients with cardiac dysfunction as evidenced by high filling pres-sures and low cardiac output or clinical signs of hypoperfusion after achievement of restoration of blood pressure following fluid resuscitation. Mortality in this group is high. Despite the increasing incidence of septic shock over the past several decades, the overall mortality rates have changed little. Stud-ies of interventions, including immunotherapy, resuscitation to pulmonary artery endpoints with hemodynamic optimization (cardiac output and O2 delivery, even to supranormal values), and optimization of mixed venous O2 measurements up to 72 hours after admission to the ICU, have not changed mortality.The advances made in the treatment of patients with sep-sis and septic shock and collaborative groups such as the Sur-viving Sepsis Campaign continue to evaluate, modify, and put forth recommendations based upon data. Negative results from previous studies have led to the suggestion that earlier inter-ventions directed at improving global tissue oxygenation may be of benefit. To this end, Rivers and colleagues reported that goal-directed therapy of septic shock and severe sepsis initiated in the emergency department and continued for 6 hours signifi-cantly improved outcome.97 This approach involved adjustment of cardiac preload, afterload, and contractility to balance O2 delivery with O2 demand. They found that goal-directed therapy during the first 6 hours of hospital stay (initiated in the emer-gency department) had significant effects, such as higher mean venous O2 saturation, lower lactate levels, lower base deficit, higher pH, and decreased 28-day mortality (49.2% vs. 33.3%) compared to the standard therapy group. The frequency of sud-den cardiovascular collapse was also significantly less in the group managed with goal-directed therapy (21.0% vs. 10.3%). Interestingly, the goal-directed therapy group received more IV fluids during the initial 6 hours, but the standard therapy group required more IV fluids by 72 hours. The authors emphasize that continued cellular and tissue decompensation is subclinical and often irreversible when obvious clinically. Goal-directed therapy allowed identification and treatment of these patients with insidious illness (global tissue hypoxia in the setting of normal vital signs).Several multicenter trials have been performed to further refine these finding. In the Protocolized Care for Early Septic Shock (ProCESS) trial, a multicenter, randomized trial in which patients were identified early in the emergency department as having septic shock and received antibiotics and other nonre-suscitation aspects of care promptly, the investigators found no significant advantage, with respect to mortality or morbid-ity, of protocol-based resuscitation over bedside care that was provided according to the treating physician’s judgment. They also found no significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients. This last finding was recapitulated in the Pro-tocolised Management in Sepsis (ProMISe) trial.98,99 Failure of these more recent trials to show a benefit of early goal-directed protocols vs. standard of care may be secondary to the gener-alized improvement in early recognition of sepsis and institu-tion of protocolized care by efforts such as the Surviving Sepsis Campaign.Hyperglycemia and insulin resistance are typical in criti-cally ill and septic patients, including patients without underly-ing diabetes mellitus. A recent study reported significant positive impact of tight glucose management on outcome in critically ill patients.100 The two treatment groups in this randomized, pro-spective study were assigned to receive intensive insulin therapy (maintenance of blood glucose between 80 and 110 mg/dL) or conventional treatment (infusion of insulin only if the blood glu-cose level exceeded 215 mg/dL, with a goal between 180 and 200 mg/dL). The mean morning glucose level was significantly higher in the conventional treatment as compared to the inten-sive insulin therapy group (153 vs. 103 mg/dL). Mortality in the intensive insulin treatment group (4.6%) was significantly lower than in the conventional treatment group (8.0%), representing a 42% reduction in mortality. This reduction in mortality was most notable in the patients requiring longer than 5 days in the ICU. Furthermore, intensive insulin therapy reduced episodes of septicemia by 46%, reduced duration of antibiotic therapy, and decreased the need for prolonged ventilatory support and renal replacement therapy.Another treatment protocol that has been demonstrated to increase survival in patients with ARDS investigated the use of lower ventilatory tidal volumes compared to traditional tidal volumes.101 The majority of the patients enrolled in this multicenter, randomized trial developed ARDS secondary to pneumonia or sepsis. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 mL/kg of predicted body weight, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 mL/kg of predicted body weight. The trial was stopped after the enroll-ment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0% vs. 39.8%, P = .007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean ± SD, 12 ± 11 vs. 10 ± 11; P = .007). The investigators concluded that in patients with acute lung injury and ARDS, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use. Additional strategies in ARDS manage-ment include higher levels of positive end expiratory pressure (PEEP), alveolar recruitment maneuvers, and prone position-ing. Prone positioning has become part of many standardized protocols. This is supported by several studies, including a Brunicardi_Ch05_p0131-p0156.indd 14729/01/19 11:06 AM 148BASIC CONSIDERATIONSPART Imeta-analysis demonstrating that prone positioning is associ-ated with significantly reduced mortality from ARDS in the low tidal volume era.102The use of corticosteroids in the treatment of sepsis and septic shock has been controversial for decades. The observa-tion that severe sepsis often is associated with adrenal insuf-ficiency or glucocorticoid receptor resistance has generated renewed interest in therapy for septic shock with corticosteroids. A single IV dose of 50 mg of hydrocortisone improved mean arterial blood pressure response relationships to norepinephrine and phenylephrine in patients with septic shock and was most notable in patients with relative adrenal insufficiency. A study evaluated therapy with hydrocortisone (50 mg IV every 6 hours) and fludrocortisone (50 µg orally once daily) vs. placebo for 1 week in patients with septic shock.103 As in earlier studies, the authors performed corticotropin tests on these patients to document and stratify patients by relative adrenal insufficiency. In this study, 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly and safely lowered the risk of death in patients with septic shock and relative adrenal insuf-ficiency. In an international, multicenter, randomized trial of corticosteroids in sepsis (CORTICUS study; 499 analyzable patients), steroids showed no benefit in intent to treat mortality or shock reversal.104 This study suggested that hydrocortisone therapy cannot be recommended as routine adjuvant therapy for septic shock. However, if SBP remains less than 90 mmHg despite appropriate fluid and vasopressor therapy, hydrocorti-sone at 200 mg/day for 7 days in four divided doses or by con-tinuous infusion should be considered.Additional adjunctive immune modulation strategies have been developed for the treatment of septic shock. These include the use of antiendotoxin antibodies, anticytokine anti-bodies, cytokine receptor antagonists, immune enhancers, a non– isoform-specific nitric oxide synthase inhibitor, and O2 radical scavengers. These compounds are each designed to alter some aspect of the host immune response to shock that is hypothesized to play a key role in its pathophysiology. However, most of these strategies have failed to demonstrate efficacy in human patients despite utility in well-controlled animal experiments. It is unclear whether the failure of these compounds is due to poorly designed clinical trials, inadequate understanding of the interactions of the complex host immune response to injury and infection, or animal models of shock that poorly represent the human disease.Cardiogenic ShockCardiogenic shock is defined clinically as circulatory pump failure leading to diminished forward flow and subsequent tis-sue hypoxia, in the setting of adequate intravascular volume. Hemodynamic criteria include sustained hypotension (i.e., SBP <90 mmHg for at least 30 minutes), reduced cardiac index (<2.2 L/min per square meter), and elevated pulmonary artery wedge pressure (>15 mmHg).105 Mortality rates for cardiogenic shock are 50% to 80%. Acute, extensive MI is the most common cause of cardiogenic shock; a smaller infarction in a patient with existing left ventricular dysfunction also may precipitate shock. Cardiogenic shock complicates 5% to 10% of acute MIs. Con-versely, cardiogenic shock is the most common cause of death in patients hospitalized with acute MI. Although shock may develop early after MI, it typically is not found on admission. Seventy-five percent of patients who have cardiogenic shock complicating acute MIs develop signs of cardiogenic shock within 24 hours after onset of infarction (average 7 hours).Recognition of the patient with occult hypoperfusion is critical to prevent progression to obvious cardiogenic shock with its high mortality rate; early initiation of therapy to maintain blood pressure and cardiac output is vital. Rapid assessment, adequate resuscitation, and reversal of the myocardial ischemia are essential in optimizing outcome in patients with acute MI. Prevention of infarct extension is a critical component. Large segments of nonfunctional but viable myocardium contribute to the development of cardiogenic shock after MI. In the setting of acute MI, expeditious restoration of cardiac output is mandatory to minimize mortality; the extent of myocardial salvage possible decreases exponentially with increased time to restoration of coronary blood flow. The degree of coronary flow after percuta-neous transluminal coronary angioplasty correlates with inhos-pital mortality (i.e., 33% mortality with complete reperfusion, 50% mortality with incomplete reperfusion, and 85% mortality with absent reperfusion).106 Inadequate cardiac function can be a direct result of cardiac injury, including profound myocardial contusion, blunt cardiac valvular injury, or direct myocardial damage (Table 5-8).105-108 The pathophysiology of cardiogenic shock involves a vicious cycle of myocardial ischemia that causes myocardial dysfunction, which results in more myocar-dial ischemia. When sufficient mass of the left ventricular wall is necrotic or ischemic and fails to pump, the stroke volume decreases. An autopsy series of patients dying from cardiogenic shock have found damage to 40% of the left ventricle.109 Isch-emia distant from the infarct zone may contribute to the systolic dysfunction in patients with cardiogenic shock. The majority of these patients have multivessel disease, with limited vasodila-tor reserve and pressure-dependent coronary flow in multiple areas of the heart. Myocardial diastolic function is impaired in cardiogenic shock as well. Decreased compliance results from myocardial ischemia, and compensatory increases in left ven-tricular filling pressures progressively occur.Diminished cardiac output or contractility in the face of adequate intravascular volume (preload) may lead to under-perfused vascular beds and reflexive sympathetic discharge. Table 5-8Causes of cardiogenic shockAcute myocardial infarctionPump failureMechanical complications Acute mitral regurgitation Acute ventricular septal defect Free wall rupture Pericardial tamponadeArrhythmiaEnd-stage cardiomyopathyMyocarditisSevere myocardial contusionLeft ventricular outflow obstruction Aortic stenosis Hypertrophic obstructive cardiomyopathyObstruction to left ventricular filling Mitral stenosis Left atrial myxomaAcute mitral regurgitationAcute aortic insufficiencyMetabolicDrug reactionsBrunicardi_Ch05_p0131-p0156.indd 14829/01/19 11:06 AM 149SHOCKCHAPTER 5Increased sympathetic stimulation of the heart, either through direct neural input or from circulating catecholamines, increases heart rate, myocardial contraction, and myocardial O2 consump-tion, which may not be relieved by increases in coronary artery blood flow in patients with fixed stenoses of the coronary arter-ies. Diminished cardiac output may also decrease coronary artery blood flow, resulting in a scenario of increased myocar-dial O2 demand at a time when myocardial O2 supply may be limited. Acute heart failure may also result in fluid accumula-tion in the pulmonary microcirculatory bed, decreasing myocar-dial O2 delivery even further.Diagnosis. Rapid identification of the patient with pump failure and institution of corrective action are essential in pre-venting the ongoing spiral of decreased cardiac output from injury causing increased myocardial O2 needs that cannot be met, leading to progressive and unremitting cardiac dysfunc-tion. In evaluation of possible cardiogenic shock, other causes of hypotension must be excluded, including hemorrhage, sepsis, pulmonary embolism, and aortic dissection. Signs of circulatory shock include hypotension, cool and mottled skin, depressed mental status, tachycardia, and diminished pulses. Cardiac exam may include dysrhythmia, precordial heave, or distal heart tones. Confirmation of a cardiac source for the shock requires electrocardiogram and urgent echocardiography. Other useful diagnostic tests include chest radiograph, arterial blood gases, electrolytes, complete blood count, and cardiac enzymes. Inva-sive cardiac monitoring, which generally is not necessary, can be useful to exclude right ventricular infarction, hypovolemia, and possible mechanical complications.Making the diagnosis of cardiogenic shock involves the identification of cardiac dysfunction or acute heart failure in a susceptible patient. In the setting of blunt traumatic injury, hemorrhagic shock from intra-abdominal bleeding, intrathoracic bleeding, and bleeding from fractures must be excluded, before implicating cardiogenic shock from blunt cardiac injury. Rela-tively few patients with blunt cardiac injury will develop cardiac pump dysfunction. Those who do generally exhibit cardiogenic shock early in their evaluation. Therefore, establishing the diag-nosis of blunt cardiac injury is secondary to excluding other etiologies for shock and establishing that cardiac dysfunction is present. Invasive hemodynamic monitoring with a pulmonary artery catheter may uncover evidence of diminished cardiac out-put and elevated pulmonary artery pressure.Treatment. After ensuring that an adequate airway is present and ventilation is sufficient, attention should be focused on sup-port of the circulation. Intubation and mechanical ventilation often are required, if only to decrease work of breathing and facilitate sedation of the patient. Rapidly excluding hypovolemia and establishing the presence of cardiac dysfunction are essen-tial. Treatment of cardiac dysfunction includes maintenance of adequate oxygenation to ensure adequate myocardial O2 deliv-ery and judicious fluid administration to avoid fluid overload and development of cardiogenic pulmonary edema. Electrolyte abnormalities, commonly hypokalemia and hypomagnesemia, should be corrected. Pain is treated with IV morphine sulfate or fentanyl. Significant dysrhythmias and heart block must be treated with antiarrhythmic drugs, pacing, or cardioversion, if necessary. Early consultation with cardiology is essential in current management of cardiogenic shock, particularly in the setting of acute MI.105When profound cardiac dysfunction exists, inotropic support may be indicated to improve cardiac contractility and cardiac output. Dobutamine primarily stimulates cardiac β1-receptors to increase cardiac output but may also vasodilate peripheral vascular beds, lower total peripheral resistance, and lower systemic blood pressure through effects on β2-receptors. Ensuring adequate preload and intravascular volume is therefore essential prior to instituting therapy with dobutamine. Dopamine stimulates receptors (vasoconstriction), β1-receptors (cardiac stimulation), and β2-receptors (vasodilation), with its effects on β-receptors predominating at lower doses. Dopamine may be preferable to dobutamine in treatment of cardiac dysfunction in hypotensive patients. Tachycardia and increased peripheral resistance from dopamine infusion may worsen myocardial ischemia. Titration of both dopamine and dobutamine infusions may be required in some patients.Epinephrine stimulates αand β-receptors and may increase cardiac contractility and heart rate; however, it also may have intense peripheral vasoconstrictor effects that impair further cardiac performance. Catecholamine infusions must be carefully controlled to maximize coronary perfusion, while minimizing myocardial O2 demand. Balancing the beneficial effects of impaired cardiac performance with the potential side effects of excessive reflex tachycardia and peripheral vasocon-striction requires serial assessment of tissue perfusion using indices such as capillary refill, character of peripheral pulses, adequacy of urine output, or improvement in laboratory param-eters of resuscitation such as pH, base deficit, and lactate. Inva-sive monitoring generally is necessary in these unstable patients. The phosphodiesterase inhibitors amrinone and milrinone may be required on occasion in patients with resistant cardiogenic shock. These agents have long half-lives and induce thrombocy-topenia and hypotension, and use is reserved for patients unre-sponsive to other treatment.Patients whose cardiac dysfunction is refractory to car-diotonics may require mechanical circulatory support with an intra-aortic balloon pump.110 Intra-aortic balloon pumping increases cardiac output and improves coronary blood flow by reduction of systolic afterload and augmentation of diastolic perfusion pressure. Unlike vasopressor agents, these beneficial effects occur without an increase in myocardial O2 demand. An intra-aortic balloon pump can be inserted at the bedside in the ICU via the femoral artery through either a cutdown or using the percutaneous approach. Aggressive circulatory support of patients with cardiac dysfunction from intrinsic cardiac disease has led to more widespread application of these devices and more familiarity with their operation by both physicians and critical care nurses.Preservation of existing myocardium and preservation of cardiac function are priorities of therapy for patients who have suffered an acute MI. Ensuring adequate oxygenation and O2 delivery, maintaining adequate preload with judicious volume restoration, minimizing sympathetic discharge through adequate relief of pain, and correcting electrolyte imbalances are all straightforward nonspecific maneuvers that may improve exist-ing cardiac function or prevent future cardiac complications. Anticoagulation and aspirin are given for acute MI. Although thrombolytic therapy reduces mortality in patients with acute MI, its role in cardiogenic shock is less clear. Patients in car-diac failure from an acute MI may benefit from pharmaco-logic or mechanical circulatory support in a manner similar to that of patients with cardiac failure related to blunt cardiac Brunicardi_Ch05_p0131-p0156.indd 14929/01/19 11:06 AM 150BASIC CONSIDERATIONSPART Iinjury. Additional pharmacologic tools may include the use of β-blockers to control heart rate and myocardial O2 consumption, nitrates to promote coronary blood flow through vasodilation, and ACE inhibitors to reduce ACE-mediated vasoconstrictive effects that increase myocardial workload and myocardial O2 consumption.Current guidelines of the American Heart Association recommend percutaneous transluminal coronary angiography for patients with cardiogenic shock, ST elevation, left bundle-branch block, and age less than 75 years.111,112 Early definition of coronary anatomy and revascularization is the pivotal step in treatment of patients with cardiogenic shock from acute MI.113 When feasible, percutaneous transluminal coronary angioplasty (generally with stent placement) is the treatment of choice. Coronary artery bypass grafting seems to be more appropriate for patients with multiple vessel disease or left main coronary artery disease.Obstructive ShockAlthough obstructive shock can be caused by a number of dif-ferent etiologies that result in mechanical obstruction of venous return (Table 5-9), in trauma patients this is most commonly due to the presence of tension pneumothorax. Cardiac tamponade occurs when sufficient fluid has accumulated in the pericardial sac to obstruct blood flow to the ventricles. The hemodynamic abnormalities in pericardial tamponade are due to elevation of intracardiac pressures with limitation of ventricular filling in diastole with resultant decrease in cardiac output. Acutely, the pericardium does not distend; thus small volumes of blood may produce cardiac tamponade. If the effusion accumulates slowly (e.g., in the setting of uremia, heart failure, or malignant effusion), the quantity of fluid producing cardiac tamponade may reach 2000 mL. The major determinant of the degree of hypotension is the pericardial pressure. With either cardiac tamponade or tension pneumothorax, reduced filling of the right side of the heart from either increased intrapleural pressure secondary to air accumulation (tension pneumothorax) or increased intra-pericardial pressure precluding atrial filling secondary to blood accumulation (cardiac tamponade) results in decreased cardiac output associated with increased central venous pressure.Diagnosis and Treatment. The diagnosis of tension pneu-mothorax should be made on clinical examination. The classic findings include respiratory distress (in an awake patient), hypo-tension, diminished breath sounds over one hemithorax, hyper-resonance to percussion, jugular venous distention, and shift of mediastinal structures to the unaffected side with tracheal deviation. In most instances, empiric treatment with pleural decompression is indicated rather than delaying to wait for radiographic confirmation. When a chest tube cannot be imme-diately inserted, such as in the prehospital setting, the pleural space can be decompressed with a large caliber needle. Immedi-ate return of air should be encountered with rapid resolution of hypotension. Unfortunately, not all of the clinical manifestations of tension pneumothorax may be evident on physical examina-tion. Hyperresonance may be difficult to appreciate in a noisy resuscitation area. Jugular venous distention may be absent in a hypovolemic patient. Tracheal deviation is a late finding and often is not apparent on clinical examination. Practically, three findings are sufficient to make the diagnosis of tension pneu-mothorax: respiratory distress or hypotension, decreased lung sounds, and hypertympany to percussion. Chest X-ray findings that may be visualized include deviation of mediastinal struc-tures, depression of the hemidiaphragm, and hypo-opacification with absent lung markings. As discussed previously, definitive treatment of a tension pneumothorax is immediate tube thora-costomy. The chest tube should be inserted rapidly, but care-fully, and should be large enough to evacuate any blood that may be present in the pleural space. Most recommend place-ment is in the fourth intercostal space (nipple level) at the ante-rior axillary line.Cardiac tamponade results from the accumulation of blood within the pericardial sac, usually from penetrating trauma or chronic medical conditions such as heart failure or uremia. Although precordial wounds are most likely to injure the heart and produce tamponade, any projectile or wounding agent that passes in proximity to the mediastinum can potentially produce tamponade. Blunt cardiac rupture, a rare event in trauma vic-tims who survive long enough to reach the hospital, can produce refractory shock and tamponade in the multiply-injured patient. The manifestations of cardiac tamponade, such as total circula-tory collapse and cardiac arrest, may be catastrophic, or they may be more subtle. A high index of suspicion is warranted to make a rapid diagnosis. Patients who present with circulatory arrest from cardiac tamponade require emergency pericardial decompression, usually through a left thoracotomy. The indi-cations for this maneuver are discussed in Chapter 7. Cardiac tamponade also may be associated with dyspnea, orthopnea, cough, peripheral edema, chest pain, tachycardia, muffled heart tones, jugular venous distention, and elevated central venous pressure. Beck’s triad consists of hypotension, muffled heart tones, and neck vein distention. Unfortunately, absence of these clinical findings may not be sufficient to exclude cardiac injury and cardiac tamponade. Muffled heart tones may be difficult to appreciate in a busy trauma center, and jugular venous disten-tion and central venous pressure may be diminished by coexis-tent bleeding. Therefore, patients at risk for cardiac tamponade whose hemodynamic status permits additional diagnostic tests frequently require additional diagnostic maneuvers to confirm cardiac injury or tamponade.Invasive hemodynamic monitoring may support the diag-nosis of cardiac tamponade if elevated central venous pressure, pulsus paradoxus (i.e., decreased systemic arterial pressure with inspiration), or elevated right atrial and right ventricular pres-sure by pulmonary artery catheter are present. These hemody-namic profiles suffer from lack of specificity, the duration of time required to obtain them in critically injured patients, and their inability to exclude cardiac injury in the absence of tam-ponade. Chest radiographs may provide information on the pos-sible trajectory of a projectile, but rarely are diagnostic because Table 5-9Causes of obstructive shockPericardial tamponadePulmonary embolusTension pneumothoraxIVC obstruction Deep venous thrombosis Gravid uterus on IVC NeoplasmIncreased intrathoracic pressure Excess positive end-expiratory pressure NeoplasmIVC = inferior vena cava.Brunicardi_Ch05_p0131-p0156.indd 15029/01/19 11:06 AM 151SHOCKCHAPTER 5the acutely filled pericardium distends poorly. Echocardiogra-phy has become the preferred test for the diagnosis of cardiac tamponade. Good results in detecting pericardial fluid have been reported, but the yield in detecting pericardial fluid depends on the skill and experience of the ultrasonographer, body habitus of the patient, and absence of wounds that preclude visualization of the pericardium. Standard two-dimensional or transesopha-geal echocardiography are sensitive techniques to evaluate the pericardium for fluid, and are typically performed by examiners skilled at evaluating ventricular function, valvular abnormali-ties, and integrity of the proximal thoracic aorta. Unfortunately, these skilled examiners are rarely immediately available at all hours of the night, when many trauma patients present; there-fore, waiting for this test may result in inordinate delays. In addition, although both ultrasound techniques may demonstrate the presence of fluid or characteristic findings of tamponade (large volume of fluid, right atrial collapse, poor distensibility of the right ventricle), they do not exclude cardiac injury per se. Pericardiocentesis to diagnose pericardial blood and potentially relieve tamponade may be used. Performing pericardiocentesis under ultrasound guidance has made the procedure safer and more reliable. An indwelling catheter may be placed for sev-eral days in patients with chronic pericardial effusions. Needle pericardiocentesis may not evacuate clotted blood and has the potential to produce cardiac injury, making it a poor alternative in busy trauma centers.Diagnostic pericardial window represents the most direct method to determine the presence of blood within the pericar-dium. The procedure is best performed in the operating room under general anesthesia. It can be performed through either the subxiphoid or transdiaphragmatic approach. Adequate equip-ment and personnel to rapidly decompress the pericardium, explore the injury, and repair the heart should be present. Once the pericardium is opened and tamponade relieved, hemody-namics usually improve dramatically and formal pericardial exploration can ensue. Exposure of the heart can be achieved by extending the incision to a median sternotomy, performing a left anterior thoracotomy, or performing bilateral anterior tho-racotomies (“clamshell”).Neurogenic ShockNeurogenic shock refers to diminished tissue perfusion as a result of loss of vasomotor tone to peripheral arterial beds. Loss of vasoconstrictor impulses results in increased vascular capacitance, decreased venous return, and decreased cardiac output. Neurogenic shock is usually secondary to spinal cord injuries from vertebral body fractures of the cervical or high thoracic region that disrupt sympathetic regulation of peripheral vascular tone (Table 5-10). Rarely, a spinal cord injury without bony fracture, such as an epidural hematoma impinging on the spinal cord, can produce neurogenic shock. Sympathetic input to the heart, which normally increases heart rate and cardiac contractility, and input to the adrenal medulla, which increases catecholamine release, may also be disrupted, preventing the typical reflex tachycardia that occurs with hypovolemia. Acute spinal cord injury results in activation of multiple secondary injury mechanisms: (a) vascular compromise to the spinal cord with loss of autoregulation, vasospasm, and thrombosis; (b) loss of cellular membrane integrity and impaired energy metabo-lism; and (c) neurotransmitter accumulation and release of free radicals. Importantly, hypotension contributes to the worsening of acute spinal cord injury as the result of further reduction in blood flow to the spinal cord. Management of acute spinal cord injury with attention to blood pressure control, oxygenation, and hemodynamics, essentially optimizing perfusion of an already ischemic spinal cord, seems to result in improved neurologic outcome. Patients with hypotension from spinal cord injury are best monitored in an ICU and carefully followed for evidence of cardiac or respiratory dysfunction.Diagnosis. Acute spinal cord injury may result in bradycardia, hypotension, cardiac dysrhythmias, reduced cardiac output, and decreased peripheral vascular resistance. The severity of the spi-nal cord injury seems to correlate with the magnitude of cardio-vascular dysfunction. Patients with complete motor injuries are over five times more likely to require vasopressors for neuro-genic shock compared to those with incomplete lesions.114 The classic description of neurogenic shock consists of decreased blood pressure associated with bradycardia (absence of reflex-ive tachycardia due to disrupted sympathetic discharge), warm extremities (loss of peripheral vasoconstriction), motor and sen-sory deficits indicative of a spinal cord injury, and radiographic evidence of a vertebral column fracture. Patients with multisys-tem trauma that includes spinal cord injuries often have head injuries that may make identification of motor and sensory defi-cits difficult in the initial evaluation. Furthermore, associated injuries may occur that result in hypovolemia, further compli-cating the clinical presentation. In a subset of patients with spi-nal cord injuries from penetrating wounds, most of the patients with hypotension had blood loss as the etiology (74%) rather than neurogenic causes, and few (7%) had the classic findings of neurogenic shock.115 In the multiply injured patient, other causes of hypotension including hemorrhage, tension pneumothorax, and cardiogenic shock, must be sought and excluded.Treatment. After the airway is secured and ventilation is ade-quate, fluid resuscitation and restoration of intravascular volume often will improve perfusion in neurogenic shock. Most patients with neurogenic shock will respond to restoration of intravas-cular volume alone, with satisfactory improvement in perfusion and resolution of hypotension. Administration of vasoconstric-tors will improve peripheral vascular tone, decrease vascular capacitance, and increase venous return, but should only be con-sidered once hypovolemia is excluded as the cause of the hypo-tension and the diagnosis of neurogenic shock is established. If the patient’s blood pressure has not responded to what is felt to be adequate volume resuscitation, dopamine may be used first. A pure α-agonist, such as phenylephrine, may be used primar-ily or in patients unresponsive to dopamine. Specific treatment for the hypotension is often of brief duration, as the need to administer vasoconstrictors typically lasts 24 to 48 hours. On the other hand, life-threatening cardiac dysrhythmias and hypo-tension may occur up to 14 days after spinal cord injury.The duration of the need for vasopressor support for neurogenic shock may correlate with the overall prognosis or chances of improvement in neurologic function. Appropriate rapid restoration of blood pressure and circulatory perfusion may improve perfusion to the spinal cord, prevent progressive Table 5-10Causes of neurogenic shockSpinal cord traumaSpinal cord neoplasmSpinal/epidural anestheticBrunicardi_Ch05_p0131-p0156.indd 15129/01/19 11:06 AM 152BASIC CONSIDERATIONSPART Ispinal cord ischemia, and minimize secondary cord injury. Res-toration of normal blood pressure and adequate tissue perfusion should precede any operative attempts to stabilize the vertebral fracture.ENDPOINTS IN RESUSCITATIONShock is defined as inadequate perfusion to maintain normal organ function. With prolonged anaerobic metabolism, tissue acidosis and O2 debt accumulate. Thus, the goal in the treatment of shock is restoration of adequate organ perfusion and tissue oxygenation. Resuscitation is complete when O2 debt is repaid, tissue acidosis is corrected, and aerobic metabo-lism restored. Clinical confirmation of this endpoint remains a challenge.Resuscitation of the patient in shock requires simultaneous evaluation and treatment; the etiology of the shock often is not initially apparent. Hemorrhagic shock, septic shock, and trau-matic shock are the most common types of shock encountered on surgical services. To optimize outcome in bleeding patients, early control of the hemorrhage and adequate volume resuscita-tion, including both red blood cells and crystalloid solutions, are necessary. Expedient operative resuscitation is mandatory to limit the magnitude of activation of multiple mediator sys-tems and to abort the microcirculatory changes, which may evolve insidiously into the cascade that ends in irreversible hemorrhagic shock. Attempts to stabilize an actively bleeding patient anywhere but in the operating room are inappropriate. Any intervention that delays the patient’s arrival in the operat-ing room for control of hemorrhage increases mortality, thus the important concept of operating room resuscitation of the critically injured patient.Recognition by care providers of the patient who is in the compensated phase of shock is equally important, but more dif-ficult based on clinical criteria. Compensated shock exists when inadequate tissue perfusion persists despite normalization of blood pressure and heart rate. Even with normalization of blood pressure, heart rate, and urine output, 80% to 85% of trauma patients have inadequate tissue perfusion, as evidenced by increased lactate or decreased mixed venous O2 saturation.56,116 Persistent, occult hypoperfusion is frequent in the ICU, with a resultant significant increase in infection rate and mortality in major trauma patients. Patients failing to reverse their lactic acidosis within 12 hours of admission (acidosis that was persis-tent despite normal heart rate, blood pressure, and urine output) developed an infection three times as often as those who normal-ized their lactate levels within 12 hours of admission. In addi-tion, mortality was fourfold higher in patients who developed infections. Both injury severity score and occult hypotension (lactic acidosis) longer than 12 hours were independent predic-tors of infection.117 Thus, recognition of subclinical hypoperfu-sion requires information beyond vital signs and urinary output.Endpoints in resuscitation can be divided into systemic or global parameters, tissue-specific parameters, and cellu-lar parameters. Global endpoints include vital signs, cardiac output, pulmonary artery wedge pressure, O2 delivery and con-sumption, lactate, and base deficit (Table 5-11).Assessment of Endpoints in ResuscitationInability to repay O2 debt is a predictor of mortality and organ failure; the probability of death has been directly cor-related to the calculated O2 debt in hemorrhagic shock. Direct measurement of the O2 debt in the resuscitation of patients is difficult. The easily obtainable parameters of arterial blood pressure, heart rate, urine output, central venous pressure, and pulmonary artery occlusion pressure are poor indicators of the adequacy of tissue perfusion. Therefore, surrogate parameters have been sought to estimate the O2 debt; serum lactate and base deficit have been shown to correlate with O2 debt.Lactate. Lactate is generated by conversion of pyruvate to lactate by lactate dehydrogenase in the setting of insufficient O2. Lactate is released into the circulation and is predominantly taken up and metabolized by the liver and kidneys. The liver accounts for approximately 50% and the kidney for about 30% of whole body lactate uptake. Elevated serum lactate is an indi-rect measure of the O2 debt, and therefore an approximation of the magnitude and duration of the severity of shock. The admission lactate level, highest lactate level, and time interval to normalize the serum lactate are important prognostic indi-cators for survival. For example, in a study of 76 consecutive patients, 100% survival was observed among the patients with normalization of lactate within 24 hours, 78% survival when lactate normalized between 24 and 48 hours, and only 14% sur-vivorship if it took longer than 48 hours to normalize the serum lactate.56 In contrast, individual variability of lactate may be too great to permit accurate prediction of outcome in any individual case. Base deficit and volume of blood transfusion required in the first 24 hours of resuscitation may be better predictors of mortality than the plasma lactate alone.Base Deficit. Base deficit is the amount of base in millimoles that is required to titrate 1 L of whole blood to a pH of 7.40 with the sample fully saturated with O2 at 37°C (98.6°F) and a partial pressure of CO2 of 40 mmHg. It usually is measured by arterial blood gas analysis in clinical practice as it is readily and quickly available. The mortality of trauma patients can be stratified according to the magnitude of base deficit measured in the first 24 hours after admission.60 In a retrospective study of over 3000 trauma admissions, patients with a base deficit worse than 15 mmol/L had a mortality of 70%. Base deficit can be stratified into mild (3 to 5 mmol/L), moderate (6 to 14 mmol/L), and severe (15 mmol/L) categories, with a trend toward higher mortality with worsening base deficit in patients with trauma. Both the magnitude of the perfusion deficit as indicated by the base deficit and the time required to correct it are major factors determining outcome in shock.Indeed, when elevated base deficit persists (or lactic acidosis) in the trauma patient, ongoing bleeding is often the 7Table 5-11Endpoints in resuscitationSystemic/global Lactate Base deficit Cardiac output Oxygen delivery and consumptionTissue specific Gastric tonometry Tissue pH, oxygen, carbon dioxide levels Near infrared spectroscopyCellular Membrane potential Adenosine triphosphateBrunicardi_Ch05_p0131-p0156.indd 15229/01/19 11:06 AM 153SHOCKCHAPTER 5etiology. Trauma patients admitted with a base deficit greater than 15 mmol/L required twice the volume of fluid infusion and six times more blood transfusion in the first 24 hours com-pared to patients with mild acidosis. Transfusion requirements increased as base deficit worsened and ICU and hospital lengths of stay increased. Mortality increased as base deficit worsened; the frequency of organ failure increased with greater base deficit.57 The probability of trauma patients developing ARDS has been reported to correlate with severity of admission base deficit and lowest base deficit within the first 24 hours postinjury.59 Persistently high base deficit is associated with abnormal O2 utilization and higher mortality. Monitoring base deficit in the resuscitation of trauma patients assists in assess-ment of O2 transport and efficacy of resuscitation.58Factors that may compromise the utility of the base defi-cit in estimating O2 debt are the administration of bicarbonate, hypothermia, hypocapnia (overventilation), heparin, ethanol, and ketoacidosis. However, the base deficit remains one of the most widely used estimates of O2 debt for its clinical relevance, accuracy, and availability.Near Infrared Spectroscopy. Near infrared (NIR) spectros-copy can measure tissue oxygenation and redox state of cyto-chrome a,a3 on a continuous, noninvasive basis. The NIR probe emits multiple wavelengths of light in the NIR spectrum (650 to 1100 nm). Photons are then either absorbed by the tissue or reflected back to the probe. Maximal exercise in laboratory stud-ies resulted in reduction of cytochrome a,a3; this correlated with tissue lactate elevation. NIR spectroscopy can be used to com-pare tissue oxyhemoglobin levels (indicating tissue O2 supply to cytochrome a,a3 with mitochondrial O2 consumption), thus demonstrating flow-independent mitochondrial oxidative dys-function and the need for further resuscitation. Trauma patients with decoupled oxyhemoglobin and cytochrome a,a3 have redox dysfunction and have been shown to have a higher incidence of organ failure (89 vs. 13%).121,122Tissue PH, Oxygen, and Carbon Dioxide Concentration.  Tissue probes with optical sensors have been used to measure tissue pH and partial pressure of O2 and CO2 in subcutaneous sites, muscle, and the bladder. These probes may use transcuta-neous methodology with Clark electrodes or direct percutaneous probes.123,124 The percutaneous probes can be inserted through an 18-gauge catheter and hold promise as continuous monitors of tissue perfusion.Right Ventricular End-Diastolic Volume Index. Right ven-tricular end-diastolic volume index (RVEDVI) seems to more accurately predict preload for cardiac index than does pulmonary artery wedge pressure.125 Chang and colleagues reported that 50% of trauma patients had persistent splanchnic ischemia that was reversed by increasing RVEDVI. 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Inflammatory media-tors in relation to the development of multiple organ fail-ure in patients after severe blunt trauma. Crit Care Med. 1995;23(3):474-480. 86. Leone M, Boutiere B, Camoin-Jau L, et al. Systemic endo-thelial activation is greater in septic than in traumatichemorrhagic shock but does not correlate with endothelial acti-vation in skin biopsies. Crit Care Med. 2002;30(4):808-814. 87. Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR. Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006;26(5):430-437. 88. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001;345(8):588-595. 89. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310. 90. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228. 91. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327. 92. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. 93. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018. 94. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sep-sis and septic shock: 2016. Intensive Care Med. 2017;43(3): 304-377. 95. Myburgh JA, Finfer S, Billot L. Hydroxyethyl starch or saline in intensive care. N Engl J Med. 2013;368(8):775. 96. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124-134. 97. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. 98. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311. 99. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015;41(9):1549-1560. 100. van den Berghe G, Wouters P, Weekers F, et al. Inten-sive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. 101. Ventilation with lower tidal volumes as compared with tra-ditional tidal volumes for acute lung injury and the acute Brunicardi_Ch05_p0131-p0156.indd 15529/01/19 11:06 AM 156BASIC CONSIDERATIONSPART Irespiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-1308. 102. Beitler JR, Shaefi S, Montesi SB, et al. Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis. Intensive Care Med. 2014;40(3):332-341. 103. Annane D, Sebille V, Charpentier C, et al. Effect of treat-ment with low doses of hydrocortisone and fludrocorti-sone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871. 104. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. 105. Hollenberg SM, Kavinsky CJ, Parrillo JE. Cardiogenic shock. Ann Intern Med. 1999;131(1):47-59. 106. Webb JG, Lowe AM, Sanborn TA, et al. Percutaneous coro-nary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol. 2003;42(8):1380-1386. 107. Edens JW, Chung KK, Pamplin JC, et al. Predictors of early acute lung injury at a combat support hospital: a prospective observational study. J Trauma. 2010;69 Suppl 1:S81-86. 108. Aji J, Hollenberg S. Cardiogenic shock: giving the heart a break. Crit Care Med. 2006;34(4):1248-1249. 109. Alonso DR, Scheidt S, Post M, Killip T. Pathophysiology of cardiogenic shock. Quantification of myocardial necrosis, clinical, pathologic and electrocardiographic correlations. Circulation. 1973;48(3):588-596. 110. Goldstein DJ, Oz MC. Mechanical support for postcardi-otomy cardiogenic shock. Semin Thorac Cardiovasc Surg. 2000;12(3):220-228. 111. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60(16):1581-1598. 112. Gibbons RJ, Smith SC, Jr., Antman E. American College of Cardiology/American Heart Association clinical practice guidelines: part II: evolutionary changes in a continuous quality improvement project. Circulation. 2003;107(24):3101-3107. 113. Menon V, Hochman JS. Management of cardiogenic shock complicating acute myocardial infarction. Heart. 2002;88(5): 531-537. 114. Levi L, Wolf A, Belzberg H. Hemodynamic parameters in patients with acute cervical cord trauma: description, intervention, and prediction of outcome. Neurosurgery. 1993;33(6):1007-1016; discussion 1016-1007. 115. Zipnick RI, Scalea TM, Trooskin SZ, et al. Hemodynamic responses to penetrating spinal cord injuries. J Trauma. 1993;35(4):578-582; discussion 582-573. 116. Abou-Khalil B, Scalea TM, Trooskin SZ, Henry SM, Hitchcock R. Hemodynamic responses to shock in young trauma patients: need for invasive monitoring. Crit Care Med. 1994;22(4):633-639. 117. Claridge JA, Crabtree TD, Pelletier SJ, Butler K, Sawyer RG, Young JS. Persistent occult hypoperfusion is associated with a significant increase in infection rate and mortality in major trauma patients. J Trauma. 2000;48(1):8-14; discussion 14-15. 118. Ivatury RR, Simon RJ, Havriliak D, Garcia C, Greenbarg J, Stahl WM. Gastric mucosal pH and oxygen delivery and oxygen consumption indices in the assessment of adequacy of resuscitation after trauma: a prospective, randomized study. J Trauma. 1995;39(1):128-134; discussion 134-136. 119. Maynard N, Beale R, Smithies M, Bihari D. Gastric intramu-cosal pH in critically ill patients. Lancet. 1992;339(8792): 550-551. 120. Gomersall CD, Joynt GM, Freebairn RC, Hung V, Buckley TA, Oh TE. Resuscitation of critically ill patients based on the results of gastric tonometry: a prospective, randomized, controlled trial. Crit Care Med. 2000;28(3):607-614. 121. Cairns CB, Moore FA, Haenel JB, et al. Evidence for early supply independent mitochondrial dysfunction in patients developing multiple organ failure after trauma. J Trauma. 1997;42(3):532-536. 122. Cohn SM, Crookes BA, Proctor KG. Near-infrared spectros-copy in resuscitation. J Trauma. 2003;54(5 Suppl):S199-202. 123. Knudson MM, Bermudez KM, Doyle CA, Mackersie RC, Hopf HW, Morabito D. Use of tissue oxygen tension measure-ments during resuscitation from hemorrhagic shock. J Trauma. 1997;42(4):608-614; discussion 614-616. 124. McKinley BA, Marvin RG, Cocanour CS, Moore FA. Tissue hemoglobin O2 saturation during resuscitation of traumatic shock monitored using near infrared spectrometry. J Trauma. 2000;48(4):637-642. 125. Cheatham ML, Nelson LD, Chang MC, Safcsak K. Right ven-tricular end-diastolic volume index as a predictor of preload status in patients on positive end-expiratory pressure. Crit Care Med. 1998;26(11):1801-1806. 126. Chang MC, Meredith JW, Kincaid EH, Miller PR. Maintain-ing survivors’ values of left ventricular power output dur-ing shock resuscitation: a prospective pilot study. J Trauma. 2000;49(1):26-33; discussion 34-37.Brunicardi_Ch05_p0131-p0156.indd 15629/01/19 11:06 AM

Surgical InfectionsRobert E. Bulander, David L. Dunn, and Greg J. Beilman 6chapterHISTORICAL BACKGROUNDAlthough treatment of infection has long been an integral part of the surgeon’s practice, the body of knowledge that led to the present field of surgical infectious disease was derived from the evolution of germ theory and antisepsis. Application of the latter to clinical practice, concurrent with the development of anesthe-sia, was pivotal in allowing surgeons to expand their repertoire to encompass complex procedures that previously were associ-ated with extremely high rates of morbidity and mortality due to postoperative infections. However, until recently the occurrence of infection related to the surgical wound was the rule rather than the exception. In fact, the development of modalities to effectively prevent and treat infection has occurred only within the last several decades.A number of observations by 19th century physicians and investigators were critical to our current understanding of the pathogenesis, prevention, and treatment of surgical infections. In 1846, Ignaz Semmelweis, a Magyar physician, took a post at the Allgemein Krankenhaus in Vienna. He noticed that the mortality rate from puerperal (“childbed”) fever was nearly three times higher in the teaching ward than in the ward where patients were delivered by midwives. He also made the observa-tion that women who delivered prior to arrival on the teaching ward had a negligible mortality rate. When a colleague died from overwhelming infection resulting from a knife scratch received during an autopsy of a woman who had died of puer-peral fever, Semmelweis observed that pathologic changes in his friend were identical to those of women dying from this postpartum disease. He hypothesized that puerperal fever was caused by putrid material carried on the examining fingers of medical students and physicians who cared for women dying of the disease, and who often went from the autopsy room to the wards. The low mortality rate in the midwives’ ward, Sem-melweis realized, was because midwives did not participate in autopsies. Fired with the zeal of his revelation, he posted a notice on the door to the ward requiring all caregivers to rinse their hands thoroughly in chlorine water prior to entering the area. This simple intervention reduced the mortality rate from puerperal fever on the teaching ward to 1.5%, surpassing the record of the midwives. In 1861, he published his classic work on childbed fever based on records from his practice. Unfor-tunately, Semmelweis’ ideas were not well accepted by the authorities of the time.1 Increasingly frustrated by the indiffer-ence of the medical profession, he began writing open letters to well-known obstetricians in Europe and was committed to an asylum due to concerns that he was losing his mind. He died shortly thereafter. His achievements were only recognized after Pasteur’s description of the germ theory of disease.Louis Pasteur performed a body of work during the lat-ter part of the 19th century that provided the underpinnings of modern microbiology, at the time known as germ theory. His work in humans followed experiments identifying infectious agents in silkworms. He was able to elucidate the principle that contagious diseases are caused by specific microbes and that these microbes are foreign to the infected organism. Using this principle, he developed techniques of sterilization criti-cal to oenology and identified several bacteria responsible for human illnesses, including Staphylococcus and Streptococcus pneumoniae (pneumococcus).Joseph Lister, the son of a wine merchant, was appointed professor of surgery at the Glasgow Royal Infirmary in 1859. In his early practice, he noted that more than half of his patients undergoing amputation died because of postoperative infection. After hearing of Pasteur’s work, Lister experimented with the use of a solution of carbolic acid, which he knew was being used to treat sewage. He first reported his findings to the British Medical Association in 1867 using dressings saturated with car-bolic acid on 12 patients with compound fractures; 10 recovered Historical Background 157Pathogenesis of Infection 159Host Defenses / 159Definitions / 160Microbiology of Infectious Agents 161Bacteria / 161Fungi / 162Viruses / 162Prevention and Treatment of  Surgical Infections 163General Principles / 163Source Control / 163Appropriate Use of Antimicrobial Agents / 164Infections of Significance in  Surgical Patients 169Surgical Site Infections / 169Intra-Abdominal Infections / 171Organ-Specific Infections / 172Infections of the Skin and Soft Tissue / 173Postoperative Nosocomial Infections / 174Sepsis / 175Resistant Organisms / 177Blood-Borne Pathogens / 177Biologic Warfare Agents 178Bacillus anthracis (Anthrax) / 178Yersinia pestis (Plague) / 178Smallpox / 178Francisella tularensis (Tularemia) / 179Brunicardi_Ch06_p0157-p0182.indd 15701/03/19 4:46 PM 158without amputation, one survived with amputation, and one died of causes unrelated to the wound. In spite of initial resistance, his methods were quickly adopted throughout much of Europe.From 1878 until 1880, Robert Koch was the district medi-cal officer for Wollstein, an area in Prussia where anthrax was endemic. Performing experiments in his home, without the ben-efit of scientific equipment and academic contact, Koch devel-oped techniques for culture of Bacillus anthracis and proved the ability of this organism to cause anthrax in healthy animals. He developed the following four postulates to identify the asso-ciation of organisms with specific diseases: (a) the suspected pathogenic organism should be present in all cases of the disease and absent from healthy animals, (b) the suspected pathogen should be isolated from a diseased host and grown in a pure culture in vitro, (c) cells from a pure culture of the suspected organism should cause disease in a healthy animal, and (d) the organism should be reisolated from the newly diseased animal and shown to be the same as the original. He used these same techniques to identify the organisms responsible for cholera and tuberculosis. During the next century, Koch’s postulates, as they came to be called, became critical to the understanding of surgi-cal infections.2The first intra-abdominal operation to treat infection via “source control” (i.e., surgical intervention to eliminate the source of infection) was appendectomy. This operation was pioneered by Charles McBurney at the New York College of Physicians and Surgeons, among others.3 McBurney’s classic report on early operative intervention for appendicitis was pre-sented before the New York Surgical Society in 1889. Appen-dectomy for the treatment of appendicitis, previously an often fatal disease, was popularized after the 1902 coronation of King Edward VII of England was delayed due to his falling ill with appendicitis. Edward insisted on carrying out his sched-ule, despite worsening abdominal pain. Sir Frederick Treves, a prominent London surgeon, was among the consultants in atten-dance upon Edward. As the prince’s condition deteriorated, and as he continued to insist that he would go to Westminster Abbey to be crowned, Treves told him, “Then Sire, you will go as a corpse.” Edward relented, Treves drained a large periappendi-ceal abscess, and the king lived.4During the 20th century the development of effective anti-microbials added a new dimension to modern surgical practice. Sir Alexander Fleming, after serving in the British Army Medical Corps during World War I, continued his work on the natural antibacterial action of the blood and antiseptics. In 1928, while studying influenza virus, he noted a zone of inhibition around a mold colony (Penicillium notatum) that serendipitously grew on a plate of Staphylococcus, and he named the active substance penicillin. Penicillin, along with the sulfonamide antibiotics, were among the first of hundreds of potent antimicrobials that became a critical component of the armamentarium to prevent and treat aggressive, lethal surgical infections.5Concurrent with the development of antimicrobial agents were advances in the field of clinical microbiology. Many new microbes were identified, including numerous anaerobes. The autochthonous microflora of the skin, gastrointestinal tract, and other parts of the body that the surgeon encountered in the pro-cess of an operation were characterized in great detail. However, it remained unclear whether these organisms were commensals or pathogens. Subsequently, the initial clinical observations of surgeons such as Frank Meleney, William Altemeier, and others provided the key when they observed that aerobic and anaerobic host flora could synergize to cause serious soft tissue and severe intra-abdominal infection.6,7 Thus, the concepts that resident Key Points1 Sepsis is a life-threatening syndrome reflecting both an infection and the systemic host response to it. It has a broad variety of presentations and manifestations that hold in com-mon some form of organ dysfunction. Outcomes in patients with sepsis are improved with an organized approach to therapy that addresses rapid resuscitation, antibiotics, and source control.2 Source control is a key concept in the treatment of most surgically relevant infections. Infected or necrotic material must be drained or removed as part of the treatment plan in this setting. Delays in adequate source control are associated with worsened outcomes.3 Principles relevant to appropriate antibiotic prophylaxis for surgery: (a) select an agent with activity against organisms commonly found at the site of surgery, (b) administer the ini-tial dose of the antibiotic within 30 minutes prior to incision, (c) redose the antibiotic during long operations based upon the half-life of the agent to ensure adequate tissue levels, and (d) limit the antibiotic regimen to no more than 24 hours after surgery for routine prophylaxis.4 When using antimicrobial agents for therapy of serious infection, several principles should be followed: (a) identify likely sources of infection, (b) select an agent (or agents) that will have efficacy against likely organisms for these sources, (c) begin therapy rapidly with broad coverage, as inadequate or delayed antibiotic therapy results in increased mortality, (d) when possible, obtain cultures early and use results to refine therapy, (e) if no infection is identified after 3 days, strongly consider discontinuation of antibiotics, based upon the patient’s clinical course, and (f) discontinue antibiotics after an appropriate course of therapy.5 The incidence of surgical site infections can be reduced by appropriate patient preparation, timely perioperative antibi-otic administration, maintenance of perioperative normo-thermia and normoglycemia, and appropriate wound management.6 The keys to good outcomes in patients with necrotizing soft tissue infection are early recognition and appropriate debridement of infected tissue with repeated debridement until no further signs of infection are present.7 Transmission of HIV and other infections spread by blood and body fluids from patient to healthcare worker can be minimized by practicing universal precautions, which include routine use of barriers when anticipating contact with blood or body fluids, washing of hands and other skin surfaces immediately after contact with blood or body fluids, and careful handling and disposal of sharp instruments dur-ing and after use.Brunicardi_Ch06_p0157-p0182.indd 15801/03/19 4:46 PM 159SURGICAL INFECTIONSCHAPTER 6microbes were nonpathogenic until they entered a sterile body cavity at the time of surgery, and that many, if not most, surgical infections were polymicrobial in nature, became critical ideas.8,9 These tenets became firmly established after microbiology lab-oratories demonstrated the invariable presence of aerobes and anaerobes in peritoneal cultures obtained at the time of surgery for intra-abdominal infection due to perforated viscus or gangre-nous appendicitis. Clinical trials provided ample evidence that optimal therapy for these infections required effective source control and the administration of antimicrobial agents directed against both types of pathogens.William Osler made an observation in 1904 in his treatise The Evolution of Modern Medicine that was to have profound implications for the future of treatment of infection: “Except on few occasions, the patient appears to die from the body’s response to infection rather than from it.”10 The discovery of cytokines began to allow insight into the human organism’s response to infection, and led to an explosion in our understand-ing of the host inflammatory response. Expanding knowledge of the multiple pathways activated during the response to invasion by infectious organisms has permitted the design of new thera-pies targeted at modifying the inflammatory response to infec-tion, which seems to cause much of the organ dysfunction and failure. Preventing and treating this process of multiple organ failure during infection is one of the major challenges of modern critical care and surgical infectious disease.PATHOGENESIS OF INFECTIONHost DefensesThe mammalian host possesses several layers of endogenous defense mechanisms that serve to prevent microbial invasion, limit proliferation of microbes within the host, and contain or eradicate invading microbes. These defenses are integrated and redundant so that the various components function as a com-plex, highly regulated system that is extremely effective in cop-ing with microbial invaders. They include site-specific defenses that function at the tissue level, as well as components that freely circulate throughout the body in both blood and lymph. Systemic host defenses invariably are recruited to a site of infec-tion, a process that begins immediately upon introduction of microbes into a sterile area of the body. Perturbation of one or more components of these defenses (e.g., via immunosuppres-sants, foreign body, chronic illness, or burns) may have substan-tial negative impact on resistance to infection.Entry of microbes into the mammalian host is precluded by a number of barriers that possess either an epithelial (integu-ment) or mucosal (respiratory, gut, and urogenital) surface. Barrier function, however, is not solely limited to physical characteristics. Host barrier cells may secrete substances that limit microbial proliferation or prevent invasion. Also, resident or commensal microbes adherent to the physical surface and to each other may preclude invasion, particularly of virulent organ-isms; this is termed colonization resistance.11The most extensive physical barrier is the integument or skin. In addition to the physical barrier posed by the epithelial surface, the skin harbors its own resident microflora that may block the attachment and invasion of noncommensal microbes. Microbes also are held in check by chemicals secreted by seba-ceous glands and by the constant shedding of epithelial cells. The endogenous microflora of the integument primarily com-prises gram-positive aerobic microbes belonging to the genera Staphylococcus and Streptococcus, as well as Corynebacterium and Propionibacterium species. These organisms plus Entero-coccus faecalis and faecium, Escherichia coli and other Entero-bacteriaceae, and yeast such as Candida albicans can be isolated from the infraumbilical regions of the body. Diseases of the skin (e.g., eczema and dermatitis) are associated with overgrowth of skin commensal organisms, and barrier breaches invariably lead to the introduction of these microbes.The respiratory tract possesses several host defense mech-anisms that facilitate the maintenance of sterility in the distal bronchi and alveoli. In the upper respiratory tract, respiratory mucus traps larger particles, including microbes. This mucus is then passed into the upper airways and oropharynx by cili-ated epithelial cells, where the mucus is cleared via coughing. Smaller particles arriving in the lower respiratory tract are cleared via phagocytosis by pulmonary alveolar macrophages. Any process that diminishes these host defenses can lead to development of bronchitis or pneumonia.The urogenital, biliary, pancreatic ductal, and distal respi-ratory tracts do not possess resident microflora in healthy indi-viduals, although microbes may be present if these barriers are affected by disease (e.g., malignancy, inflammation, calculi, or foreign body), or if microorganisms are introduced from an external source (e.g., urinary catheter or pulmonary aspiration). In contrast, significant numbers of microbes are encountered in many portions of the gastrointestinal tract, with vast numbers being found within the oropharynx and distal colon or rectum, although the specific organisms differ.One would suppose that the entire gastrointestinal tract would be populated via those microbes found in the oropharynx, but this is not the case.11 This is because after ingestion these organisms routinely are killed in the highly acidic, low-motility environment of the stomach during the initial phases of diges-tion. Thus, only small numbers of microbes populate the gas-tric mucosa (∼102 to 103 colony-forming units [CFU]/mL). This population expands in the presence of drugs or disease states that diminish gastric acidity. Microbes that are not destroyed within the stomach enter the small intestine, in which a certain amount of microbial proliferation takes place, such that approxi-mately 105 to 108 CFU/mL are present in the terminal ileum.The relatively low-oxygen, static environment of the colon is accompanied by the exponential growth of microbes that com-prise the most extensive host endogenous microflora. Anaerobic microbes outnumber aerobic species approximately 100:1 in the distal colon, and approximately 1011 to 1012 CFU/g are pres-ent in feces. Large numbers of facultative and strict anaerobes (Bacteroides fragilis, distasonis, and thetaiotaomicron, Bifido-bacterium, Clostridium, Eubacterium, Fusobacterium, Lactoba-cillus, and Peptostreptococcus species) as well as several orders of magnitude fewer aerobic microbes (E coli and other Entero-bacteriaceae, E faecalis and faecium, C albicans and other Candida spp.) are present. Intriguingly, although colonization resistance on the part of this extensive, well-characterized host microflora effectively prevents invasion of enteric pathogens such as Salmonella, Shigella, Vibrio, and other enteropathogenic bacterial species, these same organisms provide the initial inoc-ulum for infection should perforation of the gastrointestinal tract occur. It is of great interest that only some of these microbial species predominate in established intra-abdominal infections.Once microbes enter a sterile body compartment (e.g., the pleural or peritoneal cavity) or tissue, additional host defenses act to limit and/or eliminate these pathogens. Initially, several Brunicardi_Ch06_p0157-p0182.indd 15901/03/19 4:46 PM 160BASIC CONSIDERATIONSPART Iprimitive and relatively nonspecific host defenses act to con-tain the nidus of infection, which may include microbes as well as debris, devitalized tissue, and foreign bodies, depending on the nature of the injury. These defenses include the physi-cal barrier of the tissue itself, as well as the capacity of pro-teins such as lactoferrin and transferrin to sequester the critical microbial growth factor iron, thereby limiting microbial growth. In addition, fibrinogen within the inflammatory fluid has the ability to trap large numbers of microbes during the process in which it polymerizes into fibrin. Within the peritoneal cavity, unique host defenses exist, including a diaphragmatic pump-ing mechanism whereby particles—including microbes—within peritoneal fluid are expunged from the abdominal cavity via specialized structures (stomata) on the undersurface of the dia-phragm that lead to thoracic lymphatic channels. Concurrently, containment by the omentum and intestinal ileus serve to wall off infections. However, the latter processes and fibrin trapping have a high likelihood of contributing to the formation of an intra-abdominal abscess.Microbes also immediately encounter a series of host defense mechanisms that reside within the vast majority of tissues of the body. These include resident macrophages and low levels of complement (C) proteins and immunoglobulins (e.g., antibodies).12 The response in macrophages is initiated by genome-encoded pattern recognition receptors that respond to invading microbes. With exposure to a foreign organism, these receptors recognize microbial pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are a well-defined example of a PAMP that plays an important role in pathogen signaling.13 Resident macrophages secrete a wide array of sub-stances in response to the aforementioned processes, some of which appear to regulate the cellular components of the host defense response. This results in recruitment and proliferation of inflammatory cells. Macrophage cytokine synthesis is upreg-ulated. Secretion of tumor necrosis factor-alpha (TNF-α), of interleukins (IL)-1β, 6, and 8; and of gamma interferon (IFN-γ) occurs within the tissue milieu, and depending on the magnitude of the host defense response, the systemic circulation.14 Concur-rently, a counterregulatory response is initiated consisting of binding protein (TNF-BP), cytokine receptor antagonists (e.g., IL-1ra), and anti-inflammatory cytokines (IL-4 and IL-10).The interaction of microbes with these first-line host defenses leads to microbial opsonization (C1q, C3bi, and IgFc), phagocytosis, and both extracellular (C5b6-9 membrane attack complex) and intracellular microbial destruction (via cellular ingestion into phagocytic vacuoles). Concurrently, the classical and alternate complement pathways are activated both via direct contact with and via IgM and IgG binding to microbes, leading to the release of a number of different biologically active com-plement protein fragments (C3a, C4a, C5a), acting to markedly enhance vascular permeability. Bacterial cell wall components and a variety of enzymes expelled from leukocyte phagocytic vacuoles during microbial phagocytosis and killing act in this capacity as well.Simultaneously, the release of substances to which poly-morphonuclear leukocytes (PMNs) in the bloodstream are attracted takes place. These consist of C5a, microbial cell wall peptides containing N-formyl-methionine, and macrophage secretion of cytokines such as IL-8. This process of host defense recruitment leads to further influx of inflammatory fluid into the area of incipient infection and is accompanied by diapedesis of large numbers of PMNs, a process that begins within several minutes and may peak within hours or days. The magnitude of the response and eventual outcome is generally related to several factors: (a) the initial number of microbes, (b) the rate of microbial proliferation in relation to containment and killing by host defenses, (c) microbial virulence, and (d) the potency of host defenses. In regard to the latter, drugs or disease states that diminish any or multiple components of host defenses are asso-ciated with higher rates and potentially more grave infections.DefinitionsSeveral possible outcomes can occur subsequent to microbial invasion and the interaction of microbes with resident and recruited host defenses: (a) eradication; (b) containment, often leading to the presence of purulence, the hallmark of chronic infections (e.g., a furuncle in the skin and soft tissue or abscess within the parenchyma of an organ or potential space); (c) locoregional infection (cellulitis, lymphangitis, and aggressive soft tissue infection) with or without distant spread of infec-tion (metastatic abscess); or (d) systemic infection (bactere-mia or fungemia). Obviously, the latter represents the failure of resident and recruited host defenses at the local level, and is associated with significant morbidity and mortality. Disease progression commonly occurs such that serious locoregional infection is associated with concurrent systemic infection. A chronic abscess also may intermittently drain and/or be associ-ated with bacteremia.Infection is defined by the presence of microorganisms in host tissue or the bloodstream. The classic findings of rubor, calor, and dolor in areas such as the skin or subcutaneous tis-sue are common at the site of infection. Most infections in nor-mal individuals with intact host defenses are associated with these local manifestations, plus systemic manifestations such as elevated temperature, elevated white blood cell (WBC) count, tachycardia, or tachypnea. The systemic manifestations noted previously comprise what has been termed the systemic inflammatory response syndrome (SIRS). SIRS reflects a pro-inflammatory state in response to a variety of disease processes, including infection, pancreatitis, polytrauma, malignancy, and burns. There are a variety of systemic manifestations of infec-tion, with the classic factors of fever, tachycardia, and tachypnea broadened to include a variety of other variables (Table 6-1).15The definition of sepsis is evolving. Earlier models described sepsis as SIRS caused by infection. This was based upon the idea that sepsis is mediated by the production of a cascade of proinflammatory mediators produced in response to exposure to microbial products. These products include lipo-polysaccharide (endotoxin, LPS) derived from gram-negative organisms; peptidoglycans and teichoic acids from grampositive organisms; many different microbial cell wall compo-nents, such as mannan from yeast and fungi; and many others.There are several issues, however, with basing a sepsis diagnosis on the presence of SIRS. One problem is that it is insufficiently specific. Patients can exhibit SIRS criteria without the presence of the more whole-body dysregulation consistent with sepsis, and conversely can suffer from sepsis without meet-ing SIRS criteria. Patients with SIRS do not necessarily prog-ress to sepsis and do not necessarily have worsened outcomes because of the SIRS diagnosis; in other words, SIRS is not inher-ently life-threatening. Another issue is that the SIRS criteria can vary and are inconsistently applied. Numerous definitions exist, specifying differing physiologic and laboratory criteria for the Brunicardi_Ch06_p0157-p0182.indd 16001/03/19 4:46 PM 161SURGICAL INFECTIONSCHAPTER 6diagnosis. This creates difficulty in clinical, epidemiological, and research settings. Further, sepsis is not a purely inflamma-tory phenomenon, as both proand anti-inflammatory cascades have been shown to be activated in septic patients. Basing a diagnosis upon inflammatory markers alone disregards nonin-flammatory organ dysfunction, which may not manifest as SIRS but can contribute to mortality. A final concern is that defining sepsis using SIRS criteria implies that SIRS, sepsis, severe sep-sis, and septic shock exist upon a continuum, and while SIRS and sepsis have common features, the former does not necessar-ily lead to the latter. This being said, SIRS criteria have utility in that they point toward an organism experiencing physiological stress. The presence of SIRS warrants further investigation by the clinician.16An international consensus panel proposed new defini-tions of sepsis and septic shock in 2016. What is known as the Sepsis-3 model defines sepsis as life-threatening organ dysfunc-tion caused by a dysregulated host response to infection. Organ dysfunction is quantified by an increase of ≥2 points on the Sequential Organ Failure Assessment (SOFA). The SOFA score looks at PaO2/FiO2 ratio, bilirubin, platelet count, mean arterial pressure (MAP), Glasgow Coma Scale (GCS) score, creatinine level, and urine output (Table 6-2). An increase in SOFA score of 2 or more is correlated with a 10% in-hospital mortality risk, which is suggestive of the life-threatening nature of sepsis. An abbreviated version of the scoring system, the quick SOFA (qSOFA) is recommended as a screening and mon-itoring tool for patients with suspected sepsis. The qSOFA sug-gests potentially life-threatening sepsis when at least two of the following parameters are met: altered mental status, systolic blood pressure of 100 mmHg or less, and respiratory rate greater than 22 breaths/minute. The qSOFA can readily identify patients at risk of poor outcome from sepsis without reliance upon labo-ratory or imaging data.16Under the older nomenclature, severe sepsis was char-acterized as sepsis combined with the presence of new-onset organ failure. The Sepsis-3 definitions consider the term “severe sepsis” to be redundant, as by this definition all sepsis involves organ dysfunction. Under the Sepsis-3 guidelines, septic shock is a subset of sepsis in which circulatory and cellular metabolic derangements are profound enough to significantly increase the risk of death. Sepsis is the most common cause of death in non-coronary critical care units and the 11th most common cause of death overall in the United States, with a mortality rate of 10.3 cases per 100,000 population in 2010.17 Septic shock is the most severe manifestation of infection, with an attendant mortality rate in excess of 40%. It can be identified by persistent arterial hypo-tension requiring vasopressors to maintain mean arterial pressure (MAP) ≥65, and by serum lactate >2 mmol/L (18 mg/dL) despite adequate volume resuscitation.16,18,19MICROBIOLOGY OF INFECTIOUS AGENTSA partial list of common pathogens that cause infections in sur-gical patients is provided in Table 6-3.BacteriaBacteria are responsible for the majority of surgical infections. Specific species are identified using Gram stain and growth characteristics on specific media. The Gram stain is an important evaluation that allows rapid classification of bacteria by color. This color is related to the staining characteristics of the bacterial cell wall: gram-positive bacteria stain blue and gram-negative bacteria stain red. Bacteria are classified based upon a num-ber of additional characteristics, including morphology (cocci and bacilli), the pattern of division (single organisms, groups of organisms in pairs [diplococci], clusters [staphylococci], and chains [streptococci]), and the presence and location of spores.Gram-positive bacteria that frequently cause infections in surgical patients include aerobic skin commensals (Staphylo-coccus aureus and epidermidis and Streptococcus pyogenes) and enteric organisms such as E faecalis and faecium. Aerobic skin commensals cause a large percentage of surgical site infec-tions (SSIs), either alone or in conjunction with other patho-gens; enterococci can cause nosocomial infections (urinary tract infections [UTIs] and bacteremia) in immunocompromised or chronically ill patients, but are of relatively low virulence in healthy individuals.There are many pathogenic gram-negative bacterial spe-cies that are capable of causing infection in surgical patients. Most gram-negative organisms of interest to the surgeon are bacilli belonging to the family Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Enterobacter, Citrobacter, and Acinetobacter species. Other gram-negative bacilli of note include Pseudomonas, including P aeruginosa and fluorescens, and Stenotrophomonas species.1Table 6-1Criteria for systemic inflammatory response syndrome (SIRS)General variables Fever (core temp >38.3°C) Hypothermia (core temp <36°C) Heart rate >90 bpm Tachypnea Altered mental status Significant edema or positive fluid balance (>20 mL/kg  over 24 hours) Hyperglycemia in the absence of diabetesInflammatory variables Leukocytosis (WBC >12,000) Leukopenia (WBC <4,000) Bandemia (>10% band forms) Plasma C-reactive protein >2 s.d. above normal value Plasma procalcitonin >2 s.d. above normal valueHemodynamic variables Arterial hypotension (SBP <90 mmHg, MAP <70, or SBP  decrease >40 mmHg)Organ dysfunction variables Arterial hypoxemia Acute oliguria Creatinine increase Coagulation abnormalities Ileus Thrombocytopenia HyperbilirubinemiaTissue perfusion variables Hyperlactatemia Decreased capillary fillingbpm = beats per minute; MAP = mean arterial pressure; SBP = systolic blood pressure; s.d. = standard deviations; SvO2 = venous oxygen saturation; WBC = white blood cell count.Brunicardi_Ch06_p0157-p0182.indd 16101/03/19 4:46 PM 162BASIC CONSIDERATIONSPART IAnaerobic organisms divide poorly or are unable to grow in air, as most do not possess the enzyme catalase, which allows for metabolism of reactive oxygen species. Anaerobes are the predominant indigenous flora in many areas of the human body, with the particular species being dependent on the site. For example, Propionibacterium acnes and other species are a major component of the skin microflora and cause the infectious mani-festation of acne. As noted previously, large numbers of anaer-obes contribute to the microflora of the oropharynx and colon.Infection due to Mycobacterium tuberculosis was once one of the most common causes of death in Europe, causing one in four deaths in the 17th and 18th centuries. In the 19th and 20th centuries, thoracic surgical intervention was often required for severe pulmonary disease, now an increasingly uncommon occur-rence in developed countries. This organism and other related organisms (M avium-intracellulare and M leprae) are known as acid-fast bacilli. Other acid-fast bacilli include Nocardia. These organisms typically are slow growing, sometimes necessitating observation in culture for weeks to months prior to final identi-fication, although deoxyribonucleic acid (DNA)-based analysis is increasingly available to provide a means for preliminary, rapid detection.FungiFungi are typically identified by use of special stains (e.g., potas-sium hydroxide, India ink, methenamine silver, or Giemsa). Initial identification is assisted by observation of the form of branching and septation in stained specimens or in culture. Final identification is based on growth characteristics in special media, similar to bacteria, as well as on the capacity for growth at a different temperature (25°C vs. 37°C). Fungi of relevance to surgeons include those that cause nosocomial infections in surgical patients as part of polymicrobial infections or fungemia (e.g., C albicans and related species), rare causes of aggressive soft tissue infections (e.g., Mucor, Rhizopus, and Absidia spp.), and opportunistic pathogens that cause infection in the immuno-compromised host (e.g., Aspergillus fumigatus, niger, terreus, and other spp., Blastomyces dermatitidis, Coccidioides immitis, and Cryptococcus neoformans). Agents currently available for antifungal therapy are described in Table 6-4.VirusesDue to their small size and necessity for growth within cells, viruses are difficult to culture, requiring a longer time than is typically optimal for clinical decision making. Previously, viral infection was identified by indirect means (i.e., the host anti-body response); more modern techniques identify the presence of viral DNA or ribonucleic acid (RNA) using methods such as polymerase chain reaction. Similar to many fungal infections, most clinically relevant viral infections in surgical patients occur in the immunocompromised host, particularly those receiv-ing immunosuppression to prevent rejection of a solid organ allograft. Relevant viruses include adenoviruses, cytomegalo-virus, Epstein-Barr virus, herpes simplex virus, and varicella-zoster virus. Surgeons must be aware of the manifestations of hepatitis B and C viruses, as well as human immunodeficiency Table 6-2Sequential Organ Failure Assessment scoreSYSTEMSCORE01234RespiratoryPaO2/FiO2, mmHg (kPa)≥400 (53.3)<400 (53.3)<300 (40)<200 (26.7) with respiratory support<100 (13.3) with respiratory supportCoagulationPlatelets, × 103/μL≥150<150<100<50<20HepaticBilirubin, mg/dL (μmol/L)<1.2 (20)1.2–1.9 (20–32)2–5.9 (33–101)6–11.9 (102–204)>12 (204)CardiovascularMAP ≥70 mmHgMAP <70 mmHgDopamine <5 or dobutamineDopamine 5.1–15 or epinephrine ≤0.1 or norepinephrine ≤0.1Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1CNSGCS score1513–1410–126–9<6RenalCreatinine, mg/dL (μmol/L)<1.2 (110)1.2–1.9 (110–170)2–3.4 (171–299)3.5–4.9 (300–440)>5 (440)Urine output, mL/24 hours<500<200MAP = mean arterial pressure; PaO2 = partial pressure of oxygen; FiO2 = fraction of inspired oxygen; CNS = central nervous system; GCS = Glasgow Coma ScaleCatecholamine doses in μg/kg/minuteReproduced with permission from Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine, Intensive Care Med. 1996 Jul;22(7):707-710.Brunicardi_Ch06_p0157-p0182.indd 16201/03/19 4:46 PM 163SURGICAL INFECTIONSCHAPTER 6virus infections, including their capacity to be transmitted to healthcare workers (see “General Principles”). Prophylactic and therapeutic use of antiviral agents is discussed elsewhere in this textbook.PREVENTION AND TREATMENT OF SURGICAL INFECTIONSGeneral PrinciplesManeuvers to diminish the presence of exogenous (surgeon and operating room environment) and endogenous (patient) microbes are termed prophylaxis and consist of a variety of mechanical and chemical modalities. The Centers for Disease Control and Prevention (CDC) publishes updated, evidence-based guidelines on best practices for prevention of surgical site infections. Important principles in prophylaxis can be grouped into factors pertaining to skin preparation, antimicrobial therapy, and patient physiological management.Patient skin preparation should begin the night before a planned surgical procedure with a full body bath or shower using soap or an antiseptic agent. Hair removal from an opera-tive site should be performed in the operating room with clippers rather than with a razor, to avoid creating nicks in the skin that could foster bacterial growth. Prior to incision, the skin should be cleansed with an alcohol-based antiseptic agent. There is no clear evidence that use of antimicrobial-containing fluids for either irrigation or soaking prosthetic materials is beneficial in preventing infections. Preoperative antimicrobial therapy should be administered when appropriate, based on clinical guidelines, and occur within a time frame that allows bactericidal con-centration of the agent in tissues before the incision is made. Physiological management of the intraoperative patient includes maintenance of euglycemia (serum glucose <200 mg/dL) and normothermia, and optimization of tissue oxygenation.20Source ControlThe primary precept of surgical infectious disease therapy con-sists of drainage of all purulent material, debridement of all infected, devitalized tissue and debris, and/or removal of foreign bodies at the site of infection, plus remediation of the underlying cause of infection.21 This is termed source control. A dis-crete, walled-off purulent fluid collection (i.e., an abscess) 2Table 6-3Common pathogens in surgical patientsGram-positive aerobic cocci Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Streptococcus pneumoniae Enterococcus faecium, E faecalisGram-negative aerobic bacilli Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Proteus mirabilis Enterobacter cloacae, E aerogenes Serratia marcescens Acinetobacter calcoaceticus Citrobacter freundii Pseudomonas aeruginosa Stenotrophomonas maltophiliaAnaerobes Gram-positive  Clostridium difficile  Clostridium perfringens, C tetani, C septicum  Peptostreptococcus spp. Gram-negative  Bacteroides fragilis  Fusobacterium spp.Other bacteria Mycobacterium avium-intracellulare Mycobacterium tuberculosis Nocardia asteroids Legionella pneumophila Listeria monocytogenesFungi Aspergillus fumigatus, A niger, A terreus, A flavus Blastomyces dermatitidis Candida albicans Candida glabrata, C paropsilosis, C krusei Coccidiodes immitis Cryptococcus neoformans Histoplasma capsulatum Mucor/RhizopusViruses Cytomegalovirus Epstein-Barr virus Hepatitis A, B, C viruses Herpes simplex virus Human immunodeficiency virus Varicella zoster virusTable 6-4Antifungal agents and their characteristicsANTIFUNGALADVANTAGESDISADVANTAGESAmphotericin BBroad-spectrum, inexpensiveRenal toxicity, premeds, IV onlyLiposomal Amphotericin BBroad-spectrumExpensive, IV only, renal toxicityAzolesFluconazoleIV and PO availabilityNarrow-spectrum, drug interactionsItraconazoleIV and PO availabilityNarrow spectrum, no CSF penetrationDrug interactions, decreased cardiac contractilityPosaconazoleBroad-spectrum, zygomycete activityPO onlyVoriconazoleIV and PO availability, broad-spectrumIV diluent accumulates in renal failure, Visual disturbancesEchinocandinsAnidulofungin, Caspofungin, micafunginBroad-spectrumIV only, poor CNS penetrationBrunicardi_Ch06_p0157-p0182.indd 16301/03/19 4:46 PM 164BASIC CONSIDERATIONSPART Irequires drainage, either surgically or via percutaneous drain insertion. An ongoing source of contamination (e.g., bowel per-foration) or the presence of an aggressive, rapidly spreading infection (e.g., necrotizing soft tissue infection) invariably requires expedient, aggressive operative intervention, both to remove contaminated material and infected tissue (e.g., radical debridement or amputation) and to remove the initial cause of infection (e.g., bowel resection). Delay in operative interven-tion, whether due to misdiagnosis or the need for additional diagnostic studies, is associated with increased morbidity and occasional mortality. Other treatment modalities such as antimi-crobial agents, albeit critical, are of secondary importance to effective surgery with regard to treatment of surgical infections. Rarely, if ever, can an aggressive surgical infection be cured only by the administration of antibiotics, and never in the face of an ongoing source of contamination.22Appropriate Use of Antimicrobial AgentsA classification of antimicrobial agents, mechanisms of action, and spectrums of activity is shown in Table 6-5. As discussed previously, prophylaxis consists of the administration of an anti-microbial agent or agents prior to initiation of certain specific types of surgical procedures in order to reduce the number of microbes that enter the tissue or body cavity. Agents are selected according to their activity against microbes likely to be present at the surgical site, based on knowledge of host microflora. For example, patients undergoing elective colorectal surgery should receive antimicrobial prophylaxis directed against skin flora, gram-negative aerobes, and anaerobic bacteria. There are a wide variety of agents that meet these criteria with recently published guidelines.23By definition, prophylaxis is limited to the time prior to and during the operative procedure; in the vast majority of cases only a single dose of antibiotic is required, and only for certain types of procedures (see “Surgical Site Infections”). However, patients who undergo complex, prolonged procedures in which the duration of the operation exceeds the serum drug half-life should receive an additional dose or doses of the antimicrobial agent.23 There is no evidence that administration of postopera-tive doses of an antimicrobial agent provides additional benefit, and this practice should be discouraged, as it is costly and is associated with increased rates of microbial drug resistance. Guidelines for prophylaxis are provided in Table 6-6.Empiric therapy is the use of antimicrobial agents when the risk of a surgical infection is high, based on the underlying disease process (e.g., ruptured appendicitis), or when signifi-cant contamination during surgery has occurred (e.g., inad-equate bowel preparation or considerable spillage of colon contents). Obviously, prophylaxis merges into empiric therapy in situations in which the risk of infection increases markedly because of intraoperative findings. Empiric therapy also is often employed in critically ill patients in whom a potential site of infection has been identified and severe sepsis or septic shock occurs. Empiric therapy should be limited to a short course of treatment (3 to 5 days) and should be curtailed as soon as pos-sible based on microbiologic data (i.e., absence of positive cul-tures) coupled with improvements in the clinical course of the patient.Empiric therapy can merge into therapy of established infection in some patients. However, among surgical patients, the manner in which therapy is employed, particularly in rela-tion to the use of microbiologic data (culture and antibiotic sensitivity patterns), differs depending on whether the infection is monomicrobial or polymicrobial. Monomicrobial infections frequently are nosocomial infections occurring in postoperative patients, such as UTIs, pneumonia, or bacteremia. Evidence of systemic inflammatory response syndrome (fever, tachycardia, tachypnea, or elevated leukocyte count) in such individuals, coupled with evidence of local infection (e.g., an infiltrate on chest roentgenogram plus a positive Gram stain in bronchoal-veolar lavage samples) should lead the surgeon to initiate empiric antibiotic therapy. An appropriate approach to antimi-crobial treatment involves de-escalation therapy, where initial antimicrobial selection is broad, with a narrowing of agents based on patient response and culture results. Initial drug selec-tion must be based on initial evidence (gram-positive vs. gram-negative microbes, yeast), coupled with institutional and unit-specific drug sensitivity patterns. It is important to ensure that antimicrobial coverage chosen is adequate, since delay in appropriate antibiotic treatment has been shown to be associated with significant increases in mortality. A critical component of this approach is appropriate collection of culture specimens to allow for thorough analysis, since within 48 to 72 hours culture and sensitivity reports will allow refinement of the antibiotic regimen to select the most efficacious agent.Although the primary therapeutic modality to treat polymicrobial surgical infections is source control, antimicro-bial agents play an important role. Culture results are of lesser importance in managing these types of infections, as it has been repeatedly demonstrated that only a limited cadre of microbes predominate in the established infection, selected from a large number present at the time of initial contamination. Invariably it is difficult to identify all microbes that comprise the initial polymicrobial inoculum. For this reason, the antibiotic regimen should not be modified solely on the basis of culture informa-tion, as it is less important than the clinical course of the patient. As long as appropriately broad-spectrum coverage for aerobic and anaerobic microbes is provided, a worsening of the patient’s clinical course should direct the surgeon to investigate whether effective source control has been achieved.24 Duration of anti-biotic administration should be decided at the time the drug regimen is prescribed. As mentioned previously, prophylaxis is limited to a single dose administered immediately prior to creating the incision. Empiric therapy should be limited to 3 to 5 days or less and should be curtailed if the presence of a local site or systemic infection is not revealed.25 In fact, prolonged use of empirical antibiotic therapy in culture-negative critically ill patients is associated with increased mortality, highlighting the need to discontinue therapy when there is no proven evidence of infection.26Therapy for monomicrobial infections follows standard guidelines: 3 to 5 days for UTIs, 7 to 8 days for pneumonia, and 7 to 14 days for bacteremia. Longer courses of therapy in this setting do not result in improved care and are associated with increased risk of superinfection by resistant organisms.27-29 There is some evidence that measuring and monitoring serum procalcitonin trends in the setting of infection allows earlier cessation of antibiotics without decrement in the rate of clini-cal cure.30 Antibiotic therapy for osteomyelitis, endocarditis, or prosthetic infections in which it is hazardous to remove the device consists of prolonged courses of treatment for 6 to 12 weeks. The specific agents are selected based on analysis of the degree to which the organism is killed in vitro using the minimum inhibitory concentration (MIC) of a standard pure 34Brunicardi_Ch06_p0157-p0182.indd 16401/03/19 4:46 PM 165SURGICAL INFECTIONSCHAPTER 6Table 6-5Antimicrobial agentsANTIBIOTIC CLASS, GENERIC NAMETRADE NAMEMECHANISM OF ACTIONORGANISMS PyogenesMSSAMRSAS epidermidisEnterococcusVREE coliP aeruginosaANAEROBESPenicillinsCell wall synthesis inhibitors (bind penicillin-binding protein)Penicillin G1000+/–0001NafcillinNallpen, Unipen110+/–00000PiperacillinPipracil1000+/–011+/–Penicillin/a-lactamase inhibitor combinationsCell wall synthesis inhibitors/β-lactamase inhibitorsAmpicillin/sulbactamUnasyn110+/–1+/–101Ticarcillin/clavulanateTimentin110+/–+/–0111Piperacillin/tazobactamZosyn1101+/–0111First-generation cephalosporinsCell wall synthesis inhibitorsCefazolin, cephalexinAncef, Keflex110+/–00100Second-generation cephalosporinsCell wall synthesis inhibitorsCefoxitinMefoxin110+/–00101CefotetanCefotan110+/–00101CefuroximeCeftin110+/–00100Thirdand fourth-generation cephalosporinsCell wall synthesis inhibitorsCeftriaxoneRocephin110+/–00100CeftazidimeFortaz1+/–0+/–00110CefepimeMaxipime110+/–00110CefotaximeCefotaxime110+/–001+/–0CeftarolineTeflaro111100100(Continued)Brunicardi_Ch06_p0157-p0182.indd 16501/03/19 4:46 PM 166BASIC CONSIDERATIONSPART ICarbapenemsCell wall synthesis inhibitorsImipenem-cilastatinPrimaxin1101+/–0111MeropenemMerrem110100111ErtapenemInvanz1101001+/–1AztreonamAzactam000000110AminoglycosidesAlteration of cell membrane, binding and inhibition of 30S ribosomal subunitGentamicin010+/–10110Tobramycin, amikacin010+/–00110FluoroquinolonesInhibit topo-isomerase II and IV (DNA synthesis inhibition)CiprofloxacinCipro+/–10100110LevofloxacinLevaquin1101001+/–0GlycopeptidesCell wall synthesis inhibition (peptidoglycan synthesis inhibition)VancomycinVancocin111110000Quinupristin-dalfopristinSynercidInhibits 2 sites on 50S ribosome (protein synthesis inhibition)11111100+/–Table 6-5Antimicrobial agentsANTIBIOTIC CLASS, GENERIC NAMETRADE NAMEMECHANISM OF ACTIONORGANISMS PyogenesMSSAMRSAS epidermidisEnterococcusVREE coliP aeruginosaANAEROBES(Continued)Brunicardi_Ch06_p0157-p0182.indd 16601/03/19 4:46 PM 167SURGICAL INFECTIONSCHAPTER 6LinezolidZyvoxInhibits 50S ribosomal activity11111100+/–DaptomycinCubicinBinds bacterial membrane, results in depolarization, lysis111111000RifampinInhibits DNA-dependent RNA polymerase1111+/–0000ClindamycinCleocinInhibits 50S ribosomal activity110000001MetronidazoleFlagylProduction of toxic intermediates (free radicals)000000001MacrolidesInhibit 50S ribosomal activity (protein synthesis inhibition)Erythromycin1+/–0+/–00000AzithromycinZithromax110000000ClarithromycinBiaxin110000000Trimethoprim-sulfamethoxazoleBactrim, SeptraInhibits sequential steps of folate metabolism+/–10/–00100TetracyclinesBind 30S ribosomal unit (protein synthesis inhibition)MinocyclineMinocin11000000+/–DoxycyclineVibromycin1+/–000010+/–=TigacyclineTygacil111111101E coli = Escherichia coli; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive S aureus; P aeruginosa = Pseudomonas aeruginosa; S epidermidis = Staphylococcus epidermidis; S pyogenes = Streptococcus pyogenes; VRE = vancomycin-resistant Enterococcus1 = reliable activity; +/– = variable activity; 0 = no activity.The sensitivities printed here are generalizations. The clinician should confirm sensitivity patterns at the locale where the patient is being treated since these patterns may vary widely depending on location.Brunicardi_Ch06_p0157-p0182.indd 16701/03/19 4:46 PM 168BASIC CONSIDERATIONSPART ITable 6-6Prophylactic use of antibioticsSITEANTIBIOTICALTERNATIVE (E.G., PENICILLIN ALLERGIC)Cardiovascular surgeryCefazolin, cefuroximeVancomycin, clindamycinGastroduodenal areaSmall intestine, nonobstructedCefazolinClindamycin or vancomycin + aminoglycoside or aztreonem or fluoroquinoloneBiliary tract: open procedure, laparoscopic high riskCefazolin, cefoxitin, cefotetan, ceftriaxone, ampicillin-sulbactamClindamycin or vancomycin + aminoglycoside or aztreonem or fluoroquinoloneMetronidazole + aminoglycoside or fluoroquinoloneBiliary tract: laparoscopic low riskNoneNoneAppendectomy, uncomplicatedCefoxitin, cefotetan, cefazolin + metronidazoleClindamycin + aminoglycoside or aztreonem or fluoroquinoloneMetronidazole + aminoglycoside or fluoroquinoloneColorectal surgery, obstructed small intestineCefazolin or ceftriaxone plus metronidazole, ertapenem, cefoxitin, cefotetan, ampicillin-sulbactamClindamycin + aminoglycoside or aztreonem or fluoroquinolone, metronidazole + aminoglycoside or fluoroquinoloneHead and neck; clean contaminatedCefazolin or cefuroxime + metronidazole, ampicillin-sulbactamClindamycinNeurosurgical proceduresCefazolinClindamycin, vancomycinOrthopedic surgeryCefazolin, ceftriaxoneClindamycin, vancomycinBreast, herniaCefazolinClindamycin, vancomycinData from Pieracci FM, Barie PS. Management of severe sepsis of abdominal origin, Scand J Surg. 2007;96(3):184-196.inoculum of 105 CFU/mL of the organism isolated from the site of infection or bloodstream. Sensitivities are reported in rela-tion to the achievable blood level of each antibiotic in a panel of agents. The least toxic, least expensive agent to which the organism is most sensitive should be selected. Serious or recru-descent infection may require therapy with two or more agents, particularly if a multidrug-resistant pathogen is causative, limit-ing therapeutic options to drugs to which the organism is only moderately sensitive. Commonly, an agent may be administered intravenously for 1 to 2 weeks, followed by treatment with an oral drug. However, this should only be undertaken in patients who demonstrate progressive clinical improvement, and the oral agent should be capable of achieving high serum levels as well (e.g., fluoroquinolones).The 2016 Surgical Infection Society guidelines on man-agement of intra-abdominal infection recommend antibiotic duration of no more than 24 hours in patients with traumatic bowel perforation who receive surgical treatment within 12 hours, gastroduodenal perforations operated upon within 24 hours, ischemic nonperforated bowel, and gangrenous acute appen-dicitis or cholecystitis without perforation. More extensive intraperitoneal infection (perforated appendicitis, for example) should have treatment limited to 4 days. Patients with a greater degree of contamination may require longer courses of therapy; as in all facets of clinical practice, the therapeutic plan must be individualized to the patient. In the later phases of postopera-tive antibiotic treatment of serious intra-abdominal infection, the absence of an elevated white blood cell (WBC) count, lack of band forms of PMNs on peripheral smear, and lack of fever (<38°C [100.5°F]) provide close to complete assurance that infection has been eradicated.31 There is also emerging data that suggest following a patient’s procalcitonin level may provide the clinician with useful information regarding whether an infection has resolved and allow more expedient cessation of therapy.32,33 Patients who do not improve with 5 to 7 days of antibiotic therapy should be reevaluated for inadequate source control or a new extra-abdominal source of infection.Allergy to antimicrobial agents must be considered prior to prescribing them. First, it is important to ascertain whether a patient has had any type of allergic reaction in association with administration of a particular antibiotic. However, one should take care to ensure that the purported reaction consists of true allergic symptoms and signs, such as urticaria, bron-chospasm, or other similar manifestations, rather than indiges-tion or nausea. Penicillin allergy is quite common, the reported incidence ranging from 0.7% to 10%. Although avoiding the use of any β-lactam drug is appropriate in patients who mani-fest significant allergic reactions to penicillins, the incidence of cross-reactivity appears low for all related agents, with 1% cross-reactivity for carbapenems, 5% to 7% cross-reactivity for cephalosporins, and extremely small or nonexistent cross-reactivity for monobactams.34Severe allergic manifestations, such as anaphylaxis, to a specific class of agents generally preclude the use of any agents in that class, except under circumstances in which use of a certain drug represents a lifesaving measure. In some centers, patients undergo intradermal testing using a dilute solution of a particular antibiotic to determine whether a severe allergic reac-tion would be elicited by parenteral administration. A pathway, including such intradermal testing, has been effective in reduc-tion of vancomycin use to 16% in surgical patients with reported allergy to penicillin.35 This type of testing rarely is employed because it is simpler to select an alternative class of agent. Should administration of a specific agent to which the patient is Brunicardi_Ch06_p0157-p0182.indd 16801/03/19 4:46 PM 169SURGICAL INFECTIONSCHAPTER 6allergic become necessary, desensitization using progressively higher doses of antibiotic can be undertaken, providing the ini-tial testing does not cause severe allergic manifestations.Misuse of antimicrobial agents is rampant in both the inpa-tient and outpatient settings, and is associated with an enormous financial impact on healthcare costs, adverse reactions due to drug toxicity and allergy, the occurrence of new infections such as Clostridium difficile colitis, and the development of multiagent drug resistance among nosocomial pathogens. Each of these factors has been directly correlated with overall drug administration. It has been estimated that in the United States in excess of $20 billion is spent on antibiotics each year.36 The responsible practitioner limits prophylaxis to the period dur-ing the operative procedure, does not convert prophylaxis into empiric therapy except under well-defined conditions, sets the duration of antibiotic therapy from the outset, curtails antibi-otic administration when clinical and microbiologic evidence does not support the presence of an infection, and limits therapy to a short course in every possible instance. Prolonged treat-ment associated with drains and tubes has not been shown to be beneficial.INFECTIONS OF SIGNIFICANCE IN SURGICAL PATIENTSSurgical Site InfectionsSurgical site infections (SSIs) are infections of the tissues, organs, or spaces exposed by surgeons during performance of an invasive procedure. SSIs are classified into incisional and organ/space infections, and the former are further subclas-sified into superficial (limited to skin and subcutaneous tissue) and deep incisional categories.37,38 The development of SSIs is related to three factors: (a) the degree of microbial contamina-tion of the wound during surgery; (b) the duration of the proce-dure; and (c) host factors such as diabetes, malnutrition, obesity, immune suppression; and a number of other underlying disease states. Table 6-7 lists risk factors for development of SSIs. By definition, an incisional SSI has occurred if a surgical wound drains purulent material or if the surgeon judges it to be infected and opens it.Surgical wounds are classified based on the presumed mag-nitude of the bacterial load at the time of surgery (Table 6-8).39 Clean wounds (class I) include those in which no infection is present; only skin microflora potentially contaminate the wound, and no hollow viscus that contains microbes is entered. Class I D wounds are similar except that a prosthetic device (e.g., mesh or valve) is inserted. Clean/contaminated wounds (class II) include those in which a hollow viscus such as the respiratory, alimentary, or genitourinary tracts with indigenous bacterial flora is opened under controlled circumstances without significant spillage of contents.While elective colorectal cases have classically been included as class II cases, a number of studies in the last decade have documented higher SSI rates (9–25%). One study iden-tified two-thirds of infections presenting after discharge from hospital, highlighting the need for careful follow-up of these patients.40 Infection is also more common in cases involving entry into the rectal space.41 In a recent single-center quality improvement study using a multidisciplinary approach, one group of clinicians has demonstrated the ability to decrease SSI from 9.8% to 4.0%.425Table 6-7Risk factors for development of surgical site infectionsPatient factors Older age Immunosuppression Obesity Diabetes mellitus Chronic inflammatory process Malnutrition Smoking Renal failure Peripheral vascular disease Anemia Radiation Chronic skin disease Carrier state (e.g., chronic Staphylococcus carriage) Recent operationLocal factors Open compared to laparoscopic surgery Poor skin preparation Contamination of instruments Inadequate antibiotic prophylaxis Prolonged procedure Local tissue necrosis Blood transfusion Hypoxia, hypothermiaMicrobial factors Prolonged hospitalization (leading to nosocomial organisms) Toxin secretion Resistance to clearance (e.g., capsule formation)Table 6-8Wound class, representative procedures, and expected infection ratesWOUND CLASSEXAMPLES OF CASESEXPECTED INFECTION RATESClean (class I)Hernia repair, breast biopsy1–2%Clean/contaminated (class II)Cholecystectomy, elective GI surgery (not colon)2.1–9.5%Clean/contaminated (class II)Colorectal surgery4–14%Contaminated (class III)Penetrating abdominal trauma, large tissue injury, enterotomy during bowel obstruction3.4–13.2%Dirty (class IV)Perforated diverticulitis, necrotizing soft tissue infections3.1–12.8%Brunicardi_Ch06_p0157-p0182.indd 16901/03/19 4:46 PM 170BASIC CONSIDERATIONSPART IContaminated wounds (class III) include open acciden-tal wounds encountered early after injury, those with extensive introduction of bacteria into a normally sterile area of the body due to major breaks in sterile technique (e.g., open cardiac massage), gross spillage of viscus contents such as from the intestine, or incision through inflamed, albeit nonpurulent tis-sue. Dirty wounds (class IV) include traumatic wounds in which a significant delay in treatment has occurred and in which necrotic tissue is present, those created in the presence of overt infection as evidenced by the presence of purulent material, and those created to access a perforated viscus accompanied by a high degree of contamination. The microbiology of SSIs is reflective of the initial host microflora such that SSIs fol-lowing creation of a class I wound are invariably caused by skin microbes found on that portion of the body, while SSIs subsequent to a class II wound created for the purpose of elec-tive colon resection may be caused by either skin microbes or colonic microflora, or both.Surgical management of the wound is a critical determi-nant of the propensity to develop an SSI. In healthy individuals, classes I and II wounds may be closed primarily, while skin closure of class III and IV wounds is associated with high rates of incisional SSIs (∼25–50%). The superficial aspects of these latter types of wounds should be packed open and allowed to heal by secondary intention, although selective use of delayed primary closure has been associated with a reduction in inci-sional SSI rates.43 One clear example based on data from clini-cal trials is that class III wounds in healthy patients undergoing appendectomy for perforated or gangrenous appendicitis can be primarily closed as long as antibiotic therapy directed against aerobes and anaerobes is administered. This practice leads to SSI rates of approximately 3% to 4%.44Recent investigations have studied the effect of additional maneuvers in an attempt to further reduce the rate of SSIs. The adverse effects of hyperglycemia on WBC function have been well described.45 A number of studies in patients undergoing several different types of surgery describe increased risk of SSI in patients with hyperglycemia, and the 2017 CDC guidelines for prevention of surgical site infection recommend maintaining blood glucose <200 mg/dL (11.1 mmol/L) in all patients during the perioperative period.46-48The respective effects of body temperature and the level of inhaled oxygen during surgery on SSI rates also have been studied, and both hypothermia and hypoxia during surgery are associated with a higher rate of SSI. There is conflicting evi-dence regarding whether supplying higher levels of inhaled oxy-gen to perioperative patients reduces the rate of SSI. Although an initial study provided evidence that patients who received high levels of inhaled oxygen during colorectal surgery devel-oped fewer SSIs,49 a later meta-analysis suggested that the over-all benefit is small and may not warrant use.50 The 2017 CDC guidelines, however, support administration of increased FiO2 during surgery and after extubation in patients with normal pul-monary function receiving general anesthesia as there has been some evidence of benefit.20,51 Further evaluation via multicenter studies is needed prior to implementation of hyperoxia as stan-dard therapy, but it is clear that intraoperative hypothermia and hypoxia should be prevented.Effective therapy for incisional SSIs consists solely of incision and drainage without the additional use of antibiotics. Antibiotic therapy is reserved for patients in whom evidence of significant cellulitis is present, or who concurrently manifest a systemic inflammatory response syndrome. The open wound often is allowed to heal by secondary intention, with dressings being changed as the clinical team deems appropriate. The use of topical antibiotics and antiseptics to further wound healing remains unproven, although anecdotal studies indicate their potential utility in complex wounds that do not heal with routine measures.52 Despite a paucity of prospective studies, vacuum-assisted closure is increasingly used in management of large, complex open wounds and can be applied to wounds in loca-tions that are difficult to manage with dressings (Fig. 6-1).53,54 One also should consider obtaining wound cultures in patients who develop SSIs and who have been hospitalized or reside in long-term care facilities due to the increasing incidence of infec-tion caused by multidrug-resistant organisms.In the United States, hospitals are required to conduct sur-veillance for the development of SSIs for a period of 30 days ABFigure 6-1. Negative pressure wound therapy in a patient after amputation for wet gangrene (A) and in a patient with enterocutaneous fistula (B). It is possible to adapt these dressings to fit difficult anatomy and provide appropriate wound care while reducing frequency of dressing change. It is important to evaluate the wound under these dressings if the patient demonstrates signs of sepsis with an unidentified source, since typical clues of wound sepsis such as odor and drainage are hidden by the suction apparatus.Brunicardi_Ch06_p0157-p0182.indd 17001/03/19 4:46 PM 171SURGICAL INFECTIONSCHAPTER 6after the operative procedure.55 Such surveillance has been associated with greater awareness and a reduction in SSI rates, probably in large part based upon the impact of observation and promotion of adherence to appropriate care standards. Begin-ning in 2012, all hospitals receiving reimbursement from the Centers for Medicare & Medicaid Services (CMS) are required to report SSIs.A recent refinement of risk indexes has been implemented through the National Healthcare Safety Network, a secure, web-based system of surveillance used by the CDC for surveillance of healthcare-associated infections. This refinement utilized data reported from 847 hospitals in nearly one million patients over a 2-year period to develop procedure-specific risk indices for SSIs.56SSIs are associated with considerable morbidity and occasional lethality, as well as substantial healthcare costs and patient inconvenience and dissatisfaction.57 A number of healthcare organizations within the United States are interested in evaluating performance of hospitals and physicians with respect to implementing processes that support delivery of stan-dard of care. One major process of interest is reduction in SSIs, since the morbidity (and subsequent cost) of this complication is high. Several of these organizations are noted in Table 6-9. Appropriate guidelines in this area incorporating the principles discussed previously have been developed and disseminated.58 However, observers have noted that adherence to these guide-lines has been poor.59 Most experts believe that better adherence to evidence-based practice recommendations and implementing systems of care with redundant safeguards will result in reduc-tion of surgical complications and better patient outcomes. More important, the CMS, the largest third-party insurance payer in the United States, has required reporting by hospitals of many processes related to reduction of surgical infections, including appropriate use of perioperative antibiotics. This information, which is reported publicly by hospitals, has led to significant improvement in reported rates of these process measures. How-ever, the effect of this approach on the incidence of SSIs is not known at this time.Intra-Abdominal InfectionsMicrobial contamination of the peritoneal cavity is termed peri-tonitis or intra-abdominal infection and is classified according to etiology. Primary microbial peritonitis occurs when microbes invade the normally sterile confines of the peritoneal cavity via hematogenous dissemination from a distant source of infec-tion or direct inoculation. This process is more common among patients who retain large amounts of peritoneal fluid due to ascites, and among those individuals who are being treated for renal failure via peritoneal dialysis. These infections invariably are monomicrobial and rarely require surgical intervention. The diagnosis is established based on identification of risk factors as noted previously, physical examination that reveals diffuse tenderness and guarding without localized findings, absence of a surgically treatable source of infection on an imaging study, and the presence of more than 250 neutrophils/mL in fluid obtained via paracentesis.60 Cultures typically will demonstrate the presence of gram-positive organisms in patients undergoing peritoneal dialysis. In patients without this risk factor, the most common etiologic organisms are E coli, K pneumoniae, and S pneumoniae. Treatment consists of administration of an anti-biotic to which the organism is sensitive; often 14 to 21 days of therapy are required. Removal of indwelling devices, if present, may be required for effective therapy of recurrent infections.Secondary microbial peritonitis occurs subsequent to con-tamination of the peritoneal cavity due to perforation or severe inflammation and infection of an intra-abdominal organ. Exam-ples include appendicitis, perforation of any portion of the gas-trointestinal tract, or diverticulitis. As noted previously, effective therapy requires source control to resect or repair the diseased organ; debridement of necrotic, infected tissue and debris; and administration of antimicrobial agents directed against aerobes and anaerobes.61 This type of antibiotic regimen should be cho-sen because in most patients the precise diagnosis cannot be established until exploratory laparotomy is performed, and the most morbid form of this disease process is colonic perforation, due to the large number of microbes present. A combination of agents or single agents with a broad spectrum of activity can be used for this purpose; conversion of a parenteral to an oral regi-men when the patient’s ileus resolves provides results similar to those achieved with intravenous antibiotics. Effective source control and antibiotic therapy is associated with low failure rates and a mortality rate of approximately 5% to 6%; inability to control the source of infection is associated with mortality greater than 40%.62The response rate to effective source control and use of appropriate antibiotics has remained approximately 70% to 90% over the past several decades.63 Patients in whom stan-dard therapy fails typically develop one or more of the follow-ing: an intra-abdominal abscess, leakage from a gastrointestinal anastomosis leading to postoperative peritonitis, or tertiary (persistent) peritonitis. The latter is a poorly understood entity that is more common in immunosuppressed patients in whom peritoneal host defenses do not effectively clear or sequester Table 6-9Quality improvement organizations of interest to surgeons in the United StatesABBREVIATIONORGANIZATIONWEBSITENSQIPNational Surgical Quality Improvement Programacsnsqip.orgIHIInstitute for Healthcare Improvementwww.ihi.orgCMSCenters for Medicare & Medicaid Serviceswww.medicare.govwww.cms.gov/NCQANational Committee for Quality Assurancewww.ncqa.orgSISSurgical Infection Societywww.sisna.orgCDCCenters for Disease Control and Preventionwww.cdc.gov/HAI/ssi/ssi.htmlBrunicardi_Ch06_p0157-p0182.indd 17101/03/19 4:46 PM 172BASIC CONSIDERATIONSPART Ithe initial secondary microbial peritoneal infection. Microbes such as E faecalis and faecium, S epidermidis, C albicans, and P aeruginosa commonly are identified, typically in combina-tion, and their presence may be due to their lack of responsive-ness to the initial antibiotic regimen, coupled with diminished activity of host defenses. Unfortunately, even with effective antimicrobial agent therapy, this disease process is associated with mortality rates in excess of 50%.64Formerly, the presence of an intra-abdominal abscess mandated surgical reexploration and drainage. Today, the vast majority of such abscesses can be effectively diagnosed via abdominal computed tomographic (CT) imaging techniques and drained percutaneously. Surgical intervention is reserved for those individuals who harbor multiple abscesses, those with abscesses in proximity to vital structures such that percutaneous drainage would be hazardous, and those in whom an ongoing source of contamination (e.g., enteric leak) is identified. The necessity of antimicrobial agent therapy and precise guidelines that dictate duration of catheter drainage have not been estab-lished. A short course (3 to 5 days) of antibiotics that possess aerobic and anaerobic activity seems reasonable so long as the patient has good clinical response to therapy, and most practi-tioners leave the drainage catheter in situ until it is clear that cavity collapse has occurred, output is less than 10 to 20 mL/d, no evidence of an ongoing source of contamination is present, and the patient’s clinical condition has improved.33Organ-Specific InfectionsHepatic abscesses are rare, currently accounting for approximately 15 per 100,000 hospital admissions in the United States. Pyogenic abscesses account for approximately 80% of cases, the remaining 20% being equally divided among parasitic and fungal forms.65 Formerly, pyogenic liver abscesses mainly were caused by pyle-phlebitis due to neglected appendicitis or diverticulitis. Today, manipulation of the biliary tract to treat a variety of diseases has become a more common cause, although in nearly 50% of patients no cause is identified. The most common aerobic bacteria iden-tified in recent series include E coli, K pneumoniae, and other enteric bacilli, enterococci, and Pseudomonas spp., while the most common anaerobic bacteria are Bacteroides spp., anaero-bic streptococci, and Fusobacterium spp. C albicans and other related yeast cause the majority of fungal hepatic abscesses. Small (<1 cm), multiple abscesses should be sampled and treated with a 4to 6-week course of antibiotics. Larger abscesses are generally amenable to percutaneous drainage, with parameters for antibiotic therapy and drain removal similar to those men-tioned previously. Splenic abscesses are extremely rare and are treated in a similar fashion. Recurrent hepatic or splenic abscesses may require operative intervention—unroofing and marsupialization or splenectomy, respectively.Secondary pancreatic infections (e.g., infected pancreatic necrosis or pancreatic abscess) occur in approximately 10% to 15% of patients who develop severe pancreatitis with necro-sis. The surgical treatment of this disorder was pioneered by Bradley and Allen, who noted significant improvements in out-come for patients undergoing repeated pancreatic debridement of infected pancreatic necrosis.66 Care of patients with severe acute pancreatitis includes staging with dynamic, contrast-enhanced helical CT scan to evaluate the extent of pancreatitis (unless significant renal dysfunction exists, in which case one should forego the use of contrast material) coupled with the use of one of several prognostic scoring systems. Patients who exhibit clinical signs of instability (e.g., oliguria, hypoxemia, large-volume fluid resuscitation) should be carefully monitored in the ICU and undergo follow-up contrast CT examination when renal function has stabilized to evaluate for development of local pancreatic complications (Fig. 6-2). Routine use of pro-phylactic antibiotics to prevent infected pancreatic necrosis is not indicated. Early enteral feeding using nasojejunal feeding tubes placed past the ligament of Treitz has been associated with decreased development of infected pancreatic necrosis, possibly due to a decrease in gut translocation of bacteria.67,68The presence of secondary pancreatic infection should be suspected in patients whose systemic inflammatory response (fever, elevated WBC count, or organ dysfunction) fails to resolve, or in those individuals who initially recuperate, only to develop sepsis syndrome 2 to 3 weeks later. CT-guided aspira-tion of fluid from the pancreatic bed for performance of Gram stain and culture analysis can be useful. A positive Gram stain or culture from CT-guided aspiration, or identification of gas within the pancreas on CT scan, mandate surgical intervention.The approach of open necrosectomy with repeated debridements, although life-saving, is associated with sig-nificant morbidity and prolonged hospitalization. Efforts to reduce the amount of surgical injury, while still preserving the improved outcomes associated with debridement of the infected sequestrum, have led to a variety of less invasive approaches, including endoscopic and laparoscopic techniques.69 There are a limited number of randomized trials reporting the use of these new techniques. An important concept common to all of these approaches, however, is the attempt to delay surgical interven-tion, since a number of trials have identified increased mortality when intervention occurs during the first 2 weeks of illness.Data supporting the use of endoscopic approaches to infected pancreatic necrosis include nearly a dozen case series and a randomized trial.70,71 The reported mortality rate was 5%, with a 30% complication rate. Most authors noted the common requirement for multiple endoscopic debridements (similar to the open approach), with a median of four sessions required. Fewer series report experience with the laparoscopic approach, either transgastric or transperitoneal, entering the necrosis through the transverse mesocolon or gastrocolic ligament. Lap-aroscopic intervention is limited by the difficulty in achieving Figure 6-2. Contrast-enhanced CT scan of pancreas 1.5 weeks after presentation showing large central peripancreatic fluid col-lection (arrow).Brunicardi_Ch06_p0157-p0182.indd 17201/03/19 4:46 PM 173SURGICAL INFECTIONSCHAPTER 6Figure 6-3. Infected pancreatic necrosis. (A) Open necrosectomy specimen with pancreatic stent in situ. It is important to gently debride only necrotic pancreatic tissue, relying on repeated opera-tion to ensure complete removal. (B) For video-assisted retroperito-neal debridement (VARD), retroperitoneal access is gained through radiologic placement of a drain, followed by dilation 2 to 3 days later. (C) Retroperitoneal cavity seen through endoscope during VARD.BCmultiple debridements and the technical expertise required to achieve an adequate debridement. In 9 case series, mortality in a total of 65 patients was 6%.72Debridement of necrosis through a lumbar approach has been advocated by a number of authors. This approach, devel-oped with experience in a large number of patients,73 has been subjected to a single-center, randomized, prospective trial.74 This approach includes delay of intervention when possible until 4 weeks after the onset of disease. Patients receive transgastric or preferably retroperitoneal drainage of the sequestrum. If patients do not improve over 72 hours, they are treated with video-assisted retroperitoneal drainage (VARD), consisting of dilation of the retroperitoneal drain tract and debridement of the pancreatic bed (Fig. 6-3). Repeat debridements are performed as clinically indi-cated, with most patients requiring multiple debridements. In the trial reported, patients randomized to VARD (n = 43) compared to those randomized to the standard open necrosectomy (n = 45) had a decreased incidence of the composite endpoint of compli-cations and death (40% vs. 69%), with comparable mortality rate, hospital, and ICU lengths of stay. Patients randomized to VARD had fewer incisional hernias and occurrences of new-onset diabe-tes, as well as less need for pancreatic enzyme supplementation.It is apparent that patients with infected pancreatic necro-sis can safely undergo procedures that are more minimal than the gold-standard open necrosectomy with good outcomes. However, to obtain good outcomes these approaches require an experienced multidisciplinary team consisting of interventional radiologists, gastroenterologists, surgeons, and others. Impor-tant concepts for successful management include careful pre-operative planning, delay (if possible) to allow maturation of the fluid collection, and the willingness to repeat procedures as necessary until nonviable tissue has been removed.Infections of the Skin and Soft TissueThese infections can be classified according to whether sur-gical intervention is required. For example, superficial skin and skin structure infections such as cellulitis, erysipelas, and lymphangitis invariably are effectively treated with antibiotics alone, although a search for a local underlying source of infec-tion should be undertaken. Generally, drugs that possess activity against the causative gram-positive skin microflora are selected. Furuncles or boils may drain spontaneously or require surgical incision and drainage. Antibiotics are prescribed if significant cellulitis is present or if cellulitis does not rapidly resolve after surgical drainage. Community-acquired methicillin-resistant S aureus (MRSA) infection should be suspected if infection persists after treatment with adequate drainage and administra-tion of first-line antibiotics. These infections may require more aggressive drainage and altered antimicrobial therapy.75Aggressive soft tissue infections are rare, difficult to diag-nose, and require immediate surgical intervention plus adminis-tration of antimicrobial agents. Failure to rapidly recognize and treat these infections results in an extremely high mortality rate (∼80–100%), and even with expedient therapy mortality rates are high (16–24%).76 Eponyms and differing classifications in the past has led to a hodgepodge of terminology—such as Meleney’s synergistic gangrene, Fournier’s gangrene, rapidly spreading cellulitis, gas gangrene, and necrotizing fasciitis—regarding these serious infections. Today it seems best to delin-eate them based on the soft tissue layer(s) of involvement 6Brunicardi_Ch06_p0157-p0182.indd 17301/03/19 4:46 PM 174BASIC CONSIDERATIONSPART I(e.g., skin and superficial soft tissue, deep soft tissue, and mus-cle) and the pathogen(s) that cause them.Patients at risk for these types of infections include those who are elderly, immunosuppressed, or diabetic, and/or who suf-fer from peripheral vascular disease, though extremely aggressive necrotizing soft tissue infections (often caused by streptococci) have been described among healthy individuals as well. The com-mon thread among these host factors appears to be compromise of the fascial blood supply, and if this is coupled with the introduc-tion of exogenous microbes, the result can be devastating.Initially, the diagnosis is established solely upon a constel-lation of clinical findings, not all of which are present in every patient. Not surprisingly, patients often develop sepsis syndrome or septic shock without an obvious cause. The extremities, perineum, trunk, and torso are most commonly affected, in that order. Careful examination should be undertaken for an entry site such as a small break or sinus in the skin from which grayish, turbid semipurulent material (“dishwater pus”) can be expressed, as well as for the presence of skin changes (bronze hue or brawny induration), blebs, or crepitus. The patient often develops pain at the site of infection that appears to be out of proportion to any of the physical manifestations. Any of these findings man-dates immediate surgical intervention, which should consist of incision and direct visualization of potentially infected tissue (including deep soft tissue, fascia, and underlying muscle) and radical resection of affected areas. Radiologic studies should not be undertaken in patients in whom the diagnosis seriously is con-sidered, as they delay surgical intervention and frequently pro-vide confusing information. Unfortunately, surgical extirpation of infected tissue frequently entails amputation and/or disfigur-ing procedures; the surgeon must bear in mind that incomplete procedures are associated with higher rates of morbidity and mortality and debride all nonviable tissue (Fig. 6-4).During the procedure, a Gram stain should be performed on tissue fluid. Antimicrobial agents directed against gram-positive and gram-negative aerobes and anaerobes (e.g., van-comycin plus a carbapenem), as well as high-dose aqueous penicillin G (16,000,000 to 20,000,000 U/d), the latter to treat clostridial pathogens, should be administered. Approximately 50% of such infections are polymicrobial, the remainder being caused by a single organism such as S pyogenes, P aeruginosa, or C perfringens. The microbiology of these polymicrobial infections is similar to that of secondary microbial peritonitis, with the exception that gram-positive cocci are more commonly encountered. Most patients should be returned to the operat-ing room on a scheduled basis to determine if disease progres-sion has occurred. If so, additional resection of infected tissue and debridement should take place. Antibiotic therapy can be refined based on culture and sensitivity results, particularly in the case of monomicrobial soft tissue infections. Hyperbaric oxygen therapy may be of use in patients with infection caused by gas-forming organisms (e.g., C perfringens), although the evidence to support efficacy is limited to underpowered studies and case reports. In the absence of such infection, hyperbaric oxygen therapy has not been shown to be effective.77Postoperative Nosocomial InfectionsSurgical patients are prone to develop a wide variety of nosoco-mial infections during the postoperative period, which include SSIs, UTIs, pneumonia, and bacteremia. SSIs are discussed ear-lier, and the latter types of nosocomial infections are related to prolonged use of indwelling tubes and catheters for the purpose of urinary drainage, ventilation, and venous and arterial access, respectively.The presence of a postoperative UTI should be considered based on urinalysis demonstrating WBCs or bacteria, a positive test for leukocyte esterase, or a combination of these elements. The diagnosis is established after >104 CFU/mL of microbes are identified by culture techniques in symptomatic patients, or >105 CFU/mL in asymptomatic individuals. Treatment for 3 to 5 days with a single antibiotic directed against the most common organ-isms (e.g., E Coli, K pneumoniae) that achieves high levels in the urine is appropriate. Initial therapy is directed by Gram stain results and is refined as culture results become available. Postop-erative surgical patients should have indwelling urinary catheters removed as quickly as possible to avoid the development of a UTI.Prolonged mechanical ventilation is associated with nos-ocomial pneumonia. These patients present with more severe disease, are more likely to be infected with drug-resistant pathogens, and suffer increased mortality compared to patients who develop community-acquired pneumonia. The diagnosis of pneumonia is established by presence of purulent sputum, elevated leukocyte count, fever, and new chest X-ray abnor-malities, such as consolidation. The presence of two of the clini-cal findings, plus chest X-ray findings, significantly increases the likelihood of pneumonia.78 Consideration should be given to performing bronchoalveolar lavage to obtain samples for Gram stain and culture. Some authors advocate quantitative cultures as a means to identify a threshold for diagnosis.79 Surgical patients should be weaned from mechanical ventilation as soon as feasi-ble, based on oxygenation and inspiratory effort, as risk of pneu-monia increases with increased time on mechanical ventilation.Infection associated with indwelling intravascular cathe-ters is a common problem among hospitalized patients. Because of the complexity of many surgical procedures, these devices are increasingly used for physiologic monitoring, vascular access, drug delivery, and hyperalimentation. Among the sev-eral million catheters inserted each year in the United States, approximately 25% will become colonized, and approximately 5% will be associated with bacteremia. Duration of catheteriza-tion, insertion or manipulation under emergency or nonsterile conditions, use for hyperalimentation, and the use of multilu-men catheters increase the risk of infection. Use of a central line insertion protocol that includes full barrier precautions and chlorhexidine skin prep has been shown to decrease the inci-dence of infection.80 Although no randomized trials have been performed, peripherally inserted central venous catheters have a catheter-related infection rate similar to those inserted in the subclavian or jugular veins.81Many patients who develop intravascular catheter infec-tions are asymptomatic, often exhibiting solely an elevation in the blood WBC count. Blood cultures obtained from a peripheral site and drawn through the catheter that reveals the presence of the same organism increase the index of suspicion for the pres-ence of a catheter infection. Obvious purulence at the exit site of the skin tunnel, severe sepsis syndrome due to any type of organism when other potential causes have been excluded, or bacteremia due to gram-negative aerobes or fungi should lead to catheter removal. Selected catheter infections due to low-virulence microbes such as S epidermidis can be effectively treated in approximately 50% to 60% of patients with a 14to 21-day course of an antibiotic, which should be considered when no other vascular access site exists.82 The use of antibi-otic-bonded catheters and chlorhexidine sponges at the insertion Brunicardi_Ch06_p0157-p0182.indd 17401/03/19 4:46 PM 175SURGICAL INFECTIONSCHAPTER 6FIGURE 6-4. Necrotizing soft tissue infection. (A) This patient presented with hypotension due to severe late necrotizing fasci-itis and myositis due to β-hemolytic streptococcal infection. The patient succumbed to his disease after 16 hours despite aggressive debridement. (B) This patient presented with spreading cellulites and pain on motion of his right hip 2 weeks after total colectomy. Cellulitis on right anterior thigh is outlined. (C) Classic dishwater edema of tissues with necrotic fascia. (D) Right lower extremity after debridement of fascia to viable muscle.site has been associated with lower rates of colonization.83 Use of ethanol or antimicrobial catheter “locks” have shown prom-ise in reducing incidence of infection in dialysis catheters.84 The surgeon should carefully consider the need for any type of vascular access devices, rigorously attend to their maintenance to prevent infection, and remove them as quickly as possible. Use of systemic antibacterial or antifungal agents to prevent catheter infection is of no utility and is contraindicated.SepsisAs previously discussed, sepsis is increasing in incidence, with more than 1.1 million cases estimated per year in the United States with an annual cost of $24 billion. This rate is expected to increase as the population of aged in the United States increases. One third of sepsis cases occur in surgical pop-ulations and sepsis is a major cause of morbidity and mortality.85 The treatment of sepsis has improved over the last decade, with mortality rates dropping to under 30%. Factors contributing to this improvement relate both to recent randomized prospective trials demonstrating improved outcomes with new therapies, and to improvements in the process of care delivery to the sepsis patient. The “Surviving Sepsis Campaign,” a multidisciplinary group that develops treatment recommendations, published guidelines incorporating evidence-based sepsis treatment strate-gies most recently in 2016.15,86 These guidelines are summarized in Table 6-10.ABCDBrunicardi_Ch06_p0157-p0182.indd 17501/03/19 4:46 PM 176BASIC CONSIDERATIONSPART IPatients presenting with sepsis should receive resuscitation fluids early in the course of therapy. While former guidelines advocated fluids until the patient’s central venous pressure was 8 to 12 mmHg, newer guidelines recommend using dynamic monitoring systems (such as ultrasound) as well as assessment of physiological response to fluids by evaluating variables such as heart rate, blood pressure, and urine output to determine ade-quate resuscitation volumes. Resuscitation endpoints include achieving a goal mean arterial pressure of ≥65 mmHg, urine output of ≥0.5 mL/kg per hour, and normalization of serum lac-tate. Delaying this resuscitative step for as little as 3 hours has been shown to result in worse outcomes.87 Resuscitation may necessitate placement of a central venous catheter.A number of studies have demonstrated the importance of early empiric antibiotic therapy in patients who develop sep-sis or nosocomial infection; the Surviving Sepsis guidelines advocate for initiation of treatment within the first hour of the patient’s care. This therapy should be initiated as soon as pos-sible with broad-spectrum antibiotics directed against the most likely organisms. Use of institutionand unit-specific sensitivity patterns are critical in selecting an appropriate agent for patients with nosocomial infection. Obtain appropriate cultures before Table 6-10Summary of Surviving Sepsis Campaign guidelinesInitial Evaluation and Infection IssuesInitial resuscitation: Begin resuscitation immediately in patients with hypotension or elevated serum lactate with resuscitation goal of at least 30 mL/kg IV crystalloid given in the first 3 hours.Ongoing fluid administration should be guided by physiologic response as measured by clinical variables (e.g., heart rate, blood pressure, urine output) and/or other invasive or noninvasive monitoring.Resuscitation goals include mean arterial pressure >65 mmHg, urine output >0.5 mL/kg per h, and mixed venous oxygen saturation >65%.Target resuscitation to normalize lactate in patients with elevated lactate levels.Diagnosis: Obtain appropriate cultures prior to antibiotics, but do not delay antibiotic therapy. Imaging studies should be performed promptly to confirm a source of infection.Antibiotic therapy: Begin IV antibiotic therapy as early as possible and within the first hour after recognition of severe sepsis/septic shock. Use broad spectrum antibiotic regimen with penetration into presumed source, reassess regimen daily with de-escalation as appropriate, discontinue antibiotics in 7 to 10 days for most infections, stop antibiotics for noninfectious issues. Consider the use of serial procalcitonin levels, which may allow earlier cessation of antibiotic therapy.Source control: Establish anatomic site of infection as rapidly as possible; implement source control measures as soon as possible after initial resuscitation. Remove intravascular access devices if potentially infected.Hemodynamic Support and Adjunctive TherapyFluid therapy: Fluid resuscitate using crystalloid, with continued fluid challenges so long as hemodynamic parameters continue to improve (i.e., for so long as the patient remains fluid-responsive). Albumin may be used as an adjunct if large volumes of crystalloid are required, but hydroxyethyl starch and gelatin-based fluids should not be used.Vasopressors/Inotropic Therapy: Maintain MAP of >65 mmHg. Centrally-administered norepinephrine is the first-line choice. Add vasopressin if needed to raise MAP or to reduce norepinephrine requirement. Epinephrine is an alternative to vasopressin but has greater risk of reduced splanchnic blood flow. Dopamine is an appropriate alternative only in select patients (bradycardia, low risk of arrhythmia), and there is no role for low-dose “renal protection” dopamine. Phenylephrine is not recommended. Insert arterial catheters for patients requiring vasopressors. Consider dobutamine infusion for persistent hypotension after appropriate resuscitation and use of vasopressor agents.Steroids: Consider intravenous hydrocortisone (dose <300 mg/day) for adult septic shock when hypotension responds poorly to fluids and vasopressors.Other Supportive TherapyBlood product administration: Transfuse red blood cells when hemoglobin decreases to <7.0 g/dL in the absence of extenuating circumstances (e.g., myocardial ischemia, hemorrhage). It is not necessary to use fresh frozen plasma to correct INR abnormalities in the absence of bleeding. Consider prophylactic transfusion of platelets when counts are less than 10,000/mL in the absence of bleeding, <20,000/mL if there is a risk of bleeding, and <50,000 in the setting of active bleeding or need for procedure.Mechanical ventilation: Target an initial tidal volume of 6 mL/kg body weight and plateau pressure of <30 cm H2O in patients with acute lung injury. Use PEEP to avoid lung collapse. Adopt a conservative fluid strategy. In the setting of sepsis-induced ARDS with PaO2/FiO2 ratio <150, use prone ventilation over continued supine position or high-frequency oscillatory ventilation. Use a weaning protocol to evaluate the potential for discontinuing mechanical ventilation. Pulmonary artery catheter placement is not indicated for routine monitoring.Sedation: Minimize sedation using specific titration endpoints.Glucose control: Use protocolized approach to blood glucose management targeting upper blood glucose target of 180 mg/dL.Prophylaxis: Use stress ulcer (proton pump inhibitor or H2 blocker) and deep venous thrombosis (low-dose unfractionated or fractionated heparin) prophylaxis.Limitation of support: Discuss advance care planning with patients and families and set realistic expectations.Data from Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016, Intensive Care Med. 2017 Mar;43(3):304-377.Brunicardi_Ch06_p0157-p0182.indd 17601/03/19 4:46 PM 177SURGICAL INFECTIONSCHAPTER 6starting antibiotics so that appropriate de-escalation of therapy can take place when results return, but only if doing so does not delay the initiation of treatment.In patients who require vasopressor therapy, the first-line agent should be norepinephrine. This can be augmented with vasopressin, if needed, to achieve MAP ≥65 mmHg. It is impor-tant to titrate therapy based on other parameters such as mixed venous oxygen saturation and plasma lactate levels to reduce the risk of vasopressor-induced perfusion deficits. Patients who have persistently poor perfusion despite adequate fluid resus-citation may require addition of inotropic agents (epinephrine, dobutamine) or adjunctive therapy with low-dose corticoste-roids (hydrocortisone 200 mg/day).86Patients with acute lung injury associated with sepsis should receive mechanical ventilation with tidal volumes of 6 mL/kg and pulmonary airway plateau pressures of ≤30 cm H2O. Finally, red blood cell transfusion should be reserved for patients with hemoglobin of <7 g/dL, with a more liberal trans-fusion strategy reserved for those patients with severe coronary artery disease, ongoing blood loss, or severe hypoxemia.86Resistant OrganismsPenicillin was first available for widespread clinical use in the 1940s, and within a year resistant strains of S aureus had emerged. There are two major factors responsible for antibiotic resistance. First, there may be a genetic component innate to an organism that prevents the effect of a particular antibiotic. For instance, if an organism does not have a target receptor specific to the mechanism of action of a particular antibiotic, the antibi-otic will not be effective against this organism. A good example is penicillin and gram-negative organisms, as these microbes lack penicillin-binding proteins. The second component driv-ing resistance is inducible and related to natural selection. Over generations of exposure to a particular antibiotic, selection pres-sure will drive proliferation of more organisms resistant to that antibiotic. This acquired antibiotic resistance can be mutational, leading to changes in the chromosomal makeup of the microbe, or it can be extrachromosomal, induced by transfer of exog-enous genetic material in the form of a plasmid or transposon. In either case, cellular mechanisms of resistance that develop include target site modification, changes in bacterial permeabil-ity or antibiotic uptake, activation of drug efflux systems, and drug deactivation. Given that millions of kilograms of antibiot-ics are used annually in people, in agriculture, and for animal use, environmental selection pressures are high, and antibiotic resistance has now been described in all classes of antibiotics in common use. Antibiotic resistance comes at a high cost, with a significant increase in mortality associated with infection from resistant organisms, and an economic cost of billions of dollars per year.There are several drug-resistant organisms of interest to the surgeon. MRSA most commonly occurs as a hospitalassociated infection in chronically ill patients who have received multiple courses of antibiotics. However, strains of MRSA have emerged in the community among patients without preexisting risk factors for disease.75 These strains, which produce a toxin known as Panton-Valentine leukocidin, make up an increasingly high percentage of surgical site infections since they are resis-tant to commonly employed prophylactic antimicrobial agents.88 Extended spectrum β-lactamase (ESBL)-producing strains of enterobacteriaceae, originally geographically localized and infrequent, have become much more widespread and common in the last decade.89 These strains, typically Klebsiella species or E coli, produce a plasmid-mediated inducible β-lactamase. Commonly encountered plasmids also confer resistance to many other antibiotic classes. A common laboratory finding with ESBL is sensitivity to first-, second-, or third-generation cephalosporins, with resistance to other agents. Unfortunately, use of this seemingly active agent leads to rapid induction of resistance and failure of antibiotic therapy. The appropriate anti-biotic choice in this setting is a carbapenem.While Enterococcus was considered a low-virulence organ-ism in the past, infections caused by E faecium and faecalis have been found to be increasingly severe, especially in the immu-nocompromised host. The last decade has seen increased iso-lation of a vancomycin-resistant strain of Enterococcus. This resistance is transposon-mediated via the vanA gene and is typically seen in E faecium strains. A real infection control con-cern is potential for transfer of genetic material to S aureus in a host coinfected with both organisms. This is thought to be the mechanism behind emerging cases of vancomycin resistance in S aureus.90Blood-Borne PathogensThe risk of human immunodeficiency virus (HIV) transmission from patient to surgeon is low. As of May 2011, there had been six cases of surgeons with HIV seroconversion from a possible occupational exposure, with no new cases reported since 1999. Of the numbers of healthcare workers with likely occupationally acquired HIV infection (n = 200), surgeons were one of the lower risk groups (compared to nurses at 60 cases and nonsur-geon physicians at 19 cases).91 The estimated risk of transmis-sion from a needlestick from a source with HIV-infected blood is estimated at 0.3%. Transmission of HIV (and other infections spread by blood and body fluid) from patient to healthcare worker can be minimized by observation of universal precau-tions, including: (a) routine use of barriers (gloves, gown, mask, eye protection) when anticipating contact with blood or body fluids, (b) washing hands and other skin surfaces immediately after contact with blood or body fluids, and (c) careful handling and disposal of sharp instruments during and after use.Postexposure prophylaxis for HIV has significantly decreased the risk of seroconversion for healthcare workers with occupational exposure to HIV. Steps to initiate postexposure prophylaxis should be initiated within hours for the most effec-tive preventive therapy. Postexposure prophylaxis with a three-drug regimen should be initiated for healthcare workers with significant exposure to patients with an HIV-positive status. If a patient’s HIV status is unknown, it may be advisable to begin postexposure prophylaxis while testing is carried out, particu-larly if the patient is at high risk for infection due to HIV (e.g., has had a history of intravenous drug use). Generally, postexpo-sure prophylaxis is not warranted for exposure to sources with unknown status, such as deceased persons or needles from a sharps container.92The risks of acquiring HIV infection for surgeons are related to the prevalence of HIV infection in the patient popula-tion, the probability of transmission from a percutaneous injury suffered while caring for an infected patient, the number of such injuries sustained, and the use of postexposure prophylaxis. Average risk of HIV seroconversion is 0.3% from a percutane-ous exposure, and 0.09% from a mucous membrane exposure. The overall risk is influenced by the degree of viral inoculum 7Brunicardi_Ch06_p0157-p0182.indd 17701/03/19 4:46 PM 178BASIC CONSIDERATIONSPART Itransmitted from patient to surgeon, with greater risk of sero-conversion associated with hollow-bore needle injury, with larger-volume blood transmission, with direct introduction of infected blood into an artery or vein, and in exposure to blood with higher viral load. One study in Glasgow, Scotland, cal-culated annual risks and found a range in seroconversion rates from 1 in 200,000 for general surgeons not utilizing postexpo-sure prophylaxis to as low as 1 in 10,000,000 with use of routine postexposure prophylaxis after significant exposures.92,93Hepatitis B virus (HBV) is a DNA virus that affects only humans. Primary infection with HBV generally is self-limited, but it can cause fulminant hepatitis or progress to a chronic car-rier state. Death from chronic liver disease or hepatocellular cancer occurs in roughly 30% of chronically infected persons. Surgeons and other healthcare workers are at high risk for this blood-borne infection and should receive the HBV vaccine; children are routinely vaccinated in the United States.94 This vaccine has contributed to a significant decline in the number of new cases of HBV per year in the United States, from approxi-mately 250,000 annually in the 1980s to 3350 in 2010.95,96Hepatitis C virus (HCV), previously known as non-A, non-B hepatitis, is a RNA flavivirus first identified in the late 1980s. This virus is confined to humans and chimpanzees. A chronic carrier state develops in 75% to 80% of patients with the infection, with chronic liver disease occurring in three-fourths of this subgroup. The number of new infections per year has declined since the 1980s due to routine testing of blood donors for the virus. Fortunately, HCV is not transmitted efficiently through occupational exposures to blood, with the seroconver-sion rate after accidental needlestick approximately 1.8%.97 To date, a vaccine to prevent HCV infection has not been devel-oped. Experimental studies in chimpanzees with HCV immu-noglobulin using a model of needlestick injury have failed to demonstrate a protective effect, and no effective antiviral agents for postexposure prophylaxis are available. Treatment of patients with HCV infection historically included ribavirin and pegylated gamma interferon; the development of novel direct-acting antiviral agents such as sofosbuvir, boceprevir, and tela-previr has led to changes in this strategy.98,99BIOLOGIC WARFARE AGENTSSeveral infectious organisms have been studied by the United States and the former Soviet Union and presumably other entities for potential use as biologic weapons. Programs involving biologic agents in the United States were halted by presidential decree in 1971. However, concern remains that these agents could be used by rogue states or terrorist organi-zations as weapons of mass destruction, as they are relatively inexpensive to make in terms of infrastructure development. Given these concerns, physicians, including surgeons, should familiarize themselves with the manifestations of infection due to these pathogens. The typical agent is selected for the ability to be spread via the inhalational route, as this is the most efficient mode of mass exposure. Several potential agents are discussed in the following sections.Bacillus anthracis (Anthrax)Anthrax is a zoonotic disease occurring in domesticated and wild herbivores. The first identification of inhalational anthrax as a disease occurred among woolsorters in England in the late 1800s. The largest recent epidemic of inhalational anthrax occurred in 1979 in Sverdlovsk, Russia, after accidental release of anthrax spores from a military facility. Inhalational anthrax develops after a 1to 6-day incubation period, with nonspe-cific symptoms, including malaise, myalgia, and fever. Over a short period of time these symptoms worsen, with development of respiratory distress, chest pain, and diaphoresis. Character-istic chest roentgenographic findings include a widened medi-astinum and pleural effusions. Rapid antigen tests are under development for identification of this gram-positive rod, so a key element of establishing the diagnosis is eliciting an expo-sure history. Postexposure prophylaxis consists of administra-tion of either ciprofloxacin or doxycycline.100 If an isolate is demonstrated to be penicillin-sensitive, the patient should be switched to amoxicillin. Inhalational exposure followed by the development of symptoms is associated with a high mortality rate. Treatment options include combination therapy with cip-rofloxacin, clindamycin, and rifampin. Clindamycin is added to block toxin production, while rifampin penetrates into the central nervous system and intracellular locations.Yersinia pestis (Plague)Plague is caused by the gram-negative organism Y pestis. The naturally occurring disease in humans is transmitted via flea bites from rodents. It was the first biologic warfare agent, and was used in the Crimean city of Caffa by the Tartar army, whose soldiers catapulted bodies of plague victims at the Genoese. When plague is used as a biologic warfare agent, clinical manifestations include epidemic pneumonia with blood-tinged sputum if aerosolized bacteria are used, or bubonic plague if fleas are used as carriers. Individuals who develop a painful enlarged lymph node lesion, termed a “bubo,” associ-ated with fever, severe malaise, and exposure to fleas should be suspected to have plague. Diagnosis is confirmed via aspirate of the bubo and a direct antibody stain to detect plague bacil-lus, whose morphology is a bipolar, safety-pin-shaped gram-negative rod. Postexposure prophylaxis for patients exposed to plague consists of doxycycline. Treatment of the pneumonic or bubonic/septicemic form includes administration of either strep-tomycin, an aminoglycoside, doxycycline, a fluoroquinolone, or chloramphenicol.101SmallpoxVariola, the causative agent of smallpox, was a major cause of infectious morbidity and mortality until its eradication in the late 1970s. Even in the absence of laboratory-preserved virus, the prolonged viability of variola virus has been dem-onstrated in scabs up to 13 years after collection. The potential for reverse genetic engineering using the known sequence of smallpox also makes it a potential biologic weapon. This has resulted in the United States undertaking a vaccination program for key healthcare workers.102 Variola virus is highly infectious in the aerosolized form; after an incubation period of 10 to 12 days, clinical manifestations of malaise, fever, vomiting, and headache appear, followed by development of a characteristic centripetal rash (which is found to predominate on the face and extremities). The fatality rate may reach 30%. Postexposure prophylaxis with smallpox vaccine has been noted to be effec-tive for up to 4 days postexposure. Cidofovir, an acyclic nucleo-side phosphonate analogue, has demonstrated activity in animal models of poxvirus infections and may offer promise for the treatment of smallpox.103Brunicardi_Ch06_p0157-p0182.indd 17801/03/19 4:46 PM 179SURGICAL INFECTIONSCHAPTER 6Francisella tularensis (Tularemia)The principal reservoir of this gram-negative aerobic organism is the tick. After inoculation, this organism proliferates within macrophages. 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Antimicro-bial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;38:1706-1715. 59. Meeks DW, Lally KP, Carrick MM, et al. Compliance with guidelines to prevent surgical site infections: as simple as 1-2-3? Am J Surg. 2011;201(1):76-83. 60. Runyon BA. Management of adult patients with ascites due to cirrhosis: update 2012, American Association for the Study of Liver Disease practice guideline. Available at https://www .aasld.org/sites/default/files/guideline_documents/AASLD-PracticeGuidelineAsciteDuetoCirrhosisUpdate2012Edition4_ .pdf. Accessed August 8, 2017. 61. Solomkin JS, Mazuski JE, Baron EJ, et al. Infectious Diseases Society of America: guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005. 62. Solomkin JS, Dellinger EP, Christou NV, et al. 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Surg Infect (Larchmt). 2008;9(6):573-578. 68. Freeman ML, Werner J, van Santvoort HC, et al. Interven-tions for necrotizing pancreatitis: summary of a multidis-ciplinary consensus conference. Pancreas. 2012;41(8): 1176-1194. 69. Wysocki AP, McKay CJ, Carter CR. Infected pancreatic necro-sis: minimizing the cut. ANZ J Surg. 2010;80(1-2):58-70. 70. Haghshenasskashani A, Laurence JM, Kwan V, et al. Endo-scopic necrosectomy of pancreatic necrosis: a systematic review. Surg Endosc. 2011;25(12):3724-3730.Brunicardi_Ch06_p0157-p0182.indd 18001/03/19 4:46 PM 181SURGICAL INFECTIONSCHAPTER 6 71. Bakker OJ, van Santvoort HC, van Brunschot S, et al. Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis: a randomized trial. JAMA. 2012;307(10):1053-1061. 72. Fink D, Soares R, Matthews JB, Alverdy JC. History, goals, and technique of laparoscopic pancreatic necrosectomy. J Gastrointest Surg. 2011;15(7):1092-1097. 73. van Santvoort HC, Bakker OJ, Bollen TL, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology. 2011;141(4):1254-1263. 74. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362(16):1491-1502. A study assessing a minimally invasive approach to pancreatic debridement. 75. Beilman GJ, Sandifer G, Skarda D, et al. Emerging infections with community-associated methicillin-resistant Staphylococ-cus aureus in outpatients at an army community hospital. Surg Infect (Larchmt). 2005;6(1):87-92. 76. Kao LS, Lew DF, Arab SN, et al. Local variations in the epidemiology, microbiology, and outcome of necrotizing soft-tissue infections: a multicenter study. Am J Surg. 2011; 202(2):139-145. 77. George ME, Rueth NM, Skarda DE, et al. Hyperbaric oxygen does not improve outcome in patients with necrotizing soft tissue infection. Surg Infect (Larchmt). 2009;10(1):21-28. 78. Klompas M. Does this patient have ventilator-associated pneu-monia? JAMA. 2007 11;297(14):1583-1593. 79. Riaz OJ, Malhotra AK, Aboutanos MB, et al. Bronchoal-veolar lavage in the diagnosis of ventilator-associated pneu-monia: to quantitate or not, that is the question. Am Surg. 2011;77(3):297-303. 80. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52(9):e162-e193. 81. Safdar N, Maki DG. Risk of catheter-related bloodstream infection with peripherally inserted central venous catheters used in hospitalized patients. Chest. 2005;128(2):489-495. 82. Marr KA, Sexton DJ, Conlon PJ, et al. Catheter-related bac-teremia and outcome of attempted catheter salvage in patients undergoing hemodialysis. Ann Intern Med. 1997;127:275. 83. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52(9):e162-e193. 84. Broom JK, Krishnasamy R, Hawley CM, et al. A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemo-dialysis patients—the HEALTHY-CATH trial. BMC Nephrol. 2012;13:146. 85. Moore LJ, Moore FA. Epidemiology of sepsis in surgical patients. Surg Clin North Am. 2012;92(6):1425-1443. 86. Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304-377. Updated recommendations and best practice guidelines. 87. Otero RM, Nguyen HB, Huang DT, et al. Early goal-directed therapy in severe sepsis and septic shock revisited: con-cepts, controversies, and contemporary findings. Chest. 2006;130(5):1579-1595. 88. Miller LG, McKinnell JA, Vollmer ME, Spellberg B. Impact of methicillin-resistant Staphylococcus aureus prevalence among S aureus isolates on surgical site infection risk after coronary artery bypass surgery. Infect Control Hosp Epide-miol. 2011;32(4):342-350. 89. Han JH, Nachamkin I, Zaoutis TE, et al. Risk factors for gastrointestinal tract colonization with extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Kleb-siella species in hospitalized patients. Infect Control Hosp Epidemiol. 2012;33(12):1242-1245. 90. Calfee DP. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and other Gram-positives in healthcare. Curr Opin Infect Dis. 2012;25(4):385-394. 91. Centers for Disease Control and Prevention. Surveillance of occupationally acquired HIV/AIDS in healthcare personnel, as of December 2010. Available at https://www.cdc.gov/HAI/organisms/hiv/Surveillance-Occupationally-Acquired-HIV-AIDS.html. Accessed July 31, 2017. 92. Updated U.S. Public Health Service guidelines for the manage-ment of occupational exposures to HIV and recommendations for postexposure prophylaxis. Downloaded from Centers for Disease Control and Prevention, Human Immunodeficiency Virus in Healthcare Settings, https://www.cdc.gov/hai/organ-isms/hiv/hiv.html. Accessed July 31, 2017. 93. Goldberg D, Johnston J, Cameron S, et al. Risk of HIV trans-mission from patients to surgeons in the era of post-exposure prophylaxis. J Hosp Infect. 2000;44:99-105. 94. Recommended Adult Immunization Schedule-United States. Available at: http://www.cdc.gov/vaccines/schedules/hcp/adult.html. Accessed July 31, 2017. 95. Centers for Disease Control and Prevention. Hepatitis B vaccination–United States, 1982–2002. MMWR. 2002;51:549. 96. Centers for Disease Control, Viral hepatitis statistics and surveillance. Available at http://www.cdc.gov/hepatitis/Statistics/2010Surveillance/Table3.1.htm. Accessed July 31, 2017. 97. MacCannell T, Laramie AK, Gomaa A, Perz JF. Occupational exposure of health care personnel to hepatitis B and hepatitis C: prevention and surveillance strategies. Clin Liver Dis. 2010; 14(1):23-36. 98. Katz LH, Goldvaser H, Gafter-Gvili A, Tur-Kaspa R. Extended peginterferon plus ribavirin treatment for 72 weeks versus standard peginterferon plus ribavirin treatment for 48 weeks in chronic hepatitis C genotype 1 infected slow-responder adult patients. Cochrane Database Syst Rev. 2012;9:CD008516. 99. Cholongitas E, Papatheodoridis GV. Sofosbuvir: a novel oral agent for chronic hepatitis C. Ann Gastroenterol. 2014;27(4):331-337. 100. Inglesby TV, O’Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for man-agement. JAMA. 2002;287:2236-2252. 101. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a bio-logical weapon; medical and public health management. Work-ing group on civilian biodefense. JAMA. 2000;283:2281-2290. 102. Russell PK, Gronvall GK. U.S. medical countermeasure devel-opment since 2001: a long way yet to go. Biosecur Bioterror. 2012;10(1):66-76. 103. DeClercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002;55:1-13.Brunicardi_Ch06_p0157-p0182.indd 18101/03/19 4:46 PM

Brunicardi_Ch06_p0157-p0182.indd 18201/03/19 4:46 PMThis page intentionally left blankTraumaClay Cothren Burlew and Ernest E. Moore 7chapterINTRODUCTIONTrauma, or injury, is defined as cellular disruption caused by environmental energy that is beyond the body’s resilience, which is compounded by cell death due to ischemia/reperfu-sion. Trauma is the most common cause of death for all indi-viduals between the ages of 1 and 44 years, and is the third most common cause of death regardless of age.1 It is also the leading cause of years of productive life lost. Unin-tentional injuries account for over 135,000 deaths per year, with homicides, suicides, and other causes are responsible for another 60,000 deaths each year. However, death rate under-estimates the magnitude of the societal toll. For example, in 2014 there were almost 200,000 injury-related deaths, but 37.2 million injured patients treated in emergency depart-ments (EDs). Injury-related medical expenditures are esti-mated to be $117 billion each year in the United States.2 The aggregate lifetime cost for all injured patients is estimated to be in excess of $260 trillion. For these reasons, trauma must be considered a major public health issue. The American Col-lege of Surgeons Committee on Trauma addresses this issue by assisting in the development of trauma centers and sys-tems. The organization of trauma systems has had a signifi-cant favorable impact on patient outcomes, although system integration and maldistribution of trauma centers remain chal-lenges.3-5INITIAL EVALUATION AND RESUSCITATION OF THE INJURED PATIENTPrimary SurveyThe Advanced Trauma Life Support (ATLS) course of the American College of Surgeons Committee on Trauma was developed in the late 1970s, based on the premise that appro-priate and timely care can improve the outcome for the injured 1patient.6 ATLS provides a structured approach to the trauma patient with standard algorithms of care; it emphasizes the “golden hour” concept that timely, prioritized interventions are necessary to prevent death and disability. The ATLS for-mat and basic tenets are followed throughout this chapter, with some modifications. The initial management of seriously injured patients consists of phases that include the primary survey/concurrent resuscitation, the secondary survey/diag-nostic evaluation, definitive care, and the tertiary survey. The first step in patient management is performing the primary survey, the goal of which is to identify and treat conditions that constitute an immediate threat to life. The ATLS course refers to the primary survey as assessment of the “ABCs” (Airway with cervical spine protection, Breathing, and Circulation). The timing of emergent intubation in the hypovolemic patient remains controversial because of the risk of further compro-mising cardiac function. Although the concepts within the primary survey are presented in a sequential fashion, in reality they are pursued simultaneously in coordinated team resuscitation. Life-threatening injuries must be identified (Table 7-1) and treated before progressing to the secondary survey.Airway Management With Cervical Spine Protection.  Ensuring a patent airway is the first priority in the primary survey. This is essential because efforts to restore cardio-vascular integrity will be futile unless the oxygen content of the blood is adequate. Simultaneously, all patients with blunt trauma require cervical spine immobilization until injury is excluded. This is typically accomplished by applying a hard cervical collar or placing sandbags on both sides of the head with the patient’s forehead taped across the bags. Soft collars do not effectively immobilize the cervical spine. For penetrating neck wounds, however, cervical collars are not recommended because they provide no benefit and may interfere with assess-ment and treatment.7,82Introduction 183Initial Evaluation and  Resuscitation of the  Injured Patient 183Primary Survey / 183Secondary Survey / 195Mechanisms and Patterns of Injury / 195Regional Assessment and Special Diagnostic Tests / 196General Principles of Management 205Transfusion Practices / 206Prophylactic Measures / 208Operative Approaches and Exposure / 209Damage Control Surgery / 215Treatment of Specific Injuries 217Head Injuries / 217Cervical Injuries / 219Chest Injuries / 222Abdominal Injuries / 225Pelvic Fracture Hemorrhage Control / 234Extremity Vascular Injuries, Fractures, and Compartment Syndromes / 235Surgical Intensive Care  Management 237Postinjury Resuscitation / 237Abdominal Compartment Syndrome / 238Special Populations 240Pregnant Patients / 240Geriatric Patients / 243Pediatric Patients / 244Brunicardi_Ch07_p0183-p0250.indd 18310/12/18 6:16 PM 184Table 7-1Immediately life-threatening injuries to be identified during the primary surveyAirwayAirway obstructionAirway injuryBreathingTension pneumothoraxOpen pneumothoraxMassive air leak from tracheobronchial injuryFlail chest with underlying pulmonary contusionCirculationHemorrhagic shockMassive hemothoraxMassive hemoperitoneumMechanically unstable pelvis fracture with bleedingExtremity blood lossCardiogenic shockCardiac tamponadeNeurogenic shockDisabilityIntracranial hemorrhageCervical spine injuryPatients who are conscious, without tachypnea, and have a normal voice are unlikely to require early airway intervention. Exceptions are penetrating injuries to the neck with an expanding hematoma; evidence of chemical or thermal injury to the mouth, nares, or hypopharynx; extensive subcutaneous air in the neck; complex maxillofacial trauma; or airway bleeding. Although these patients may initially have an adequate airway, it may become compromised if soft tissue swelling, hematoma forma-tion, or edema progresses. In these cases, preemptive intubation should be performed before airway access becomes challenging.Patients who have an abnormal voice, abnormal breathing sounds, tachypnea, or altered mental status require further air-way evaluation. Blood, vomit, the tongue, teeth, foreign objects, and soft tissue swelling can cause airway obstruction; suction-ing affords immediate relief in many patients. In the comatose patient, the tongue may fall backward and obstruct the hypo-pharynx; this can be relieved by either a chin lift or jaw thrust. An oral airway or a nasal trumpet is also helpful in maintaining airway patency, although the former is usually not tolerated by an awake patient. Establishing a definitive airway (i.e., endotra-cheal intubation) is indicated in patients with apnea; inability to protect the airway due to altered mental status; impending airway compromise due to inhalation injury, hematoma, facial bleeding, soft tissue swelling, or aspiration; and inability to maintain oxygenation. Altered mental status is the most com-mon indication for intubation. Agitation or obtundation, often attributed to intoxication or drug use, may actually be due to hypoxia. But the timing of endotracheal intubation may be criti-cal in the hypovolemic patient because positive airway pres-sure may further compromise cardiac function and precipitate cardiac arrest; thus, Circulation may take priority over Airway.Options for endotracheal intubation include nasotracheal, orotracheal, or operative routes. Nasotracheal intubation can be accomplished only in patients who are breathing spontaneously. Although nasotracheal intubation is frequently used by prehospital providers, the technique is limited in the ED to those patients requiring emergent airway support in whom chemical paralysis Key Points1 Trauma is the most common cause of death for all indi-viduals between the ages of 1 and 44 years and is the third most common cause of death regardless of age.2 The initial management of seriously injured patients usu-ally follows the primary survey (the “ABCs”—Airway with cervical spine protection, Breathing, and Circulation), although at times restoring Circulatory volume may pro-ceed active Airway intervention; the goals of the primary survey are to identify and treat conditions that constitute an immediate threat to life.3 All patients with blunt injury should be assumed to have unstable cervical spine injuries until proven otherwise; one must maintain cervical spine precautions and in-line stabilization.4 Patients with ongoing hemodynamic instability, whether “nonresponders” or “transient responders,” require prompt intervention; one must consider the dominant causes of acute shock, i.e., hemorrhagic, cardiogenic, and neuro-genic shock.5 Patients with trauma-induced coagulopathy (TIC) are at risk for massive transfusion and need to be identified early.6 Indications for immediate operative intervention for pene-trating cervical injury include hemodynamic instability and significant external arterial hemorrhage; the management algorithm for hemodynamically stable patients is based on the presenting symptoms and anatomic location of injury, with the neck being divided into three distinct zones.7 The gold standard for determining if there is a blunt descending aortic injury is computed tomography angiog-raphy (CTA) scanning; indications are primarily based on injury mechanism.8 The abdomen is a diagnostic black box. Physical examina-tion and FAST ultrasound can identify patients requiring emergent laparotomy. Computed tomography (CT) scan-ning is the mainstay of evaluation in the remaining patients to more precisely identify the site and magnitude of injury.9 Manifestation of the “bloody vicious cycle” (the lethal combination of coagulopathy, hypothermia, and metabolic acidosis) is the most common indication for damage con-trol surgery. The primary objectives of damage control laparotomy are to control bleeding and limit gastrointesti-nal spillage.10 Blunt injuries to the carotid and vertebral arteries are usu-ally managed with systemic antithrombotic therapy.11 The abdominal compartment syndrome may be primary (i.e., due to the injury of abdominal organs, bleeding, and packing) or secondary (i.e., due to reperfusion visceral edema, retroperitoneal edema, and ascites).Brunicardi_Ch07_p0183-p0250.indd 18410/12/18 6:16 PM 185TRAUMACHAPTER 7AFigure 7-1. Cricothyroidotomy is recommended for emergent surgical establishment of a patent airway. A vertical skin incision avoids injury to the anterior jugular veins, which are located just lateral to the midline. Hemorrhage from these vessels obscures vision and prolongs the procedure. When a transverse incision is made in the cricothyroid membrane, the blade of the knife should be angled inferiorly to avoid injury to the vocal cords. A. Use of a tracheostomy hook stabilizes the thyroid cartilage and facilitates tube insertion. B. A 6.0 endotracheal tube is inserted after digital confirmation of airway access.Figure 7-2. A “clothesline” injury can partially or completely tran-sect the anterior neck structures, including the trachea. With com-plete tracheal transection, the endotracheal tube is placed directly into the distal aperture, with care taken not to push the trachea into the mediastinum.incision, with sharp division of the subcutaneous tissues. Visu-alization may be improved by having an assistant retract lat-erally on the neck incision using retractors. The cricothyroid membrane is verified by digital palpation and opened in a hori-zontal direction. The airway may be stabilized before incision of the membrane using a tracheostomy hook; the hook should be placed under the thyroid cartilage to elevate the airway. A 6.0 endotracheal tube (maximum diameter in adults) is then advanced through the cricothyroid opening and sutured into place. In patients under the age of 11, cricothyroidotomy is rela-tively contraindicated due to the risk of subglottic stenosis, and tracheostomy should be performed.Emergent tracheostomy is indicated in patients with laryn-gotracheal separation or laryngeal fractures, in whom cricothy-roidotomy may cause further damage or result in complete loss of the airway. This procedure is best performed in the operating room (OR) where there is optimal lighting and availability of advanced equipment (e.g., sternal saw). In these cases, often after a “clothesline” injury, direct visualization and instrumenta-tion of the trachea usually is done through the traumatic anterior neck defect or after a generous collar skin incision (Fig. 7-2). If the trachea is completely transected, a nonpenetrating clamp should be placed on the distal aspect to prevent tracheal retrac-tion into the mediastinum; this is particularly important before placement of the endotracheal tube.Breathing and Ventilation. Once a secure airway is obtained, adequate oxygenation and ventilation must be ensured. All injured patients should receive supplemental oxygen and be monitored by pulse oximetry. The following conditions con-stitute an immediate threat to life due to inadequate ventilation and should be recognized during the primary survey: tension pneumothorax, open pneumothorax, flail chest with underlying pulmonary contusion, massive hemothorax, and major air leak due to a tracheobronchial injury.Tension pneumothorax is presumed in any patient mani-festing respiratory distress and hypotension in combination with any of the following physical signs: tracheal deviation away from the affected side, lack of or decreased breath sounds on cannot be used. Orotracheal intubation is the preferred technique to establish a definitive airway. Because all patients are presumed to have cervical spine injuries, manual in-line cervical immobilization is essential.6 Correct endotracheal placement is verified with direct laryngoscopy, capnography, audible bilateral breath sounds, and finally a chest film. The GlideScope®, a video laryngoscope that uses fiberoptics to visualize the vocal cords, is being employed more frequently.9 Advantages of orotracheal intubation include the direct visualization of the vocal cords, ability to use larger-diameter endotracheal tubes, and applicability to apneic patients. The disadvantage of orotracheal intubation is that conscious patients usually require neuromuscular blockade, which may result in the inability to intubate, aspiration, or medication complications. Those who attempt rapid-sequence induction must be thoroughly familiar with the procedure (see Chapter 13).Patients in whom attempts at intubation have failed or who are precluded from intubation due to extensive facial inju-ries require operative establishment of an airway. Cricothy-roidotomy (Fig. 7-1) is performed through a generous vertical 3Brunicardi_Ch07_p0183-p0250.indd 18510/12/18 6:16 PM 186BASIC CONSIDERATIONSPART Ithe affected side, and subcutaneous emphysema on the affected side. Patients may have distended neck veins due to impedance of venous return, but the neck veins may be flat due to concur-rent systemic hypovolemia. Tension pneumothorax and simple pneumothorax have similar signs, symptoms, and examination findings, but hypotension qualifies the pneumothorax as a ten-sion pneumothorax. Although immediate needle thoracostomy decompression with a 14-gauge angiocatheter may be indicated in the field, tube thoracostomy in the midaxillary line should be performed immediately in the ED before a chest radiograph is obtained (Fig. 7-3). Recent studies suggest that preferred loca-tion for needle decompression may be the fifth intercostal space in the anterior axillary line due to body habitus.10 In cases of tension pneumothorax, the parenchymal tear in the lung acts as a one-way valve, with each inhalation allowing additional air to accumulate in the pleural space. The normally negative intra-pleural pressure becomes positive, which depresses the ipsilat-eral hemidiaphragm and shifts the mediastinal structures into the contralateral chest. Subsequently, the contralateral lung is compressed and the heart rotates about the superior and inferior vena cava; this decreases venous return and ultimately cardiac output, which culminates in cardiovascular collapse.An open pneumothorax or “sucking chest wound” occurs with full-thickness loss of the chest wall, permitting free com-munication between the pleural space and the atmosphere (Fig. 7-4). This compromises ventilation due to equilibration of atmospheric and pleural pressures, which prevents lung inflation Figure 7-3. A. Tube thoracostomy is performed in the midaxillary line at the fourth or fifth intercostal space (inframammary crease) to avoid iatrogenic injury to the liver or spleen. B. Heavy scissors are used to cut through the intercostal muscle into the pleural space. This is done on top of the rib to avoid injury to the intercostal bun-dle located just beneath the rib. C. The incision is digitally explored to confirm intrathoracic location and identify pleural adhesions. D. A 28Fr chest tube is directed superiorly and posteriorly with the aid of a large clamp.Figure 7-4. A. Full-thickness loss of the chest wall results in an open pneumothorax. B. The defect is temporarily managed with an occlusive dressing that is taped on three sides, which allows accumulated air to escape from the pleural space and thus prevents a tension pneumothorax. Repair of the chest wall defect and tube thoracostomy remote from the wound is definitive treatment.and alveolar ventilation, and results in hypoxia and hypercar-bia. Complete occlusion of the chest wall defect without a tube thoracostomy may convert an open pneumothorax to a tension pneumothorax. Temporary management of this injury includes covering the wound with an occlusive dressing that is taped on three sides. This acts as a flutter valve, permitting effective ven-tilation on inspiration while allowing accumulated air to escape from the pleural space on the untapped side, so that a tension pneumothorax is prevented. Definitive treatment is closure of the chest wall defect and tube thoracostomy remote from the wound.Flail chest occurs when three or more contiguous ribs are fractured in at least two locations. Paradoxical movement of this free-floating segment of chest wall is usually evident in patients with spontaneous ventilation, due to the negative intra-pleural pressure of inspiration. The additional work of breathing and chest wall pain caused by the flail segment is rarely suf-ficient to compromise ventilation. Instead, it is the decreased compliance and increased shunt fraction caused by the associ-ated pulmonary contusion that is the source of acute respiratory failure. Pulmonary contusions often progress during the first 12 hours. Resultant hypoventilation and hypoxemia may require intubation and mechanical ventilation. The patient’s initial chest Brunicardi_Ch07_p0183-p0250.indd 18610/12/18 6:17 PM 187TRAUMACHAPTER 7radiograph often underestimates the extent of the pulmonary parenchymal damage (Fig. 7-5); close monitoring and frequent clinical reevaluation are warranted.Major air leak occurs from tracheobronchial injuries. Type I injuries are those occurring within 2 cm of the carina.11,12 These may not be associated with a pneumothorax due to the envelopment in the mediastinal pleura. Type II injuries are more distal injuries within the tracheobronchial tree and hence mani-fest with a pneumothorax. Bronchoscopy confirms the extent of the injury and its location, and directs management.Circulation With Hemorrhage Control. With a secure airway and adequate ventilation established, circulatory status is the next focus. An initial approximation of the patient’s cardiovascular status can be obtained by palpating peripheral pulses. In gen-eral, systolic blood pressure (SBP) must be 60 mmHg for the carotid pulse to be palpable, 70 mmHg for the femoral pulse, and 80 mmHg for the radial pulse. Any episode of hypotension (defined as a SBP <90 mmHg) is assumed to be caused by hem-orrhage until proven otherwise. Patients with rapid massive blood loss may have paradoxical bradycardia.13 Blood pressure and pulse should be measured at least every 5 minutes in patients with significant blood loss until normal vital sign values are restored.Intravenous (IV) access for fluid resuscitation and medi-cation administration is obtained with two peripheral catheters, 16-gauge or larger in adults. For patients in whom peripheral angiocatheter access is difficult, intraosseous (IO) needles Figure 7-5. A. Admission chest film may not show the full extent of the patient’s pulmonary parenchymal injury. B. This patient’s left pulmonary contusion blossomed 12 hours later, and its associ-ated opacity is noted on repeat chest radiograph.should be rapidly placed in the proximal humerus or tibia (Fig. 7-6).14,15 All medications administered IV may be admin-istered in a similar dosage intraosseously. Although safe for emergent use, the needle should be removed once alternative access is established to prevent potential osteomyelitis. Blood should be drawn simultaneously for a bedside hemoglobin level and routine trauma laboratory tests. In the seriously injured patient arriving in shock, an arterial blood gas for base deficit (BD), cross-matching for possible blood component (RBC and plasma) transfusion, and a coagulation panel/viscoelastic hemo-statis assay (e.g., TEG, ROTEM) should be obtained. In these patients, secondary large bore (7 to 9 Fr) cannulae should be obtained via the femoral or subclavian veins; Cordis introducer catheters are preferred over triple-lumen catheters. In general, initial access in trauma patients is best secured in the groin so that placement of the catheter will not interfere with the perfor-mance of other diagnostic and therapeutic thoracic procedures. A rule of thumb to consider for secondary access is placement of femoral access for thoracic trauma and jugular or subclavian access for abdominal trauma. Internal jugular or subclavian catheters provide a more reliable measurement of central venous pressure (CVP), which may be helpful in determining the vol-ume status of the patient and in excluding cardiac tamponade. Saphenous vein cutdowns at the ankle can also provide excel-lent access (Fig. 7-7). The saphenous vein is reliably found 1 cm anterior and 1 cm superior to the medial malleolus. Stan-dard 14-gauge catheters can be quickly placed, even in an exsanguinating patient with collapsed veins. In severely injured children younger than 6 years of age, the preferred venous access is peripheral intravenous catheters followed by an IO needle. Central venous catheter placement or saphenous vein cutdown may be considered as the third choice of access based upon provider experience. Inadvertent femoral artery cannula-tion, however, may result in limb-threatening arterial spasm.External control of any visible hemorrhage should be achieved promptly while circulating volume is restored. For Figure 7-6. Intraosseous infusions are indicated for patients in whom one or two attempts at IV access have failed. A. The proxi-mal tibia or humerus is the preferred location. Alternatively, the distal femur can be used if the tibia is fractured. B. The position is satisfactory if bone marrow can be aspirated and saline can be eas-ily infused without evidence of extravasation.Brunicardi_Ch07_p0183-p0250.indd 18710/12/18 6:17 PM 188BASIC CONSIDERATIONSPART Iopen wounds with ongoing bleeding, manual compression should be done with a single 4 × 4 gauze and a gloved hand. Covering the wound with excessive dressings may permit ongoing unrecognized blood loss that is hidden underneath the dressing. Blind clamping of bleeding vessels should be avoided because of the risk to adjacent structures, including nerves. This is particularly true for penetrating injuries of the neck, thoracic outlet, and groin, where bleeding may be torrential and aris-ing deep within the wound. In these situations, a gloved finger placed through the wound directly onto the bleeding vessel can apply enough pressure to control active bleeding. The surgeon performing this maneuver must then walk with the patient to the OR for definitive treatment. For bleeding of the extremi-ties, it is tempting to apply tourniquets for hemorrhage control, Figure 7-7. Saphenous vein cutdowns are excellent sites for fluid resuscitation access. A. The vein is consistently found 1 cm ante-rior and 1 cm superior to the medial malleolus. B. Proximal and distal traction sutures are placed with the distal suture ligated. C. A 14-gauge IV catheter is introduced and secured with sutures and tape to prevent dislodgment.Figure 7-8. More than 1500 mL of blood in the pleural space is considered a massive hemothorax. Chest film findings reflect the positioning of the patient. A. In the supine position, blood tracks along the entire posterior section of the chest and is most notable pushing the lung away from the chest wall. B. In the upright position, blood is visible dependently in the right pleural space.but digital occlusion will usually control the bleeding; complete vascular occlusion with a tourniquet risks permanent neuromus-cular impairment. Patients in shock have a lower tolerance to warm ischemia, and an occluded extremity is prone to small vessel thrombosis. For patients with open fractures, fracture reduction with stabilization via splints will limit bleeding both externally and into the subcutaneous tissues. Scalp lacerations through the galea aponeurotica tend to bleed profusely; these can be temporarily controlled with skin staples, Raney clips, or a full-thickness continuous running nylon stitch.During the circulation section of the primary survey, four life-threatening injuries must be identified promptly: (a) mas-sive hemothorax, (b) cardiac tamponade, (c) massive hemo-peritoneum, and (d) mechanically unstable pelvic fractures with bleeding. Massive hemoperitoneum and mechanically unstable pelvic fractures are discussed in “Emergent Abdomi-nal Exploration” and “Pelvic Fractures and Emergent Hemor-rhage Control,” respectively. Critical tools used to differentiate these in the multisystem trauma patient are the chest and pelvis radiographs, and extended focused abdominal sonography for trauma (eFAST) (see “Regional Assessment and Special Diag-nostic Tests”). A massive hemothorax (life-threatening injury number one) is defined as >1500 mL of blood or, in the pediatric population, >25% of the patient’s blood volume in the pleural space (Fig. 7-8). Although it may be estimated on chest radio-graph, tube thoracostomy is the only reliable means to quantify the amount of hemothorax. After blunt trauma, a hemothorax is usually due to multiple rib fractures with severed intercostal vessels, but occasionally bleeding is from lacerated lung paren-chyma, which is usually associated with an air leak. After pen-etrating trauma, a great vessel or pulmonary hilar vessel injury should be presumed. In either scenario, a massive hemothorax is an indication for operative intervention, but tube thoracostomy is critical to facilitate lung reexpansion, which may improve oxygenation and cardiac performance as well as tamponade venous bleeding. In patients arriving in shock with a high risk of pelvic fracture (e.g., autopedestrian accident), the pelvis should be presumptively stabilized with a sheet or binder.Brunicardi_Ch07_p0183-p0250.indd 18810/12/18 6:17 PM 189TRAUMACHAPTER 7Cardiac tamponade occurs most commonly after penetrat-ing thoracic wounds, although occasionally blunt rupture of the heart, particularly the atrial appendage, is seen. Acutely, <100 mL of pericardial blood may cause pericardial tamponade.16 The classic Beck’s triad—dilated neck veins, muffled heart tones, and a decline in arterial pressure—is usually not appreciated in the trauma bay because of the noisy environment and associ-ated hypovolemia. Because the pericardium is not acutely dis-tensible, the pressure in the pericardial sac will rise to match that of the injured chamber. When this pressure exceeds that of the right atrium, right atrial filling is impaired and right ventricular preload is reduced. This ultimately leads to decreased right ven-tricular output. Additionally, increased intrapericardial pressure impedes myocardial blood flow, which leads to subendocardial ischemia and a further reduction in cardiac output.Diagnosis of hemopericardium is best achieved by ultra-sound of the pericardium (Fig. 7-9). Early in the course of tamponade, blood pressure and cardiac output will transiently improve with fluid administration due to increased central venous pressure. In patients with any hemodynamic distur-bance, a pericardial drain can be placed using ultrasound guid-ance (Fig. 7-10). Removing as little as 15 to 20 mL of blood will Figure 7-9. Subxiphoid pericardial ultrasound reveals a large peri-cardial fluid collection. LV = left ventricle; RV = right ventricle.Figure 7-10. Pericardiocentesis is indicated for patients with evidence of pericardial tamponade. A. Access to the pericardium is obtained through a subxiphoid approach, with the needle angled 45° up from the chest wall and toward the left shoulder. B. Seldinger technique is used to place a pigtail catheter. Blood can be repeatedly aspirated with a syringe, or the tubing may be attached to a gravity drain. Evacuation of unclotted pericardial blood prevents subendocardial ischemia and stabilizes the patient for transport to the operating room for sternotomy.often temporarily stabilize the patient’s hemodynamic status and alleviate the subendocardial ischemia that can be associ-ated with lethal arrhythmias; this allows safe transport to the OR for sternotomy. Pericardiocentesis is successful in decompress-ing tamponade in approximately 80% of cases17; the majority of failures are due to the presence of clotted blood within the pericardium. Patients with a persistent SBP <60 mmHg warrant resuscitative thoracotomy (RT) with opening of the pericardium for rapid decompression and control of bleeding.The utility of RT has been debated for decades. Current indi-cations are based on 40 years of prospective data (Table 7-2).18-20 RT is associated with the highest survival rate after isolated cardiac injury; 35% of patients presenting in shock and 20% without vital signs (i.e., no pulse or obtainable blood pressure) are salvaged after Table 7-2Current indications and contraindications for emergency department thoracotomyIndicationsSalvageable postinjury cardiac arrest:Patients sustaining witnessed penetrating trauma to the torso with <15 min of prehospital CPRPatients sustaining witnessed blunt trauma with <10 min of prehospital CPRPatients sustaining witnessed penetrating trauma to the neck or extremities with <5 min of prehospital CPRPersistent severe postinjury hypotension (SBP ≤60 mmHg) due to:Cardiac tamponadeHemorrhage—intrathoracic, intra-abdominal, extremity, cervicalAir embolismContraindicationsPenetrating trauma: CPR >15 min and no signs of life (pupillary response, respiratory effort, motor activity)Blunt trauma: CPR >10 min and no signs of life or asystole without associated tamponadeCPR = cardiopulmonary resuscitation; SBP = systolic blood pressure.Brunicardi_Ch07_p0183-p0250.indd 18910/12/18 6:17 PM 190BASIC CONSIDERATIONSPART Iisolated penetrating injury to the heart. For all penetrating wounds, survival rate is 15%. Conversely, patient outcome is limited when RT is done for blunt trauma, with 2% survival among patients in shock and <1% survival among those with no vital signs. Thus, patients undergoing cardiopulmonary resuscitation (CPR) upon arrival to the ED should undergo RT selectively based on injury and duration of CPR (Fig. 7-11). RT is best accomplished using a generous left anterolateral thoracotomy, with the skin incision started to the right of the sternum (Fig. 7-12). A longitudinal peri-cardiotomy anterior to the phrenic nerve is used to release cardiac tamponade and permits access to the heart for cardiac repair and open cardiac massage. The cardiac wound should be repaired prior to vigorous efforts of myocardial resuscitation (e.g., epinephrine, calcium). Cross-clamping of the aorta improves central circula-tion, augments cerebral and coronary blood flow, and limits further abdominal blood loss (Fig. 7-13). The patient must sustain a SBP of 70 mmHg after RT and associated interventions to be considered resuscitable, and hence transported to the OR.18,19Disability and Exposure. The Glasgow Coma Scale (GCS) score should be determined for all injured patients (Table 7-3). It is calculated by adding the scores of the best motor response, best verbal response, and the best eye response. Scores range from 3 (the lowest) to 15 (normal). Scores of 13 to 15 indicate mild head injury, 9 to 12 moderate injury, and ≤8 severe injury. The GCS is a quantifiable determination of neurologic function that is useful for triage, treatment, and prognosis.Neurologic evaluation, including spinal cord integrity, is critical before administration of neuromuscular blockade for intubation. Subtle changes in mental status can be caused by hypoxia, hypercarbia, or hypovolemia, or may be an early sign of increasing intracranial pressure. An abnormal mental status should prompt an immediate reevaluation of the patient’s ABCs and consideration of central nervous system injury. Deterioration in mental status may be subtle and may not progress in a predict-able fashion. For example, previously calm, cooperative patients may become anxious and combative as they become hypoxic. However, a patient who is agitated and combative from drugs or alcohol may become somnolent if hypovolemic shock develops. Patients with neurogenic shock are typified by hypotension with relative bradycardia, and are often first recognized due to paraly-sis, decreased rectal tone, or priapism. Patients with high spinal cord disruption are at greatest risk for neurogenic shock due to physiologic disruption of sympathetic fibers; treatment consists of volume loading and a dopamine infusion, which is both inotropic and chronotropic, as well as a vasoconstrictor.Seriously injured patients must have all of their clothing removed to avoid overlooking limbor life-threatening injuries, but warmed blankets should be placed immediately to avoid hypothermia.Shock Classification and Initial Fluid Resuscitation.  Classic signs and symptoms of shock are tachycardia, hypoten-sion, tachypnea, altered mental status, diaphoresis, and pallor PatientUndergoingCPR–No Signs ofLife*Blunt TraumaCPR <10 min----------Penetrating Torso TraumaCPR <15 min----------Penetrating Non-Torso TraumaCPR <5 minResuscitative ThoracotomyYesDeadCardiacActivity?NoTamponade?NoRepair HeartAssessViabilityYesORThoracicHemorrhageAir EmboliTamponadeExtrathoracicHemorrhageSBP <70,apply aorticX-clampHilar X-clampControlNoYes*no respiratory ormotor effort, electricalactivity, or pupillaryactivityProfoundRefractoryShockFigure 7-11. Algorithm directing the use of resuscitative thoracotomy (RT) in the injured patient undergoing cardiopulmonary resuscitation (CPR). OR = operating room; SBP = systolic blood pressure.Brunicardi_Ch07_p0183-p0250.indd 19010/12/18 6:17 PM 191TRAUMACHAPTER 7Figure 7-12. A. Resuscitative tho-racotomy (RT) is performed through the fifth intercostal space using the anterolateral approach. B and C. The pericardium is opened anterior to the phrenic nerve, and the heart is rotated out for evaluation. D. Open cardiac massage should be performed with a hinged, clapping motion of the hands, with sequential closing from palms to fingers. The two-handed technique is strongly recommended because the one-handed massage technique poses the risk of myocar-dial perforation with the thumb.Figure 7-13. A. Aortic cross-clamp is applied with the left lung retracted superiorly, below the inferior pulmonary ligament, just above the diaphragm. B. The flaccid aorta is identified as the first structure encountered on top of the spine when approached from the left chest.(Table 7-4). In general, the quantity of acute blood loss cor-relates with physiologic abnormalities. For example, patients in class II shock are tachycardic, but they do not exhibit a reduction in blood pressure until over 1500 mL of blood loss, or class III shock. Physical findings should be used as an aid in the evaluation of the patient’s response to treatment. The goal of fluid resuscitation is to re-establish tissue perfusion. Fluid resuscitation usually begins with isotonic crystalloid, typically Ringer’s lactate. However, for patients arriving in shock (persistent SBP <90 mmHg in an adult), instead of crystalloid the current practice is to activate a massive trans-fusion protocol (MTP) in which red blood cells (RBC) and fresh frozen plasma (FFP) are administered. The details of a MTP are discussed later. Patients who have a good response to Brunicardi_Ch07_p0183-p0250.indd 19110/12/18 6:17 PM 192BASIC CONSIDERATIONSPART Ifluid infusion (i.e., normalization of vital signs, clearing of the sensorium) and evidence of good peripheral perfusion (warm extremities with normal capillary refill) are presumed to have adequate overall perfusion. Urine output is a reliable indicator of organ perfusion but requires time to quantitate. Adequate urine output is 0.5 mL/kg per hour in an adult, 1 mL/kg per hour in a child, and 2 mL/kg per hour in an infant <1 year of age. Because measurement of this resuscitation-related vari-able is time dependent, it is generally more useful in the OR and intensive care unit (ICU) setting, than in initial evaluation in the trauma bay.There are several caveats to be considered when evaluat-ing the injured patient for shock. Tachycardia (HR >110 bpm) is often the earliest sign of ongoing blood loss, but the critical issue is change in HR over time. Individuals in good physical condition with a resting pulse rate in the 50s may manifest a relative tachycardia in the 90s; although clinically significant, this does not meet the standard definition of tachycardia. Con-versely, patients on cardiac medications such as β-blockers may not be capable of increasing their heart rate to compensate for hypovolemia. Bradycardia can occur with rapid severe blood loss13; this is an ominous sign, often heralding impending car-diovascular collapse. Other physiologic stresses, aside from hypovolemia, may produce tachycardia, such as hypoxia, pain, anxiety, and stimulant drugs (cocaine, amphetamines). As noted previously, decreased SBP is not a reliable early sign of hypo-volemia because blood loss must exceed 30% before hypoten-sion is evident. Additionally, younger patients may maintain their SBP due to sympathetic tone despite severe intravascular deficits until they are on the verge of cardiac arrest. Pregnant Table 7-3Glasgow Coma ScaleaADULTSINFANTS/CHILDRENEye opening4SpontaneousSpontaneous3To voiceTo voice2To painTo pain1NoneNoneVerbal5OrientedAlert, normal vocalization4ConfusedCries, but consolable3Inappropriate wordsPersistently irritable2Incomprehensible wordsRestless, agitated, moaning1NoneNoneMotor response6Obeys commandsSpontaneous, purposeful5Localizes painLocalizes pain4WithdrawsWithdraws3Abnormal flexionAbnormal flexion2Abnormal extensionAbnormal extension1NoneNoneaScore is calculated by adding the scores of the best motor response, best verbal response, and eye opening. Scores range from 3 (the lowest) to 15 (normal).Table 7-4Signs and symptoms of advancing stages of hemorrhagic shockCLASS ICLASS IICLASS IIICLASS IVBlood loss (mL)Up to 750750–15001500–2000>2000Blood loss (% BV)Up to 15%15%–30%30%–40%>40%Pulse rate<100>100>120>140Blood pressureNormalNormalDecreasedDecreasedPulse pressure (mmHg)Normal or increasedDecreasedDecreasedDecreasedRespiratory rate14–20>20–3030–40>35Urine output (mL/h)>30>20–305–15NegligibleCNS/mental statusSlightly anxiousMildly anxiousAnxious and confusedConfused and lethargicBV = blood volume; CNS = central nervous system.Brunicardi_Ch07_p0183-p0250.indd 19210/12/18 6:17 PM 193TRAUMACHAPTER 7patients have a progressive increase in circulating blood volume over gestation; therefore, they must lose a relatively larger vol-ume of blood before manifesting signs and symptoms of hypo-volemia (see “Special Populations”).Based on the initial response to fluid resuscitation, hypo-volemic injured patients can be separated into three broad cat-egories: responders, transient responders, and nonresponders. Individuals who are stable or have a good response to initial fluid therapy as evidenced by normalization of vital signs, men-tal status, and urine output are unlikely to have significant ongo-ing hemorrhage, and further diagnostic evaluation for occult injuries can proceed in an orderly fashion (see “Secondary Sur-vey”). At the other end of the spectrum are patients classified as “nonresponders” who have persistent hypotension despite aggressive resuscitation. These patients mandate immediate identification of the source of hypotension with appropriate intervention to prevent a fatal outcome. Transient responders are those who respond initially to volume loading with improve-ment in vital signs, but subsequently deteriorate hemodynami-cally. This group of patients can be challenging to triage for definitive management.Persistent Hypotension. Patients with ongoing hemodynamic instability, whether “nonresponders” or “transient responders,” require systematic evaluation and prompt intervention. The spectrum of disease in patients with persistent hypotension ranges from easily reversible problems such as a tension pneu-mothorax to multisystem injury with a number of sites of ongo-ing active hemorrhage. One must first consider the dominant categories of postinjury shock that may be the underlying cause: hemorrhagic, cardiogenic, and neurogenic. In patients with per-sistent hypotension and tachycardia, cardiogenic or hemorrhagic shock are the likely causes. Ultrasound evaluation of the pericar-dium, pleural cavities, and abdomen in combination with plain radiographs of the chest and pelvis will usually identify the source of shock. In patients with persistent hypotension follow-ing blunt trauma, the pelvis should be wrapped with a sheet for stabilization until radiography can be done; external blood loss should be controlled, and extremity fractures should be splinted to minimize further blood loss. Evaluation of the CVP or ultra-sound of the IVC may further assist in distinguishing between cardiogenic and hypovolemic shock. Base deficit measurement is critical; a base deficit of >8 mmol/L implies ongoing cellular shock.21,22 Serum lactate also is used to monitor the patient’s physiologic response to resuscitation.23 Evolving technology, such as measurement of the critical reserve index, may provide noninvasive monitoring.24The differential diagnosis of cardiogenic shock in the trauma patient is: (a) tension pneumothorax, (b) pericardial tam-ponade, (c) blunt cardiac injury, (d) myocardial infarction, and (e) bronchovenous air embolism. Tension pneumothorax, the most frequent cause of cardiac failure, and pericardial tampon-ade have been discussed earlier. Although as many as one-third of patients sustaining significant blunt chest trauma experience some degree of blunt cardiac injury (BCI), few such injuries result in hemodynamic embarrassment. Patients with electro-cardiographic (ECG) abnormalities or dysrhythmias require continuous ECG monitoring and antidysrhythmic treatment as indicated. Unless myocardial infarction is suspected, there is no role for routine serial measurement of cardiac enzyme levels—they lack specificity and do not predict significant dysrhythmias.25 In patients with no identified injuries who are being considered for discharge from the ED, the combination of a normal EKG and troponin level rules out significant BCI.26 The patient with hemodynamic instability from BCI requires appropriate resuscitation and may benefit from hemodynamic monitoring to optimize preload and guide inotropic support. Echocardiography (ECHO) is performed to exclude valvular or septal injuries; the most common ECHO finding in BCI is right ventricular dyskinesia due to the anterior orientation of the right ventricle. Transthoracic and transesophageal ECHO are now becoming routine in the trauma bay and surgical intensive care unit (SICU).27,28 Rarely, patients with refractory cardio-genic shock may require placement of an intra-aortic balloon pump to enhance coronary perfusion and decrease myocardial work. Acute myocardial infarction may be the cause of a motor vehicle collision or other trauma in older patients. Although optimal initial management includes treatment for the evolving infarction, such as thrombolytic therapy, anticoagulation, and emergent angioplasty, these decisions must be individualized in accordance with the patient’s other injuries.Bronchovenous air embolism is a frequently overlooked lethal complication of pulmonary injury. Air emboli can occur after blunt or penetrating trauma, when air from an injured bron-chus enters an adjacent injured pulmonary vein and returns air to the left heart. Air accumulation in the left ventricle impedes diastolic filling, and during systole air is pumped into the coro-nary arteries, disrupting coronary perfusion. The typical case is a patient with a penetrating thoracic injury who is hemody-namically stable but experiences sudden cardiac arrest after being intubated and placed on positive pressure ventilation. The patient should be placed immediately in Trendelenburg’s posi-tion to trap the air in the apex of the left ventricle. Emergency thoracotomy is followed by cross-clamping of the pulmonary hilum on the side of the injury to prevent further introduction of air (Fig. 7-14). Air is aspirated from the apex of the left ventricle and then the aortic root with an 18-gauge needle and 50-mL syringe. Vigorous massage is used to force the air bubbles through the coronary arteries; if this is unsuccessful, a tuber-culin syringe is used to aspirate air bubbles from the coronary artery (most common is the right). Once circulation is restored, the patient should be kept in Trendelenburg’s position with the pulmonary hilum clamped until the pulmonary venous injury is controlled operatively.Persistent hypotension due to uncontrolled hemorrhage is associated with high mortality. A rapid search for the source or sources of hemorrhage includes visual inspection with knowledge of the injury mechanism, eFAST, and chest and pelvic radiographs. During diagnostic evaluation, type O RBCs (O-negative for women of childbearing age) and thawed AB plasma should be administered at a ratio of 2:1. Type-specific RBCs should be administered as soon as available. The acute coagulopathy of trauma is now well recognized and underscores the importance of preemptive blood component administration.29 The resurgent interest in viscoelastic hemostatic assays (throm-belastography [TEG] and thrombelastometry [ROTEM]) has facilitated the appropriate and timely use of clotting adjuncts, including the prompt recognition of fibrinolysis.30 In patients with clear indications for operation, essential radiographs should be taken, and the patient should be transported to the OR imme-diately. Such patients include those with blunt trauma and mas-sive hemothorax, those with penetrating trauma and an initial chest tube output of >1 L, and those with abdominal trauma and ultrasound evidence of extensive hemoperitoneum. In patients with gunshot wounds to the chest or abdomen, a chest and 4Brunicardi_Ch07_p0183-p0250.indd 19310/12/18 6:17 PM 194BASIC CONSIDERATIONSPART Iabdominal film, with radiopaque markers at the wound sites, should be obtained to determine the trajectory of the bullet or location of a retained fragment prior to transport to the OR. For example, a patient with a gunshot wound to the upper abdo-men should have a chest radiograph to ensure that the bullet did not traverse the diaphragm causing intrathoracic injury. Simi-larly, a chest radiograph is important in a patient with a gunshot wound to the right chest to evaluate the left hemithorax. If a patient arrives with a penetrating weapon remaining in place, the weapon should not be removed in the ED because it could be tamponading a lacerated blood vessel (Fig. 7-15). The sur-geon should extract the offending instrument in the controlled environment of the OR, ideally once an incision has been made with adequate exposure for vascular control. In situations where knives are embedded in the head or neck, preoperative imaging may be useful to anticipate arterial injuries.In patients with persistent hypotension and no clear operative indications, one should systematically evaluate the five potential sources of blood loss: scalp, chest, abdomen, pelvis, and extremities. Significant bleeding at the scene may be reported by paramedics, but its quantification is unreliable. Examination should exclude active bleeding from a scalp lac-eration that may be readily controlled with clips or staples. Thoracoabdominal trauma should be evaluated with a combi-nation of eFAST, chest radiograph, and pelvic radiograph. If the FAST results are negative and no other source of hypo-tension is obvious, diagnostic peritoneal aspiration should be entertained.31 Extremity examination and radiographs should be used to identify associated fractures. Fracture-related blood loss, when additive, may be a potential source of the patient’s hemodynamic instability. Each rib fracture can produce 100 to 200 mL of blood loss; for tibial fractures, 300 to 500 mL; for Figure 7-14. A. A Satinsky clamp is used to clamp the pulmonary hilum to prevent further bronchovenous air embolism. B. Sequential sites of aspiration include the left ventricle, the aortic root, and the right coronary artery.Figure 7-15. If a weapon is still in place, it should be removed in the operating room because it could be tamponading a lacerated blood vessel.Brunicardi_Ch07_p0183-p0250.indd 19410/12/18 6:17 PM 195TRAUMACHAPTER 7femur fractures, 800 to 1000 mL; and for pelvic fractures >2000 mL. Although no single injury can account for the patient’s hemo-dynamic instability, the sum of the injuries may result in life-threatening blood loss. The diagnostic measures advocated earlier are those that can be easily performed in the trauma bay. Transport of a hypotensive patient out of the ED for CT scan-ning is hazardous; monitoring is compromised, and the envi-ronment is suboptimal for dealing with acute problems. Fast track CT scanning should be used in all patients manifesting evidence of shock. The surgeon must accompany the patient and be prepared to abort the CT scan with diversion to the OR. This dilemma is becoming less common in many trauma centers where CT scanning is available in the ED.The concept of hypotensive resuscitation remains contro-versial, and it is primarily relevant for patients with penetrating vascular injuries. Experimental work suggests that an endog-enous sealing clot of an injured artery may be disrupted at a SBP of >90 mmHg32; thus, many believe that this should be the preoperative blood pressure target for patients with potential noncompressible arterial injuries. On the other hand, optimal management of traumatic brain injury (TBI) includes maintain-ing the SBP >100 mmHg,33 and thus, hypotensive resuscitation is not appropriate for most blunt trauma patients.Secondary SurveyOnce the immediate threats to life have been addressed, a thor-ough history is obtained, and the patient is examined in a sys-tematic fashion. The patient and surrogates should be queried to obtain an AMPLE history (Allergies, Medications, Past illnesses or Pregnancy, Last meal, and Events related to the injury). The physical examination should be literally head to toe, with special attention to the patient’s back, axillae, and perineum, because injuries here are easily overlooked. All seriously injured patients should undergo digital rectal examination to evaluate for sphincter tone, presence of blood, rectal perforation, or a high-riding prostate; this is particularly critical in patients with suspected spinal cord injury, pelvic fracture, or transpelvic gun-shot wounds. Vaginal examination with a speculum should be performed in women with pelvic fractures to exclude an open fracture. Specific injuries, their associated signs and symptoms, diagnostic options, and treatments are discussed in detail later in this chapter.Adjuncts to the physical examination include vital sign and ECG monitoring, nasogastric tube placement, Foley cath-eter placement, radiographs, hemoglobin, base deficit measure-ments, urinalysis, and repeat FAST exam. A nasogastric tube should be inserted in all intubated patients to decrease the risk of gastric aspiration, but it may not be necessary in the awake patient. Nasogastric tube placement in patients with complex mid-facial fractures is contraindicated; rather, a tube should be placed orally if required. Nasogastric tube evaluation of stomach contents for blood may suggest occult gastroduodenal injury, or the errant path of the nasogastric tube on a chest film may indicate a left diaphragm injury. A Foley catheter should be inserted in patients unable to void to decompress the blad-der, obtain a urine specimen, and monitor urine output. Gross hematuria demands evaluation of the genitourinary system for injury. Foley catheter placement may be deferred until urologic evaluation in patients with signs of urethral injury: blood at the meatus, perineal or scrotal hematomas, or a high-riding prostate. Although policies vary at individual institutions, most agree that patients in extremis should undergo one attempt at Foley catheter placement; if the catheter does not pass easily, a supra-pubic cystostomy should be considered.Selective radiography and laboratory tests are done early in the evaluation after the primary survey. For patients with severe blunt trauma, chest and pelvic radiographs should be obtained. Historically, a lateral cervical spine radiograph was also obtained, hence the reference to the big three films, but currently patients preferentially undergo CT scanning of the spine rather than plain film radiography. For patients with truncal gunshot wounds, anteroposterior and at times lateral radiographs of the chest and abdomen are warranted. It is important to mark the entrance and exit sites of penetrating wounds with ECG pads, metallic clips, or staples so that the trajectory of the missile can be estimated. Limited one-shot extremity radiographs may also be appropriate to assist in application of a splint. In critically injured patients, blood samples for a routine trauma panel (type and crossmatch, complete blood count, blood chemistries, coagulation studies, and arterial blood gas analysis) should be sent to the laboratory. For less severely injured patients, only a complete blood count and urinalysis may be required. Because older patients may pres-ent in subclinical shock, even with minor injuries, routine analy-sis of an arterial blood gas in patients over the age of 55 should be considered. Repeat FAST is mandatory if there are any signs of abdominal injury or unexplained blood loss.Many trauma patients cannot provide specific information about the mechanism of their injury. Emergency medical ser-vice personnel and police are trained to evaluate an injury scene and should be questioned while they are present in the ED. For automobile collisions, the speed of the vehicles involved, angle of impact, location of the patient within the vehicle, use of restraints, airbag deployment, condition of the steer-ing wheel and windshield, amount of intrusion, ejection of the patient from the vehicle, and fate of other passengers should be ascertained. For other injury mechanisms, critical information includes such things as height of a fall, surface impact, helmet use, and weight of an object by which the patient was crushed. In patients sustaining gunshot wounds, bullet characteris-tics, distance, and presumed path of the bullet are important, if known. For patients with stab wounds, the length and type of object is helpful. Finally, some patients experience a com-bination of blunt and penetrating trauma. Do not assume that someone who was stabbed was not also assaulted; the patient may have a multitude of injuries and cannot be presumed to have only injuries associated with the more obvious penetrat-ing wound. In short, these details of information are critical to the clinician to determine overall mechanism of injury and anticipate associated injury patterns.Mechanisms and Patterns of InjuryIn general, more energy is transferred over a wider area during blunt trauma than from a penetrating wound. As a result, blunt trauma is associated with multiple widely distributed injuries, whereas in penetrating wounds the damage is localized to the path of the bullet or knife. In blunt trauma, organs that can-not yield to impact by elastic deformation are most likely to be injured, namely, the solid organs (liver, spleen, and kidneys). For penetrating trauma, organs with the largest surface area are most prone to injury (small bowel, liver, and colon). Addition-ally, because bullets and knives usually follow straight lines, adjacent structures are commonly injured.Patients who have sustained blunt trauma separate them into categories according to their risk for multiple injuries: those Brunicardi_Ch07_p0183-p0250.indd 19510/12/18 6:17 PM 196BASIC CONSIDERATIONSPART Isustaining high energy transfer injuries and those sustaining low energy transfer injuries. Injuries involving high energy transfer include auto-pedestrian accidents, motor vehicle collisions in which the car’s change of velocity (ΔV) exceeds 20 mph or in which the patient has been ejected, motorcycle collisions, and falls from heights >20 ft.34 In fact, for motor vehicle collisions the vari-ables strongly associated with life-threatening injuries, and hence reflective of the magnitude of the mechanism, are death of another occupant in the vehicle, extrication time of >20 minutes, ΔV >20 mph, lack of restraint use, and lateral impact.34 Low-energy trauma, such as being struck with a club or falling from a bicycle, usually does not result in widely distributed injuries. However, potentially lethal injuries of internal organs can occur because the net energy transfer to any given location may be substantial.In blunt trauma, particular constellations of injury or injury patterns are associated with specific injury mechanisms. For example, when an unrestrained driver sustains a frontal impact, the head strikes the windshield, the chest and upper abdomen hit the steering column, and the legs or knees contact the dashboard. The resultant injuries can include facial fractures, cervical spine fractures, injury of the descending thoracic aorta, myocardial contusion, injury to the spleen and liver, and fractures of the pel-vis and lower extremities. When such patients are evaluated, the discovery of one of these injuries should prompt a search for the others. Collisions with side impact also carry the risk of cervical spine and thoracic trauma, diaphragm rupture, and crush injuries of the pelvic ring, but solid organ injury usually is limited to either the liver or spleen based on the direction of impact. However, patients ejected from a vehicle or thrown a significant distance from a motorcycle have the risk of any injury pattern.Penetrating injuries are classified according to the wound-ing agent (i.e., stab wound, gunshot wound, or shotgun wound). Gunshot wounds are subdivided further into highand low-velocity injuries because the speed of the bullet is much more important than its weight in determining potential kinetic energy transfer. High-velocity gunshot wounds (bullet speed >2000 ft/s) are infrequent in the civilian setting. Shotgun injuries are divided into close-range (<20 feet) and long-range wounds. Close-range shotgun wounds are tantamount to high-velocity wounds because the entire energy of the load is delivered to a small area, often with devastating results. In contrast, long-range shotgun blasts result in a diffuse pellet pattern in which many pellets miss the victim, and those that do strike are dis-persed and are of comparatively low energy.Regional Assessment and Special Diagnostic TestsBased on mechanism, location of injuries identified on physi-cal examination, screening radiographs, and the patient’s over-all condition, additional diagnostic studies often are indicated. However, the seriously injured patient is in constant jeopardy when undergoing special diagnostic testing; therefore, the sur-geon must be in attendance and must be prepared to alter plans as circumstances demand. Hemodynamic, respiratory, and men-tal status will determine the most appropriate course of action. With these issues in mind, additional diagnostic tests are dis-cussed on an anatomic basis.Head. Evaluation of the head includes examination for injuries to the scalp, eyes, ears, nose, mouth, facial bones, and intracra-nial structures. Palpation of the head is done to identify scalp lacerations, which should be evaluated for depth, and pres-ence of associated depressed or open skull fractures. The eye examination includes not only pupillary size and reactivity, but also examination for visual acuity and for hemorrhage within the globe. Ocular entrapment, caused by orbital fractures with impingement of the ocular muscles, is evident when the patient cannot move his or her eyes through an entire range of motion. It is important to perform the eye examination early because significant orbital swelling may prevent later evaluation. A lat-eral canthotomy may be needed to relieve periorbital pressure. The tympanic membrane is examined to identify hemotym-panum, otorrhea, or rupture, which may signal an underlying head injury. Otorrhea, rhinorrhea, raccoon eyes, and Battle’s sign (ecchymosis behind the ear) suggest a basilar skull fracture. Although such fractures may not require treatment, there is an association with blunt cerebrovascular injuries, cranial nerve injuries, and risk of meningitis.Anterior facial structures should be examined to rule out fractures. This entails palpating for bony step-off of the facial bones and instability of the midface (by grasping the upper pal-ate and seeing if this moves separately from the patient’s head). A good question to ask awake patients is whether their bite feels normal to them; abnormal dental closure suggests malalignment of facial bones and the possibility for a mandible or maxillary fracture. Nasal fractures, which may be evident on direct inspec-tion or palpation, typically bleed vigorously. This may result in the patient having airway compromise due to blood running down the posterior pharynx, or there may be vomiting provoked by swallowed blood. Nasal packing or balloon tamponade may be necessary to control bleeding. Examination of the oral cavity includes inspection for open fractures, loose or fractured teeth, and sublingual hematomas.All patients with a significant closed head injury (GCS score <14) should undergo CT scanning of the head. Addition-ally, elderly patients or those patients on antiplatelet agents or anticoagulation should be imaged despite a GCS of 15.35,36 For penetrating injuries, plain skull films may be helpful in the trauma bay to determine the trajectory of the bullet. The presence of later-alizing findings (e.g., a unilateral dilated pupil unreactive to light, asymmetric movement of the extremities either spontaneously or in response to noxious stimuli, or unilateral Babinski’s reflex) suggests an intracranial mass lesion or major structural damage.Such intracranial lesions following trauma include hemato-mas, contusions, hemorrhage into ventricular and subarachnoid spaces, and diffuse axonal injury (DAI). Epidural hematomas occur when blood accumulates between the skull and dura, and are caused by disruption of the middle meningeal artery or other small arteries in that potential space, typically after a skull frac-ture (Fig. 7-16). Subdural hematomas occur between the dura and cortex and are caused by venous disruption or laceration of the parenchyma of the brain. Due to associated parenchy-mal injury, subdural hematomas have a much worse prognosis than epidural collections. Hemorrhage into the subarachnoid space may cause vasospasm and further reduce cerebral blood flow. Intraparenchymal hematomas and contusions can occur anywhere within the brain. DAI results from high-speed decel-eration injury and represents direct axonal damage from shear effects. CT scan may demonstrate blurring of the gray and white matter interface and multiple small punctate hemorrhages, but magnetic resonance imaging is a more accurate test. Although prognosis for these injuries is extremely variable, early evidence of DAI is associated with a poor outcome. Stroke syndromes should prompt a search for carotid or vertebral artery injury using multislice CTA (Fig. 7-17).Brunicardi_Ch07_p0183-p0250.indd 19610/12/18 6:17 PM 197TRAUMACHAPTER 7Significant intracranial penetrating injuries usually are produced by bullets from handguns, but an array of other weap-ons or instruments can injure the cerebrum via the orbit or through the thinner temporal region of the skull. Although the diagnosis usually is obvious, in some instances wounds in the auditory canal, mouth, and nose can be elusive. Prognosis is variable, but virtually all supratentorial wounds that injure both hemispheres are fatal.Neck. All blunt trauma patients should be assumed to have cer-vical spine injuries until proven otherwise. During the physi-cal examination, one must maintain cervical spine precautions and in-line stabilization. Due to the devastating consequences of quadriplegia, a diligent evaluation for occult cervical spine injuries is mandatory. In the awake patient, the presence of posterior midline pain or tenderness should provoke a thor-ough radiologic evaluation. Additionally, intubated patients, patients with distracting injuries, significant mechanism, or another identified spine fracture should undergo CT imaging.37 A ligamentous injury may not be visible with standard imaging techniques. Flexion and extension views or magnetic resonance imaging (MRI) are obtained to further evaluate patients at risk or those with persistent symptoms.Spinal cord injuries can vary in severity. Complete injuries cause either quadriplegia or paraplegia, depending on the level of injury. These patients have a complete loss of motor func-tion and sensation two or more levels below the bony injury. Patients with high spinal cord disruption are at risk for shock due to physiologic disruption of sympathetic fibers. Significant neurologic recovery is rare. However, there are several partial or incomplete spinal cord injury syndromes where the prognosis is better. Central cord syndrome typically occurs in older persons who experience hyperextension injuries. Motor function, pain, and temperature sensation are preserved in the lower extremi-ties but diminished in the upper extremities. Some functional ABFigure 7-16. Epidural hematomas (A) have a distinctive convex shape on computed tomo-graphic scan, whereas subdural hematomas (B) are concave along the surface of the brain.Figure 7-17. A. A right middle cerebral infarct noted on a computed tomographic scan of the head. Such a finding should prompt imaging to rule out an associated extracranial cerebrovascular injury. B. An inter-nal carotid artery pseudoaneurysm documented by angiography.Brunicardi_Ch07_p0183-p0250.indd 19710/12/18 6:17 PM 198BASIC CONSIDERATIONSPART Irecovery usually occurs, but is often not a return to normal. Anterior cord syndrome is characterized by diminished motor function, pain, and temperature sensation below the level of the injury, but position sensing, vibratory sensation, and crude touch are maintained. Prognosis for recovery is poor. Brown-Séquard syndrome is usually the result of a penetrating injury in which one-half of the spinal cord is transected. This lesion is characterized by the ipsilateral loss of motor function, proprio-ception, and vibratory sensation, whereas pain and temperature sensation are lost on the contralateral side.During the primary survey, identification of injuries to the neck with exsanguination, expanding hematomas, airway obstruc-tion, or aerodigestive injuries is a priority. A more subtle injury that may not be identified is a fracture of the larynx due to blunt trauma. Signs and symptoms include hoarseness, subcutaneous emphysema (Fig. 7-18), or a palpable fracture. Penetrating inju-ries of the anterior neck that violate the platysma are potentially life-threatening because of the density of critical structures in this region. Although operative exploration is appropriate for overt injuries, selective nonoperative management has been proven safe (Fig. 7-19).38 Indications for immediate operative intervention for penetrating cervical injury include hemodynamic instability, sig-nificant external hemorrhage, or evidence of aerodigestive injury. The management algorithm for hemodynamically stable patients is based on the presenting symptoms and anatomic location of injury, with the neck being divided into three distinct zones (Fig. 7-20). Zone I is inferior to the clavicles encompassing the thoracic outlet structures, zone II is between the thoracic outlet and the angle of the mandible, and zone III is above the angle of the mandible. Due to technical difficulties of injury expo-sure and varying operative approaches, a precise preoperative diagnosis is desirable for symptomatic zone I and III injuries. Therefore, these patients should ideally undergo diagnostic imag-ing before operation if they remain hemodynamically stable. Management of patients is further divided into those who are symptomatic and those who are not (see Fig 7-19). Specific symptoms or signs that should be identified include dysphagia, hoarseness, hematoma, venous bleeding, minor hemoptysis, and 5PenetratingNeck InjuryHemodynamically UnstableUncontrolled HemorrhageHard signs: massive hemoptysis, rapidly expanding hematomaOperativeExplorationObserveHemodynamically StableSoft signs: dysphagia, venous bleeding,subcutaneous emphysema, hematoma,hoarseness, stridor, odynophagiaAsymptomaticZone IZone IIZone IIIangioembolizationfor Zone III+Zone IZone IIZone IIITranscervical GSWAll OthersCTAneck/chest+angiographyesophagrambronchoscopyCTAneck/chest+ angiographyesophagrambronchoscopy+Figure 7-19. Algorithm for the management of penetrating neck injuries. CTA = computed tomographic angiography; GSW = gunshot wound.Figure 7-18. A laryngeal fracture results in air tracking around the trachea along the prevertebral space (arrows).Brunicardi_Ch07_p0183-p0250.indd 19810/12/18 6:17 PM 199TRAUMACHAPTER 7subcutaneous emphysema. Symptomatic patients, without overt injuries, should undergo CTA with further evaluation or operation based upon the imaging findings. Overall, less than 15% of pen-etrating cervical trauma requires neck exploration.39 Asymptom-atic patients are typically observed for 6 to 12 hours. The one caveat is asymptomatic patients with a transcervical gunshot wound; these patients should undergo CTA to determine the tra-jectory of the bullet; further studies are performed based on prox-imity to major structures.39 Such additional imaging includes angiography, soluble contrast esophagram followed by barium esophagram, esophagoscopy, or bronchoscopy. Angiographic diagnosis, particularly of zone III injuries, can then be managed by selective angioembolization.Chest. Blunt trauma to the chest may involve the chest wall, tho-racic spine, heart, lungs, thoracic aorta and great vessels, and rarely the esophagus. Most of these injuries can be evaluated by physi-cal examination and chest radiography, with supplemental CT scanning to exclude vascular injury. Any patient who undergoes an intervention in the ED—endotracheal intubation, central line placement, tube thoracostomy—needs a repeat chest radiograph to document the adequacy of the procedure. This is particularly true in patients undergoing tube thoracostomy for a pneumothorax or hemothorax. Patients with persistent pneumothorax, large air leaks after tube thoracostomy, or difficulty ventilating should undergo fiber-optic bronchoscopy to exclude a tracheobronchial injury or presence of a foreign body. Patients with hemothorax must have a chest radiograph documenting complete evacuation of the chest; a persistent hemothorax that is not drained by two chest tubes is termed a caked hemothorax and mandates immediate thoracotomy IIIIIIIIFigure 7-20. For the purpose of evaluating penetrating injuries, the neck is divided into three zones. Zone I is to the level of the clavicu-lar heads and is also known as the thoracic outlet. Zone II is located between the clavicles and the angle of the mandible. Zone III is above the angle of the mandible.(Fig. 7-21). Pneumomediastinum following blunt trauma that is identified on CT imaging is a poor predictor of aerodigestive injury; selective workup is appropriate.40Occult thoracic vascular injury must be diligently sought due to the high mortality of a missed lesion. Widening of the mediastinum on initial anteroposterior chest radiograph, caused by a hematoma around an injured vessel that is contained by the mediastinal pleura, suggests an injury of the great vessels. The mediastinal abnormality may suggest the location of the arterial injury (i.e., left-sided hematomas are associated with descend-ing blunt aortic injuries [BAI], whereas right-sided hematomas are seen with innominate injuries) (Fig. 7-22). Posterior rib frac-tures, sternal fractures with laceration of small vessels, and mediastinal venous bleeding also can produce similar hemato-mas. Other chest radiographic findings suggestive of a BAI are summarized in Table 7-5 (Fig. 7-23). However, at least 7% of patients with a descending BAI have a normal chest radio-graph.41 Therefore, screening CTA is performed based on the mechanism of injury: high-energy deceleration motor vehicle collision with frontal or lateral impact (>30 mph frontal impact and >23 mph lateral impact), motor vehicle collision with ejection, falls of >25 ft, or direct impact (horse kick to chest, snowmobile, or ski collision with tree).42,43 In >95% of patients who survive to reach the ED, the BAI occurs just distal to the left subclavian artery, where it is tethered by the ligamen-tum arteriosum (Fig. 7-24). In 2% to 5% of patients the injury occurs in the ascending aorta, in the transverse arch, or at the diaphragm. Reconstructions with multislice CTA obviate the need for invasive arteriography.42For penetrating thoracic trauma, physical examination, plain posteroanterior and lateral chest radiographs with metallic markings of wounds, and pericardial ultrasound will identify the majority of injuries.44 Injuries of the esophagus and tra-chea are the exceptions. Bronchoscopy should be performed to evaluate the trachea in patients with a persistent air leak from the chest tube or mediastinal air. Patients at risk for an esopha-geal injury should undergo bedside esophagoscopy or soluble contrast esophagography followed by barium examination to look for extravasation of contrast.45 As with neck injuries, 6Figure 7-21. Persistence of a hemothorax despite two tube tho-racostomies is termed a caked hemothorax and is an indication for prompt thoracotomy.Brunicardi_Ch07_p0183-p0250.indd 19910/12/18 6:18 PM 200BASIC CONSIDERATIONSPART Ihemodynamically stable patients with transmediastinal gunshot wounds should undergo CT scanning to determine the path of the bullet; trajectory in proximity to vascular or visceral struc-tures dictates the need for angiography, endoscopy, or opera-tive plan. If there is a suspicion of a subclavian artery injury, brachial-brachial indices should be measured, but >60% of patients with an injury may not have a pulse deficit.46 Therefore, CTA should be performed based on injury proximity to intra-thoracic vasculature. Finally, with GSWs identified on the chest, penetrating trauma should not be presumed to be isolated to the thorax. Injury to contiguous body cavities (i.e., the abdomen and neck) must be excluded; plain radiographs are a rapid, effective screening modality to identify retained bullet fragments.Abdomen. The abdomen is a diagnostic black box. Fortunately, with few exceptions, it is not necessary to determine in the ED which intra-abdominal organs are injured, only whether an explor-atory laparotomy is necessary. However, physical examina-tion of the abdomen can be unreliable in making this determination, and drugs, alcohol, and head and spinal cord injuries can complicate the clinical evaluation. The presence of abdominal rigidity and hemodynamic compromise is an undisputed indication 7Figure 7-22. Location of the hematoma within the mediastinal silhouette suggests the type of great vessel injury. A predominant hematoma on the left suggests the far more common descending torn aorta (A; arrows), whereas a hematoma on the right indicates a relatively unusual but life-threatening innominate artery injury (B; arrows).Table 7-5Findings on chest radiograph suggestive of a descending thoracic aortic tear1. Widened mediastinum2. Abnormal aortic contour3. Tracheal shift4. Nasogastric tube shift5. Left apical cap6. Left or right paraspinal stripe thickening7. Depression of the left main bronchus8. Obliteration of the aorticopulmonary window9. Left pulmonary hilar hematomaFigure 7-23. Chest film findings associated with descending torn aorta include apical capping (A; arrows) and tracheal shift (B; arrows).Brunicardi_Ch07_p0183-p0250.indd 20010/12/18 6:18 PM 201TRAUMACHAPTER 7Figure 7-24. Imaging to diagnose descending torn aorta includes computed tomographic angiography (A), with three-dimensional reconstructions (B, anterior; C, posterior) demonstrating the proxi-mal and distal extent of the injury (arrows).for prompt surgical exploration. For the remainder of patients, a variety of diagnostic adjuncts are used to identify abdominal injury.The diagnostic approach differs for penetrating trauma and blunt abdominal trauma. As a rule, laparotomy is warranted for gunshot or shotgun wounds that penetrate the peritoneal cavity because most have significant internal injuries. The standard has been that anterior truncal gunshot wounds between the fourth intercostal space and the pubic symphysis whose trajectory as determined by radiograph or wound location indicates perito-neal penetration should undergo laparotomy (Fig. 7-25). How-ever, there has been increased use of CT scanning to facilitate nonoperative management of abdominal GSWs.47 The exception is penetrating trauma isolated to the right upper quadrant; in hemodynamically stable patients with trajectory confined to the liver by CT scan, nonoperative observation may be reasonable.48 In obese patients, if the gunshot wound is thought to be tangen-tial through the subcutaneous tissues, CT scan can delineate the track and exclude peritoneal violation. Laparoscopy is another option to assess peritoneal penetration for tangential wounds it should not be done in unstable patients. In the scenario of tan-gential high energy GSWs, however, it is possible to sustain a transmitted intraperitoneal hollow visceral injury due to a blast insult. Gunshot wounds to the back or flank are more difficult to evaluate because of the retroperitoneal location of the injured abdominal organs. Triple-contrast CT scan can delineate the trajectory of the bullet and identify peritoneal violation or retro-peritoneal entry, and associated injuries.In contrast to gunshot wounds, stab wounds that penetrate the peritoneal cavity are less likely to injure intra-abdominal organs. Anterior abdominal stab wounds (from costal margin to inguinal ligament and bilateral midaxillary lines) should be explored under local anesthesia in the ED to determine if the fascia has been violated. Injuries that do not penetrate the peri-toneal cavity do not require further evaluation, and the patient Brunicardi_Ch07_p0183-p0250.indd 20110/12/18 6:18 PM 202BASIC CONSIDERATIONSPART Imay be discharged from the ED. Patients with fascial pen-etration must be further evaluated for intra-abdominal injury because there is up to a 50% chance of requiring laparotomy. Debate remains over whether the optimal diagnostic approach is serial examination, diagnostic peritoneal lavage (DPL), or CT scanning. The most recent evidence supports serial examination and laboratory evaluation.49,50 Patients with stab wounds to the right upper quadrant can undergo CT scanning to determine tra-jectory and confinement to the liver for potential nonoperative care.48 Those with stab wounds to the flank and back should undergo contrasted CT to assess for the potential risk of retro-peritoneal injuries of the colon, duodenum, and urinary tract.Penetrating thoracoabdominal wounds may cause occult injury to the diaphragm. Patients with gunshot or stab wounds to the left lower chest should be evaluated with diagnostic lapa-roscopy or DPL to exclude diaphragmatic injury. In general, penetrating right diaphragm injury is ignored unless there is a major underlying liver injury with a risk of biliopleural fistula. Diagnostic laparoscopy may be preferred in patients with a posi-tive chest radiograph (hemothorax or pneumothorax) or in those who would not tolerate a DPL. For patients undergoing DPL evaluation, laboratory value cutoffs to rule out diaphragm injury are different from traditional values formerly used for abdomi-nal stab wounds (Table 7-6). An RBC count of >10,000/μL is considered a positive finding and an indication for abdominal evaluation; patients with a DPL RBC count between 1000/μL and 10,000/μL should undergo laparoscopy or thoracoscopy.PenetratingAbdominalTraumaHemodynamicallyUnstableHemodynamicallyStableOperatingRoomGSWSWAnteriorAbdomenRUQTangential*,Back/FlankCTScan AASWwith+ LWE** Back/FlankSerialExams/Labs+*Tangential GSWs may also be evaluated with diagnostic laparoscopy.** A positive local wound exploration is defined as violation of the posterior fascia. CTScanLeft-sided thoracoabdominalDPL vs.laparoscopy++Evisceration/PeritonitisFigure 7-25. Algorithm for the evaluation of penetrating abdominal injuries. AASW = anterior abdominal stab wound; CT = computed tomography; DPL = diagnostic peritoneal lavage; GSW = gunshot wound; LWE = local wound exploration; RUQ = right upper quadrant; SW = stab wound.Table 7-6Criteria for “positive” finding on diagnostic peritoneal lavageABDOMINAL TRAUMATHORACOABDOMINAL STAB WOUNDSRed blood cell count>100,000/mL>10,000/mLWhite blood cell count>500/mL>500/mLAmylase level>19 IU/L>19 IU/LAlkaline phosphatase level>2 IU/L>2 IU/LBilirubin level>0.01 mg/dL>0.01 mg/dLBlunt abdominal trauma is now evaluated initially by FAST examination, and this has supplanted DPL (Fig. 7-26). FAST is not 100% sensitive, however, so diagnostic peritoneal aspiration is warranted in hemodynamically unstable patients without a defined source of blood loss to rule out abdominal hemorrhage.31 FAST is used to identify free intraperitoneal fluid (Fig. 7-27) in Morrison’s pouch, the left upper quadrant, and the pelvis. Although this method is sensitive for detecting Brunicardi_Ch07_p0183-p0250.indd 20210/12/18 6:18 PM 203TRAUMACHAPTER 7HemodynamicallystableFAST +DPALaparotomyEquivocalPeritonitis?FAST +Candidate fornonoperativemanagementorpatient withcirrhosisIndications for CT:-Altered mental status-Confounding injury-Gross hematuria-Pelvic fracture-Abdominal tenderness-Unexplained Hct <35%Abdominal CTRepeat FASTin 30 minutesNoNoNoNoYesYesYesYesYesNoNoFigure 7-26. Algorithm for the initial evaluation of a patient with suspected blunt abdominal trauma. CT = computed tomography; DPA = diagnostic peritoneal aspiration; FAST = focused abdominal sonography for trauma; Hct = hematocrit.Figure 7-27. Focused abdominal sonography for trauma imag-ing detects intra-abdominal hemorrhage. Hemorrhage is presumed when a fluid stripe is visible between the right kidney and liver (A), between the left kidney and spleen (B), or in the pelvis (C).Brunicardi_Ch07_p0183-p0250.indd 20310/12/18 6:18 PM 204BASIC CONSIDERATIONSPART IFigure 7-28. Computed tomography images reveal critical infor-mation about solid organ injuries, such as associated contrast extravasation from a grade IV laceration of the spleen (A; arrow) and the amount of subcapsular hematoma in a grade III liver lacera-tion (B; arrows).intraperitoneal fluid of >250 mL, it does not reliably deter-mine the source of hemorrhage nor grade solid organ inju-ries.51 Patients with fluid on FAST examination, considered a “positive FAST,” who do not have immediate indications for laparotomy (hemodynamically stable, no evidence of perito-nitis) undergo CT scanning to quantify their injuries. Injury grading using the American Association for the Surgery of Trauma (AAST) grading scale (Table 7-7) is an important component of nonoperative management of solid organ inju-ries. Additional findings that should be noted on CT scan in patients with solid organ injury include contrast extravasa-tion (i.e., a “blush”), the amount of intra-abdominal hemor-rhage, and presence of pseudoaneurysms (Fig. 7-28). CT also is indicated for hemodynamically stable patients for whom the physical examination is unreliable. Despite the increasing diagnostic accuracy of multidetector CT scanners, identifica-tion of intestinal injuries remains a limitation. Bowel injury is suggested by findings of thickened bowel wall, “streak-ing” in the mesentery, free fluid without associated solid organ injury, or free intraperitoneal air.52,53 Patients with free intra-abdominal fluid without solid organ injury are closely monitored for evolving signs of peritonitis; if patients have a significant closed head injury or cannot be serially examined, DPL should be performed to exclude bowel injury. If DPL is pursued, an infraumbilical approach is used (Fig. 7-29). After placement of the catheter, a 10-mL syringe is connected and the abdominal contents aspirated (termed a diagnostic perito-neal aspiration). The aspirate is considered positive if >10 mL of blood is aspirated. If <10 mL is withdrawn, a liter of normal saline is instilled. The effluent is withdrawn via siphoning and sent to the laboratory for RBC count, white blood cell (WBC) count, and determination of amylase, bilirubin, and alkaline phosphatase levels. Values representing positive findings are summarized in Table 7-6.Table 7-7American Association for the Surgery of Trauma grading scales for solid organ injuriesSUBCAPSULAR HEMATOMALACERATIONLiver Injury GradeGrade I<10% of surface area<1 cm in depthGrade II10%–50% of surface area1–3 cmGrade III>50% of surface area or >10 cm in depth>3 cmGrade IV25%–75% of a hepatic lobeGrade V>75% of a hepatic lobeGrade VIHepatic avulsionSplenic Injury GradeGrade I<10% of surface area<1 cm in depthGrade II10%–50% of surface area1–3 cmGrade III>50% of surface area or >10 cm in depth>3 cmGrade IV>25% devascularizationHilumGrade VShattered spleenComplete devascularizationPelvis. Blunt injury to the pelvis may produce mechanically unstable fractures with major hemorrhage (Fig. 7-30). Plain radiographs will reveal gross abnormalities, but CT scanning is necessary to determine the precise geometry. Sharp spicules of bone can lacerate the bladder, rectum, or vagina. Alterna-tively, bladder rupture may result from a direct blow to the torso if the bladder is full. CT cystography is performed if the urinalysis demonstrates RBCs. Urethral injuries are suspected if examination reveals blood at the meatus, scrotal or perineal hematomas, or a high-riding prostate on rectal examination. Urethrograms should be obtained for stable patients before placing a Foley catheter to avoid false passage and subsequent stricture. Major vascular injuries of the external iliacs caus-ing bleeding are uncommon in blunt pelvic trauma; however, thrombosis of either the arteries or veins in the iliofemoral system may occur, and CTA should be performed for evalu-ation if there is a pulse differential. Life-threatening hemor-rhage can be associated with pelvic fractures and may initially Brunicardi_Ch07_p0183-p0250.indd 20410/12/18 6:18 PM 205TRAUMACHAPTER 7Figure 7-29. Diagnostic peritoneal lavage is performed through an infraumbilical incision unless the patient has a pelvic fracture or is preg-nant. A. The linea alba is sharply incised, and the catheter is directed into the pelvis. B. The abdominal contents should initially be aspirated using a 10-mL syringe.preclude definitive imaging. Treatment algorithms for patients with complex pelvic fractures and hemodynamic instability are presented later in the chapter.Extremities. Blunt or penetrating trauma to the extremities requires an evaluation for fractures, ligamentous disruption, and neurovascular injury. Plain radiographs are used to evaluate fractures, whereas ligamentous injuries, particularly those of the knee and shoulder, can be imaged with magnetic resonance imaging. Physical examination identifies the majority of arte-rial injuries, and findings are classified as either hard signs or soft signs of vascular injury (Table 7-8). In general, hard signs constitute indications for operative exploration, whereas soft signs are indications for further testing or observation. Bony fractures or knee dislocations should be realigned before defini-tive vascular examination. In management of vascular trauma, controversy exists regarding the treatment of patients with soft signs of injury, particularly those with injuries in proximity to major vessels. It is known that some of these patients will have arterial injuries that require repair. The most common approach has been to measure SBP using Doppler ultrasonography and compare the value for the injured side with that for the unin-jured side, termed the A-A index.54 If the pressures are within 10% of each other, a significant injury is unlikely, and no fur-ther evaluation is performed. If the difference is >10%, CTA or arteriography is indicated. Others argue that there are occult injuries, such as pseudoaneurysms or injuries of the profunda femoris or peroneal arteries, which may not be detected with this technique. If hemorrhage occurs from these injuries, com-partment syndrome and limb loss may occur. Although busy trauma centers continue to debate this issue, the surgeon who is obliged to treat the occasional injured patient may be better served by performing CTA in selected patients with soft signs. In patients with hard signs of vascular injury, on-table angi-ography may be useful to localize the arterial injury and thus, limit tissue dissection. For example, a patient with an absent popliteal pulse and femoral shaft fracture due to a bullet that entered the lateral hip and exited below the medial knee could have injured either the femoral or popliteal artery anywhere along its course (Fig. 7-31).GENERAL PRINCIPLES OF MANAGEMENTOver the past 25 years there has been a remarkable change in management practices and operative approach for the injured patient. With the advent of CT scanning, nonoperative man-agement of solid organ injuries has replaced routine operative exploration. Those patients who do require operation may be treated with less radical resection techniques, such as splen-orrhaphy or partial nephrectomy. Colonic injuries, previously mandating colostomy, are now repaired primarily in virtually all cases. Additionally, the type of anastomosis has shifted from a double-layer closure to a continuous running single-layer clo-sure; this method is technically equivalent to and faster than the interrupted multilayer techniques.55 Adoption of damage con-trol surgical techniques in physiologically deranged patients has resulted in limited initial operative time, with definitive injury repair delayed until after resuscitation in the surgical intensive care unit (SICU) with physiologic restoration.56 Abdominal drains, once considered mandatory for parenchymal injuries and some anastomoses, have disappeared; fluid collections are managed by percutaneous techniques. Newer endovascular Brunicardi_Ch07_p0183-p0250.indd 20510/12/18 6:18 PM 206BASIC CONSIDERATIONSPART ITable 7-8Signs and symptoms of peripheral arterial injuryHARD SIGNS (OPERATION MANDATORY)SOFT SIGNS (FURTHER EVALUATION INDICATED)Pulsatile hemorrhageProximity to vasculatureAbsent pulsesSignificant hematomaAcute ischemiaAssociated nerve injuryA-A index of <0.9Thrill or bruitA-A index = systolic blood pressure on the injured side compared with that on the uninjured side.techniques such as stenting of arterial injuries and angioem-bolization are routine adjuncts. Blunt cerebrovascular injuries have been recognized as a significant, preventable source of neurologic morbidity and mortality. The use of preperitoneal pelvic packing for unstable pelvic fractures as well as early frac-ture immobilization with external fixators are paradigm shifts in management. Recently resuscitative endovascular balloon occlusion (REBOA) has been added to the armamentarium for life-threatening pelvic fracture bleeding57,58 (Fig. 7-32). Finally, the institution of massive transfusion protocols balances the benefit of blood component therapy against immunologic risk. Viscoelastic hemostatic assays (TEG and ROTEM) have been shown to be superior to traditional laboratory tests and have been central to the evolving concept of goal-directed hemo-stasis.59 These many conceptual changes have significantly improved survival of critically injured patients; they have been promoted and critically reviewed by academic trauma centers via forums such as the American College of Surgeons Com-mittee on Trauma, the American Association for the Surgery of Trauma, the International Association of Trauma Surgery and Intensive Care, the Pan-American Trauma Congress, and other surgical organizations.Transfusion PracticesInjured patients with life-threatening hemorrhage develop acute coagulopathy of trauma (ACOT).60,61 The mechanism for inad-equate clot formation remains uncertain, but it is believed to involve activation of protein C, which impairs Va and VIIa, glycocalyx breakdown, which releases heparin sulfate, immune Figure 7-30. The three types of mechanically unstable pelvis fractures are lateral compression (A), anteroposterior compression (B), and vertical shear (C).Brunicardi_Ch07_p0183-p0250.indd 20610/12/18 6:18 PM 207TRAUMACHAPTER 7activation with the releases of DAMPs, DNA, histone, poly-phosphate, and PMN elastase, and complement activation. Fibrinolysis is an important component of the ACOT; hyper-fibrinolysis and fibrinolysis shutdown are both associated with increased mortality.62 Fresh whole blood, arguably the optimal replacement, has not been available in the United States since the early 1980s. Rather, its component parts, packed red blood cells (PRBCs), fresh frozen plasma, platelets, and cryoprecipi-tate, are administered. Specific transfusion triggers for indi-vidual blood components remain debated.63 Although current critical care guidelines indicate that PRBC transfusion should occur once the patient’s hemoglobin level is <7 g/dL,64 in the acute phase of resuscitation a hemoglobin of 10 g/dL is suggested to facilitate hemostasis via platelet margination.65 The traditional Figure 7-31. On-table angiography in the operating room isolates the area of vascular injury to the superficial femoral artery in a patient with a femoral fracture after a gunshot wound to the lower extremity.ABthresholds for blood component replacement in the patient mani-festing a coagulopathy have been INR >1.5, PTT >1.5 normal, platelet count >50,000/μL, and fibrinogen >100 mg/dl. However, these guidelines have been replaced by TEG and ROTEM cri-teria in many trauma centers. Such guidelines are designed to limit the transfusion of immunologically active blood compo-nents and decrease the risk of transfusion-associated lung injury and secondary multiple organ failure.66,67In the critically injured patient requiring large amounts of blood component therapy, a massive transfusion protocol should be followed (Fig. 7-33). This approach calls for administration of various components in a specific ratio during transfusion to achieve restoration of blood volume to reverse shock and cor-rect coagulopathy. Although the optimal ratio is unknown, cur-rent evidence suggests a presumptive 1:2 red cell:plasma ratio in patients at risk for massive transfusion (10 units of PRBCs in 6 hours).67-72 Because complete typing and cross-matching takes up to 45 minutes, patients requiring emergent transfusions are given type O-negative RBCs. Similarly, without time for blood typing, AB plasma is the universal donor, although A plasma appears to be a safe option. Blood typing, and to a lesser extent cross-matching, is essential to avoid life-threatening intravas-cular hemolytic transfusion reactions. Trauma centers and their associated blood banks must have the capability of transfusing tremendous quantities of blood components because it is not unusual to have >50 component units transfused during one procedure and have the patient survive. Massive transfusion protocols, established preemptively, permit coordination of the activities of surgeons, anesthesiologists, and blood bankers to facilitate transfusion of the appropriate blood products.Postinjury coagulopathy due to shock is aggravated by core hypothermia and metabolic acidosis, termed the bloody vicious cycle,56 and now commonly referred to as the lethal triad. The pathophysiology is multifactorial and includes inhibition of temperature-dependent enzyme-acti-vated coagulation cascades, platelet dysfunction, endothelial abnormalities, and fibrinolytic activity. Such coagulopathy may be insidious, so the surgeon must be cognizant of subtle signs such as excessive bleeding from the cut edges of skin. Point-of-care viscoelastic assays (TEG and ROTEM), which provide a comprehensive assessment of clot capacity and fibri-nolysis, can provide useful information within 15 minutes. In contrast, traditional laboratory tests of coagulation capability (i.e., INR, PTT, fibrinogen levels, and platelet count) requires at least 45 minutes. Using damage control techniques to limit operative time and provide physiologic restoration in the SICU can be lifesaving (see “Damage Control Surgery”).8Figure 7-32. A. Resuscitative endovascular balloon of the aorta (REBOA) is introduced through a 7Fr arterial sheath in the common femoral artery using ultrasound guidance. B. For patients with pelvic fractures and hemodynamic instabil-ity, the balloon is positioned in zone III just above the aortic bifurcation; a mixture of saline and contrast is used to inflate the balloon, which can be visualized on bedside plain radiography.Brunicardi_Ch07_p0183-p0250.indd 20710/12/18 6:18 PM 208BASIC CONSIDERATIONSPART IFigure 7-33. Denver Health Medical Center’s Massive Transfusion Protocol (MTP). ACT = activated clotting time; Cryo = cryoprecipitate; FFP = fresh frozen plasma; MA = maximum amplitude; PRBC = packed red blood cells; PTT = partial thromboplastin time; SBP = systolic blood pressure; TEG = thromboelastography.Prophylactic MeasuresAll injured patients undergoing an operation should receive preoperative antibiotics. The type of antibiotic is determined by the anticipated source of contamination in the abdomen or other operative region; additional doses should be adminis-tered during the procedure based on blood loss and the half-life of the antibiotic. Extended postoperative antibiotic therapy is administered only for contaminated open fractures. Tetanus prophylaxis is administered to all patients according to pub-lished guidelines.Trauma patients are at risk for venous thromboembolism and its associated morbidity and mortality. In fact, pulmo-nary embolus can occur much earlier in the patient’s hospital course than previously believed.73 Patients at higher risk for venous thromboembolism are those with multiple fractures of the pelvis and lower extremities, those with TBI or spinal cord injury, and those requiring ligation of large veins in the abdo-men and lower extremities. Morbidly obese patients and those over 55 years of age are at additional risk. Administration of low molecular weight heparin (LMWH) is initiated as soon MASSIVE TRANSFUSION PROTOCOL FOR TRAUMAAny of these in the ED:• Penetrating Torso Injury• Major Pelvic Fracture• FAST ˜ >1 Body Region• SBP 70 OR• SBP 71–90 AND HR š108 if ... your patient has these VS in the FIELD or EDACTIVATE MTPCaCl2 1 gr. i.v.Transfuse RBC 4 Unitsand FFP 2 UnitsOrder Citrated Rapid TEGContinue to component transfusion based on TEG Resultsif patient is bleedingANDACT>128 sec Angle<65°MA<55 mmLY30 š10%FFP 2 UnitsCryo10 UnitsPlatelets1 UnitTXA1 gmReassess via Citrated Rapid TEGMassive Transfusion ProtocolTriggers: SBP <70 with penetrating torso injury, major pelvic injury, FAST + SBP <71-90 mmHg and HR >108 with penetrating torso injury, major pelvic injury, FAST + ** order citrated rapid TEGContinued Treatment of ShockHemorrhage Control, Correct Hypothermia, Correct AcidosisNormalize Ca++Empiric Transfusion Until Lab Results AvailableShipmentPRBCsFFPPlateletsCryo142242110TEG Based Resuscitation*rapidTEG-ACT >128 sec ˜ 2 units thawed plasmarapidTEG-MA <55mm ˜ 1 unit of apheresis plateletsrapidTEG-angle <66 degrees ˜ 10 units pooled cryoprecipitaterapidTEG EPL >9% ˜ 1g tranexamic acid*Transfusion Triggers if TEGis UnavailablePT, PTT > 1.5 control ˜2 units thawed plasmaPlatelet count <50,000/mcL ˜1 unit of apheresis plateletsFibrinogen <100 mg/dL ˜10 units pooled cryoprecipitateBrunicardi_Ch07_p0183-p0250.indd 20810/12/18 6:18 PM 209TRAUMACHAPTER 7Figure 7-34. A. Unilateral neck exploration is performed through an incision along the anterior border of the sternocleidomastoid muscle; exposure of the carotid artery requires early division of the facial vein. B. The distal internal carotid artery is exposed by dividing the ansa cervicalis, which permits mobilization of the hypoglossal nerve. C. Further exposure is facilitated by resection of the posterior belly of the digastric muscle.as bleeding has been controlled and there is stable intracranial pathology. In high-risk patients, antiplatelet therapy should be added.74 Removable inferior vena caval filters should be con-sidered if there are prolonged contraindications to administra-tion of LMWH. Additionally, pulsatile compression stockings (also termed sequential compression devices) are used routinely unless there is a fractured lower extremity or vascular injury.A final prophylactic measure that is usually not consid-ered is thermal protection. Hemorrhagic shock impairs perfu-sion and metabolic activity throughout the body, with resultant decrease in heat production and body temperature. Removing the patient’s clothes causes a second thermal insult, and infu-sion of cold PRBCs or room temperature crystalloid exacerbates the problem. As a result, injured patients can become hypother-mic, with temperatures below 34°C (93.2°F) upon arrival in the OR. Hypothermia aggravates coagulopathy and provokes myocardial irritability. Therefore, prevention must begin in the ED by maintaining a comfortable ambient temperature, cover-ing patients with warm blankets, and administering warmed IV fluids and blood products. Additionally, in the OR a Bair Hug-ger® warmer (the upper body or lower body blanket) and heated inhalation via the ventilatory circuit is instituted. For cases of severe hypothermia (temperature <30°C [86°F]), arteriovenous rewarming should be considered.Operative Approaches and ExposureCervical Exposure. Operative exposure for midline structures of the neck (e.g., trachea, thyroid, bilateral carotid sheaths) is obtained through a collar incision; this is typically performed two finger breadths above the sternal notch, but can be varied based on the level of anticipated injury. After subplatysmal flap elevation, the strap muscles are divided in the midline to gain access to the central neck compartment. More superior and lateral structures are accessed by extending the collar incision upward along the sternocleidomastoid muscle; this may be done bilaterally if neces-sary. For unilateral injuries, neck exploration is done through an incision extending from the mastoid down to the clavicle, along the anterior border of the sternocleidomastoid muscle (Fig. 7-34). Brunicardi_Ch07_p0183-p0250.indd 20910/12/18 6:19 PM 210BASIC CONSIDERATIONSPART IBFigure 7-36. A. A “clamshell” thoracotomy provides exposure to bilateral thoracic cavities. B. Sternal transection requires individual ligation of both the proximal and distal internal mammary arteries on the undersurface of the sternum.123Figure 7-35. Options for thoracic exposure include the most versa-tile incision, the anterolateral thoracotomy (1), as well as a median sternotomy (2) and a “trap door” thoracotomy (3). Any thoracic incision may be extended into a supraclavicular or anterior neck incision for wider exposure.The carotid sheath, containing the carotid artery, jugular vein, and vagus nerve, is opened widely to examine these structures. The facial vein, which marks the carotid bifurcation, is usually ligated for exposure of the internal carotid artery and the hypoglossal nerve is the next structure encountered.Exposure of the distal carotid artery in zone III is difficult (see Fig. 7-34). The first step is division of the ansa cervicalis to facilitate mobilization of the hypoglossal nerve. Next, the poste-rior portion of the digastric muscle, which overlies the internal carotid, is transected. The glossopharyngeal and vagus nerves are also mobilized and retracted as necessary. If accessible, the styloid process and attached muscles are removed. In desperate situations, anterior displacement of the mandible (subluxation) may be helpful or the vertical ramus of the mandible may be divided. However, the latter maneuver often entails resection of the parotid gland, and the facial nerve is at risk of injury.Thoracic Incisions. An anterolateral thoracotomy, with the patient placed supine, is the most versatile incision for emer-gent thoracic exploration. The location of the incision is in the fifth interspace, in the inframammary line (Fig. 7-35). If access is needed to both pleural cavities, the original incision can be extended across the sternum with a Lebsche knife, into a “clam-shell” thoracotomy (Fig. 7-36). If the sternum is divided, the internal mammary arteries should be ligated to prevent blood loss. The heart, lungs, descending aorta, pulmonary hilum, and esophagus are accessible with this approach. For control of the great vessels, the superior portion of the sternum may be divided vertically with extension of the incision into the neck considered. A method advocated for access to the proximal left subclavian artery is through a fourth interspace anterolateral thoracotomy, superior sternal extension, and left supraclavicular incision (“trap door” thoracotomy). Although the trap door procedure is appro-priate after resuscitative thoracotomy, the proximal left subcla-vian artery can be accessed more easily via a sternotomy with a supraclavicular extension. If the left subclavian artery is injured outside the thoracic outlet, vascular control can be obtained via the sternotomy and definitive repair done through the supraclavicular incision. Emergent median sternotomy is optimal for anterior stab wounds to the heart. Typically, these patients have pericardial tamponade and may undergo placement of a pericardial drain before a semiurgent median sternotomy is performed. Patients in extremis, however, should undergo anterolateral thoracotomy.Median sternotomy with cervical extension is used for rapid exposure in patients with presumed proximal subclavian, innominate, or proximal carotid artery injuries. Care must be taken to avoid injury to the phrenic and vagus nerves that pass over the subclavian artery and to the recurrent laryngeal nerve passing posteriorly. Posterolateral thoracotomies are used for exposure of injuries to the trachea or main stem bronchi near the carina or the upper esophagus (right posterolateral thoracotomy) and tears of the descending thoracic aorta or lower esophagus (left posterolateral thoracotomy).Emergent Abdominal Exploration. Abdominal exploration in adults is performed using a midline incision because of its versatility. For children under the age of 6, a transverse inci-sion may be advantageous. Making the incision is faster with a scalpel than with an electrosurgical unit; incisional abdominal wall bleeding should be ignored until intra-abdominal sources of hemorrhage are controlled. Liquid and clotted blood are Brunicardi_Ch07_p0183-p0250.indd 21010/12/18 6:19 PM 211TRAUMACHAPTER 7Figure 7-37. A sagittal view of packs placed to control hepatic hemorrhage. LAP = laparotomy.Figure 7-38. The Pringle maneuver, performed with a vascular clamp, occludes the hepatic pedicle containing the portal vein, hepatic artery, and common bile duct.evacuated with multiple laparotomy pads to identify the major source(s) of active bleeding. After blunt trauma, the spleen and liver should be palpated first and packed if fractured, and the infracolic mesentery should be inspected for zone I vascular injury. In contrast, after a penetrating wound the search for bleeding should pursue the trajectory of the penetrating device. If the patient has an SBP of <70 mmHg when the abdomen is opened, digital pressure or a clamp should be placed on the aorta at the diaphragmatic hiatus. After the source of hemorrhage is localized, direct digital occlusion (vascular injury) or laparot-omy pad packing (solid organ injury) is used to control bleed-ing (Fig. 7-37). If the liver is the source in a hemodynamically Figure 7-39. To mobilize the spleen, an incision is made into the endoabdominal fascia 1 cm lateral to the reflection of the peritoneum onto the spleen (A). While the spleen is gently rotated medially, a plane is developed between the pancreas and left kidney (B). With complete mobilization, the spleen can reach the level of the abdominal incision.unstable patient, additional control of bleeding is obtained by clamping the hepatic pedicle with a vascular clamp or Rummel tourniquet (termed the Pringle maneuver) (Fig. 7-38). Similarly, clamping the splenic hilum may be required for hilar bleeding. When the spleen is mobilized, it should be gently rotated medi-ally to expose the lateral peritoneum; this peritoneum and endo-abdominal fascia are incised, which allows blunt dissection of the spleen and pancreas as a composite from the retroperito-neum anterior to Gerota’s fascia (Fig. 7-39).Rapid exposure of the intra-abdominal vasculature can prove challenging in the face of exsanguinating hemorrhage. Proximal control of the aorta is obtained at the diaphragmatic hiatus; if an aortic injury is supraceliac, transecting the left crus of diaphragm or extending the laparotomy via a left thoracotomy may be necessary. Brunicardi_Ch07_p0183-p0250.indd 21110/12/18 6:19 PM 212BASIC CONSIDERATIONSPART IAn alternative for a contained hematoma is placement of a trans-femoral REBOA into zone I. The first decision is whether the patient has a supracolic or an infracolic vascular injury. Supracolic injuries (aorta, celiac axis, proximal superior mesenteric artery [SMA], and left renal arteries) are best approached via a left medial visceral rotation (Fig. 7-40). This is done by incising the lateral peritoneal reflection (white line of Toldt) beginning at the distal descending colon and extending the incision along the colonic splenic flexure, around the posterior aspect of the spleen, and behind the gastric fundus, ending at the esophagus. The left colon, spleen, pancreas, and stomach are then rotated toward the midline. The authors prefer to leave the kidney in situ when mobilizing the viscera because this exaggerates the separation of the renal vessels from the SMA. The operative approach for SMA injuries is based on the level of injury. Fullen zone I SMA injuries, located posterior to the pancreas, are best exposed by a left medial visceral rotation. Fullen zone II SMA injuries, extending from the pancreatic edge to the middle colic branch, on the other hand, are approached via the lesser sac along the inferior edge of the pancreas at the base of the transverse mesocolon; the pancreatic body may be divided to gain proximal vascular access. More distal SMA injuries, Fullen zones III and IV, are approached directly within the mesentery. A venous injury behind the pancreas, from the junction of the superior mesenteric, splenic, and portal veins, is accessed by dividing the neck of the pancreas. Inferior vena cava injuries are approached by a right medial visceral rotation (Fig. 7-41). Proximal control is Figure 7-41. A right medial visceral rotation is used to expose the infrahepatic vena cava.Figure 7-40. A left medial visceral rotation is used to expose the abdominal aorta.obtained just above the iliac bifurcation with direct pressure via a sponge stick; the injury is identified by cephalad dissection along the anterior surface of the inferior vena cava. A Satinsky clamp can be used to control anterior caval wounds.Injuries of the iliac vessels pose a unique problem for emergent vascular control due to the number of vessels, their close proximity, and cross circulation. Proximal control at the infrarenal aorta arrests the arterial bleeding and avoids splanch-nic and renal ischemia; however, venous injuries are not con-trolled with aortic clamping. Tamponade with digital pressure or with a folded laparotomy pad held directly over the bleeding site usually will establish hemostasis sufficient to prevent exsan-guination. If hemostasis is not adequate to expose the vessel proximal and distal to the injury, sponge sticks can be strategi-cally placed on either side of the injury and carefully adjusted to improve hemostasis. Alternatively, complete pelvic vascular isolation (Fig. 7-42) may be required to control hemorrhage for adequate visualization of the injuries. The right common iliac artery obscures the bifurcation of the vena cava and the right iliac vein; the iliac artery may require division to expose venous injuries in this area (Fig. 7-43). The artery must be repaired after the venous injury is treated, however, because of limb-threatening ischemia.Once overt hemorrhage is controlled, sources of enteric contamination are identified by serially running along the small and large bowel, looking at all surfaces. Associated hematomas should be unroofed to rule out adjacent bowel injury. The ante-rior and posterior aspects of the stomach should be inspected, which requires opening the lesser sac for complete visualiza-tion. Duodenal injuries should be evaluated with a wide Kocher maneuver. During exploration of the lesser sac, visualization and palpation of the pancreas is done to exclude injury. Palpat-ing the anterior surface is not sufficient because the investing Brunicardi_Ch07_p0183-p0250.indd 21210/12/18 6:19 PM 213TRAUMACHAPTER 7fascia may mask a pancreatic injury; mobilization, including evaluation of the posterior aspect, is critical. After injuries are identified, whether to use damage control techniques or per-form primary repair of injuries is based on the patient’s intraop-erative physiologic status (see “Damage Control Surgery” and “Treatment of Specific Injuries”). In a patient with multisys-tem trauma, enteral access via gastrostomy or jejunostomy tube should be considered. If abdominal closure is indicated after the patient’s injuries are addressed, the abdomen is irrigated with warm saline and the midline fascia is closed with a running heavy absorbable suture. The skin is closed selectively based on the amount of intra-abdominal contamination.Figure 7-42. Pelvic vascular isolation. A. Initially, clamps are placed on the aorta, inferior vena cava, and bilateral external iliac vessels. B. With continued dissection, the clamps can be moved progressively closer to the vascular injury to limit unwarranted ischemia.Figure 7-43. The right common iliac artery can be divided to expose the bifurcation of the inferior vena cava and the right common iliac vein.Table 7-9Options for the treatment of vascular injuriesObservationLigationLateral suture repairEnd-to-end primary anastomosisInterposition graftsAutogenous veinPolytetrafluoroethylene graftDacron graftTranspositionsExtra-anatomic bypassEndovascularStentsEmbolizationVascular Repair Techniques. Initial control of vascular inju-ries is accomplished digitally by applying enough direct pres-sure to stop the hemorrhage. Sharp dissection is used to define the injury and mobilize sufficient length for proximal and distal control. Fogarty thromboembolectomy should be done proxi-mally and distally to optimize collateral blood flow. Heparin-ized saline (50 units/mL) is then injected into the proximal and distal ends of the injured vessel to prevent small clot formation on the exposed intima and media. Ragged edges of the injury site should be debrided using sharp dissection. Intravascular shunts are used when there are multiple life-threatening injuries or the arterial injury is anticipated to require saphenous vein interposition reconstruction.Options for the treatment of vascular injuries are listed in Table 7-9. Arterial repair should always be done for the aorta, carotid, innominate, brachial, superior mesenteric, proper hepatic, renal, iliac, femoral, and popliteal arteries. Named arter-ies that usually tolerate ligation include the right or left hepatic artery and the celiac artery. In the lower extremities, at least one artery with distal runoff should be salvaged. Arterial injuries that may be treated nonoperatively include small pseudoaneurysms, intimal dissections, small intimal flaps, and small arteriovenous Brunicardi_Ch07_p0183-p0250.indd 21310/12/18 6:19 PM 214BASIC CONSIDERATIONSPART IFigure 7-45. The parachute technique is helpful for accurate placement of the posterior sutures of an anastomosis when the arte-rial end is fixed and an interposition graft is necessary. Traction must be maintained on both ends of the suture to prevent loosening and leakage of blood. Six stitches should be placed before the graft is pulled down to the artery.Figure 7-44. Small arteries repaired with an end-to-end anastomo-sis are prone to stricture. Enlarging the anastomosis by beveling the cut ends of the injured vessel can minimize this problem. A curved hemostat is a useful adjunct to create the curve.fistulas in the extremities. Follow-up imaging is performed 1 to 2 weeks after injury to confirm healing. Venous repair should be performed for injuries of the superior vena cava, the inferior vena cava proximal to the renal veins, and the portal vein, although the portal vein may be ligated in extreme cases. The SMV should be repaired optimally, but >80% of patients will survive follow-ing ligation. Similarly, the left renal vein can usually be ligated adjacent to the IVC due to collateral decompression.The type of operative repair for a vascular injury is based on the extent and location of injury. Lateral suture repair is preferred for arterial injuries with minimal loss of tissue. End-to-end primary anastomosis is performed if the vessel can be repaired without tension. Arterial defects of 1 to 2 cm often can be bridged by mobilizing the severed ends of the vessel after ligating small branches. The aorta, subclavian artery, brachial artery, and popliteal artery however, are difficult to mobilize for additional length. To avoid postoperative stenosis, particularly in smaller arteries, beveling or spatulation should be used so that the completed anastomosis is slightly larger in diameter than the native artery (Fig. 7-44). The authors emphasize the parachute technique to ensure precision placement of the posterior suture line (Fig. 7-45). If this technique is used, traction must be main-tained on both ends of the suture, or leakage from the posterior aspect of the suture line may occur.Interposition grafts are used when end-to-end anastomosis cannot be accomplished without tension despite mobilization. For vessels <6 mm in diameter (e.g., internal carotid, brachial, superficial femoral, and popliteal arteries), autogenous greater saphenous vein (GSV) from the contralateral groin should be used because polytetrafluoroethylene (PTFE) grafts of <6 mm have a prohibitive rate of thrombosis. When GSV is not avail-able, autologous options include the cephalic and basilic veins. Larger arteries (e.g., subclavian, innominate, aorta, common iliac) are bridged by PTFE grafts. PTFE is preferred over Dacron because of the reported decreased risk of infection.75 Aortic or iliac arterial injuries may be complicated by enteric contami-nation from colon or small bowel injuries. There is a natural reluctance to place artificial grafts in such circumstances, but graft infections are rare, and the time required to perform an axillofemoral bypass is excessive. Therefore, after the control of hemorrhage, bowel contamination is contained and the abdomen irrigated before placing PTFE grafts.76 After placement of the graft, it is covered with peritoneum or omentum before defini-tive treatment of the enteric injuries.Transposition procedures can be used when an artery has a bifurcation and one vessel can be ligated safely. Injuries of the proximal internal carotid can be treated by mobilizing the adja-cent external carotid, dividing it distal to the internal injury, and performing an end-to-end anastomosis between it and the distal internal carotid (Fig. 7-46). The proximal stump of the internal carotid is oversewn, with care taken to avoid a blind pocket where a clot may form. Injuries of the common and external iliac arteries can be handled in a similar fashion (Fig. 7-47), while maintaining flow in at least one internal iliac artery.Venous injuries should be repaired when technically fea-sible. Small injuries without loss of tissue can be treated with lateral suture repair. More complex repairs with interposition grafts may thrombose, but this typically occurs gradually over 1 to 2 weeks. During this time adequate collateral circulation develops, which is sufficient to avoid acute venous hyperten-sion. Therefore, it is reasonable to use ringed PTFE for venous interposition grafting and accept a gradual, but eventual, throm-bosis while allowing time for collateral circulation to develop. Such an approach is reasonable for venous injuries of the supe-rior vena cava, suprarenal vena cava, SMV, and popliteal vein because ligation of these is associated with significant morbid-ity. In the remainder of venous injuries, the vein may be ligated. In such patients, chronic venous hypertensive complications in the lower extremities often can be avoided by (a) temporary use of elastic bandages (Ace wraps) applied from the toes to the hips at the end of the procedure, and (b) judicious elevation of the lower extremities. These measures should be maintained for Brunicardi_Ch07_p0183-p0250.indd 21410/12/18 6:19 PM 215TRAUMACHAPTER 7Figure 7-46. Carotid transposition is an effective approach for treating injuries of the proximal internal carotid artery.ABCFigure 7-47. Transposition procedures can be used for iliac artery injuries to eliminate the dilemma of placing an interposition polytetra-fluoroethylene graft in the presence of enteric contamination. A. Right common iliac artery transposed to left common iliac artery. B. Left internal iliac artery transposed to the distal right common iliac artery. C. Right internal iliac artery transposed to the right external iliac artery.1 week; if the patient has no peripheral edema with ambulation, these maneuvers are no longer required.Damage Control SurgeryThe recognition of the bloody vicious cycle and the introduction of damage control surgery (DCS) have improved the survival of critically injured patients. Conceptually, the bloody vicious cycle, first described in 1981, is the lethal combination of coag-ulopathy, hypothermia, and metabolic acidosis (Fig. 7-48).56 Hypothermia from evaporative and conductive heat loss and diminished heat production occurs despite the use of warming blankets and blood warmers. The metabolic acidosis of shock is exacerbated by aortic clamping, administration of vasopres-sors, massive RBC transfusions, and impaired myocardial per-formance. The ACOT, described previously, is compounded by hemodilution, hypothermia, and acidosis. Once the cycle starts, each component magnifies the other, which leads to a down-ward spiral and ultimately a fatal arrhythmia. The purpose of DCS is to limit operative time so that the patient can be returned to the SICU for physiologic restoration and the cycle thereby broken. Indications to limit the initial operation and institute DCS techniques include a combination of refractory hypother-mia (temperature <35°C), profound acidosis (arterial pH <7.2, base deficit >15 mmol/L), and refractory coagulopathy.56,77 The decision to abbreviate a trauma laparotomy is made intraopera-tively as the patient’s clinical course becomes clearer and labo-ratory values become available.The goal of DCS is to control surgical bleeding and limit GI spillage. The operative techniques used are temporary mea-sures, with definitive repair of injuries delayed until the patient is physiologically replete. Controlling surgical bleeding while preventing ischemia is of utmost importance during DCS. Aortic injuries must be repaired using an interposition PTFE Brunicardi_Ch07_p0183-p0250.indd 21510/12/18 6:19 PM 216BASIC CONSIDERATIONSPART Igraft. Although celiac artery injuries may be ligated, the SMA must maintain flow, and the early insertion of an intravascu-lar shunt is advocated. Similarly, perfusion of the iliac system and infrainguinal vessels can be restored with a vascular shunt, with interposition graft placement delayed. Arterial reconstruc-tion following shunt placement should be done optimally within 6 hours.78 Venous injuries are preferentially treated with ligation in damage control situations, except for the suprarenal inferior vena cava and popliteal vein. For extensive solid organ injuries to the spleen or one kidney, excision is indicated rather than an attempt at operative repair. For hepatic injuries, perihe-patic packing of the liver will usually tamponade bleeding (see Fig. 7-37). Translobar gunshot wounds of the liver are best con-trolled with balloon catheter tamponade, whereas deep lacera-tions can be controlled with Foley catheter inflation deep within the injury track (Fig. 7-49). For thoracic injuries requiring DCS several options exist. For bleeding peripheral pulmonary inju-ries, wedge resection using a stapler is performed. In penetrating injuries, pulmonary tractotomy is used to divide the parenchyma (Fig. 7-50); individual vessels and bronchi are then ligated using a 3-0 polydioxanone suture (PDS), and the track is left open. Patients who sustain more proximal injuries may require formal pulmonary resection, but pneumonectomy is poorly tolerated. Recent experimental work suggests inhaled nitric oxide (NO) will reduce right heart failure following pneumonectomy.79 Car-diac injuries may be temporarily controlled using a running 3-0 nonabsorbable polypropylene suture or skin staples. Pledgeted repair should be performed for the relatively thin right ventricle.The second key component of DCS is limiting enteric content spillage. Small GI injuries (stomach, duodenum, small intestine, and colon) may be controlled using a rapid whipstitch of 3-0 PDS. Complete transection of the bowel or segmental damage is controlled using a GIA stapler, often with resection of the injured segment. Alternatively, open ends of the bowel may be ligated using umbilical tapes to limit spillage. Pancreatic injuries, regardless of location, are packed and the evaluation of ductal integrity postponed. Urologic injuries may require cath-eter diversion. Before the patient is returned to the SICU, the abdomen must be closed temporarily. Temporary closure of the abdomen is accomplished using an antimicrobial surgical incise drape (Ioban, 3M Health Care, St Paul, MN) (Fig. 7-51). In this technique, the bowel is covered with a fenestrated subfascial sterile drape (45 × 60 cm Steri-Drape 3M Health Care), and two Jackson-Pratt drains are placed along the fascial edges; this is Severe TraumaBlood LossTissue InjuryMassive RBCTransfusionIatrogenicFactorsCellularShockCoreHypothermiaMetabolic AcidosisHypocalcemiaImmuno-ActivationActivation/Consumptionof Complement SystemProgressiveSystemicCoagulopathyAcuteEndogenousCoagulopathyClotting FactorDeficienciesPreexistingDiseasesFFP resistantFFP sensitiveFigure 7-48. The bloody vicious cycle. FFP = fresh frozen plasma; RBC = red blood cell.Brunicardi_Ch07_p0183-p0250.indd 21610/12/18 6:19 PM 217TRAUMACHAPTER 7Figure 7-49. A. An intrahepatic balloon used to tamponade hemorrhage from transhepatic penetrating injuries is made by placing a red rubber catheter inside a 1-inch Penrose drain, with both ends of the Penrose drain ligated. B. Once placed inside the injury tract, the balloon is inflated with saline until hemorrhage stops. C. A Foley catheter with a 30-mL balloon can be used to halt hemorrhage from deep lacerations to the liver.Figure 7-50. Pulmonary tractotomy divides the pulmonary paren-chyma using a gastrointestinal anastomosis (GIA) stapler. The opened track permits direct access to injured vessels or bronchi for individual ligation.then covered using an Ioban drape, which allows closed suction to control reperfusion-related ascitic fluid egress while provid-ing adequate space for bowel expansion to prevent abdomi-nal compartment syndrome. During the initial DCS stage, the subfascial sterile drape is not covered by a blue towel so that the status of the bowel and hemorrhage control can be assessed. The use of direct peritoneal resuscitation following DCS should be considered; 18 Fr round Blake drains may be placed intraop-eratively for the instillation of the dialysate solution.80 Return to the OR within 24 hours is planned once the patient clini-cally improves, as evidenced by normothermia, normalization of coagulation test results, and correction of acidosis.TREATMENT OF SPECIFIC INJURIESHead InjuriesIntracranial Injuries. CT scanning, performed on all patients with a significant closed head injury (GCS score <14), identi-fies and quantitates intracranial lesions as well as intracranial hypertension. Patients with intracranial hemorrhage, including epidural hematoma, subdural hematoma, subarachnoid hemor-rhage, intracerebral hematoma or contusion, and diffuse axo-nal injury, are admitted to the SICU. In patients with abnormal findings on CT scans and GCS scores of ≤8, intracranial pres-sure (ICP) should be monitored using fiber-optic intraparenchy-mal devices or intraventricular catheters.33,81 Although an ICP of 10 mmHg is the upper limit of normal, therapy is targeted to maintain an ICP of <20 mmHg.33 The newest neurosurgery guidelines additionally recommend maintaining the cerebral perfusion pressure (CPP) at >60 mmHg. Indications for opera-tive intervention to remove space-occupying hematomas are based on the clot volume, amount of midline shift, location of the clot, GCS score, and ICP.29 A shift of >5 mm typically is considered an indication for evacuation, but this is not an abso-lute rule. Smaller hematomas that are in treacherous locations, such as the posterior fossa, may require drainage due to brain stem compression or impending herniation. Removal of small hematomas may also improve ICP and cerebral perfusion in patients with elevated ICP that is refractory to medical therapy. Patients with diffuse cerebral edema resulting in excessive ICP may require a decompressive craniectomy, although a recent AAST multicenter trial questioned the benefits.82,83 Patients with open or depressed skull fractures, with or without sinus involvement, may require operative intervention. Penetrating injuries to the head may require operative intervention for hem-orrhage control, evacuation of blood, skull fracture fixation, or debridement.General surgeons in communities without emergency neu-rosurgical coverage should have a working knowledge of burr hole placement in the event that emergent evacuation is required for a life-threatening epidural hematoma (Fig. 7-52).84 The typi-cal clinical course of an epidural hematoma is an initial loss of consciousness, a lucid interval, and recurrent loss of conscious-ness with an ipsilateral fixed and dilated pupil. While decom-pression of subdural hematomas may be delayed, epidural hematomas require evacuation within 70 minutes.83 The final stages of this sequence are caused by blood accumulation that forces the temporal lobe medially, with resultant compression of the third cranial nerve and eventually the brain stem. The burr hole is made on the side of the dilated pupil to decompress the intracranial space. After stabilization, the patient is transferred to a facility with neurosurgical capability for formal craniotomy.In addition to operative intervention, postinjury care directed at limiting secondary injury to the brain is critical. The goal of resuscitation and management in patients with head injuries is to avoid hypotension (SBP of <100 mmHg) and hypoxia (partial pressure of arterial oxygen of <60 or arterial oxygen saturation of <90%).33 Attention, therefore, is focused on maintaining cerebral perfusion rather than merely lowering Brunicardi_Ch07_p0183-p0250.indd 21710/12/18 6:20 PM 218BASIC CONSIDERATIONSPART IABCDFigure 7-51. Temporary closure of the abdomen entails covering the bowel with a fenestrated subfascial 45 × 60 cm sterile drape (A), placing Jackson-Pratt drains along the fascial edge (B), and then occluding with an Ioban drape (C, D).ICP. Resuscitation efforts aim for a euvolemic state and a SBP of >100 mmHg. Cerebral perfusion pressure (CPP) is equal to the mean arterial pressure minus the ICP, with a target range of >60 mmHg.33 CPP can be increased by either lowering ICP or raising mean arterial pressure. Sedation, osmotic diuresis, paralysis, ventricular drainage, and barbiturate coma are used in sequence, with coma induction being the last resort. The role of decompressive craniectomy for refractory ICH remains contro-versial.82 The partial pressure of carbon dioxide (PCO2) should be maintained in a normal range (35–40 mmHg), but for tem-porary management of acute intracranial hypertension, induc-ing cerebral vasoconstriction by hyperventilation to a PCO2 of Brunicardi_Ch07_p0183-p0250.indd 21810/12/18 6:20 PM 219TRAUMACHAPTER 7<30 mmHg is occasionally warranted. Moderate hypothermia (32°–33°C [89.6°–91.4°F]) has been shown experimentally to improve neurologic outcomes, but clinical studies have not vali-dated this concept.33,85,86 Patients with intracranial hemorrhage should be monitored for postinjury seizures, and prophylactic anticonvulsant therapy is indicated for 7 days after injury.33Maxillofacial Injuries. Maxillofacial injuries are common with multisystem trauma and require coordinated management by the trauma surgeon and the specialists in otolaryngology, plastic surgery, ophthalmology, and oral and maxillofacial surgery. Delay in addressing these systems that control vision, hearing, smelling, breathing, eating, and phonation may pro-duce dysfunction and disfigurement with serious psychological impact. The maxillofacial complex is divided into three regions; the upper face containing the frontal sinus and brain; the mid-face containing the orbits, nose, and zygomaticomaxillary com-plex; and the lower face containing the mandible. High-impact kinetic energy is required to fracture the frontal sinus, orbital rims, and mandible, whereas low-impact forces will injure the nasal bones and zygoma.The most common scenario, which at times may be life-threatening, is bleeding from facial fractures.87 Temporizing measures include nasal packing, Foley catheter tamponade of posterior nasal bleeding, and oropharyngeal packing. Prompt angioembolization will halt exsanguinating hemorrhage. Frac-tures of tooth-bearing bone are considered open fractures and require antibiotic therapy and semiurgent repair to preserve the Figure 7-52. A burr hole is made for decompression of an epidural hematoma as a life-saving maneuver. One or more branches of the external carotid artery usually must be ligated to gain access to the skull. No attempt should be made to control intracranial hemor-rhage through the burr hole. Rather, the patient’s head should be wrapped with a bulky absorbent dressing and the patient transferred to a neurosurgeon for definitive care.Figure 7-53. Three-dimensional computed tomography scan illustrating Le Fort II maxillary (L) and alveolar (A) fractures, and fracture of the mandible (M) at the midline and at the weaker con-dyle (C). (Used with permission from Vincent D. Eusterman, MD, DDS.)airway as well as the functional integrity of the occlusion (bite) and the aesthetics of the face. Orbital fractures may compro-mise vision, produce muscle injury causing diplopia, or change orbital volume to produce a sunken appearance to the orbit. Nose and nasoethmoidal fractures should be assessed carefully to identify damage to the lacrimal drainage system or to the cribriform plate producing cerebrospinal fluid rhinorrhea. After initial stabilization, a systematic physical examination of the head and neck should be performed that also includes cranial nerve examination and three-dimensional CT scanning of the maxillofacial complex (Fig. 7-53).Cervical InjuriesSpine. Treatment of injuries to the cervical spine is based on the level of injury, the stability of the spine, the presence of subluxation, the extent of angulation, the level of neurologic deficit, and the overall condition of the patient. In general, phy-sician-supervised axial traction, via cervical tongs or the more commonly used halo vest, is used to reduce subluxations and stabilize the injury. Immobilization of injuries also is achieved with spinal orthoses (braces), particularly in those with asso-ciated thoracolumbar injuries. Surgical fusion typically is performed in patients with neurologic deficit, those with angu-lation of >11° or translation of >3.5 mm, and those who remain unstable after halo placement. Indications for immediate opera-tive intervention are deterioration in neurologic function and fractures or dislocations with incomplete deficit. Historically, methylprednisolone was administered to patients with acute spi-nal cord injury after blunt injury, with clinical data suggesting a small benefit to initiating a 24-hour infusion if started within 3 hours and a 48-hour infusion if started within 3 to 8 hours.88 Current guidelines, however, no longer recommend steroids for acute injuries.89 The role and timing of operative surgical decompression after acute spinal cord injury is debated, and Brunicardi_Ch07_p0183-p0250.indd 21910/12/18 6:20 PM 220BASIC CONSIDERATIONSPART Ithe concept of damage control has been suggested. However, evidence supports urgent decompression of bilateral locked fac-ets in patients with incomplete tetraplegia or with neurologic deterioration. Performing surgery within 24 hours may decrease length of stay and complications.90 Complete injuries of the spi-nal cord remain essentially untreatable. Yet, approximately 3% of patients who present with flaccid quadriplegia have concus-sive injuries, and these patients represent the very few who seem to have miraculous recoveries.Vascular. Cervical vascular injuries due to either blunt or pen-etrating trauma can result in devastating neurologic sequelae or exsanguination. Penetrating injuries to the carotid artery and internal jugular vein usually are obvious on operative neck exploration. The principles of vascular repair techniques (dis-cussed previously) apply to carotid injuries, and options for repair include end-to-end primary repair (often possible with mobilization of the common carotid), graft interposition, and transposition procedures. All carotid injuries should be repaired except in patients who present in coma with a delay in transport. Prompt revascularization of the internal carotid artery, using a temporary Pruitt-Inahara shunt, should be considered in patients arriving in profound shock. Otherwise, carotid shunting should be done selectively as in elective carotid endarterectomy, but the patient should be systemically anticoagulated. Currently, we administer heparin with an ACT target of 250 sec. Tangential wounds of the internal jugular vein should be repaired by lateral venorrhaphy, but extensive wounds are efficiently addressed by ligation. However, it is not advisable to ligate both jugular veins due to potential intracranial hypertension. Vertebral artery inju-ries due to penetrating trauma are difficult to control operatively because of the artery’s protected location within the foramen transversarium. Although exposure from an anterior approach can be accomplished by removing the anterior elements of the bony canal and the tough fascia covering the artery between the elements, typically the most efficacious control of such inju-ries is angioembolization. Fogarty catheter balloon occlusion, however, is useful for controlling acute bleeding if encountered during neck exploration.Blunt injury to the carotid or vertebral arteries may cause dissection, thrombosis, or pseudoaneurysm, typically in the surgi-cally inaccessible distal internal carotid (Fig. 7-54).91 Early recog-nition and management of these injuries is paramount because patients treated with antithrombotics have a stroke rate of <1% compared with stroke rates of 20% in untreated patients.92 Because treatment must be instituted during the latent period between injury and onset of neurologic sequelae, diagnostic imaging is performed based on identified risk factors (Fig. 7-55).92 After identification of an injury, antithrombotics are administered if the patient does not have contraindications (intra-cranial hemorrhage, falling hemoglobin level with solid organ injury or complex pelvic fractures). Heparin, started without a loading dose at 15 units/kg per hour, is titrated to achieve a PTT between 40 and 50 seconds or antiplatelet agents are initiated (aspirin 325 mg/d or clopidogrel 75 mg/d). The types of 9Figure 7-54. The Denver grading scale for blunt cerebrovascular injuries. Grade I: irregularity of the vessel wall, dissection/intramural hematoma with <25% luminal stenosis. Grade II: visualized intraluminal thrombus or raised intimal flap, or dissection/intramural hematoma with 25% or more luminal narrowing. Grade III: pseudoaneurysm. Grade IV: vessel occlusion. CAI = carotid artery injury; VAI = vertebral artery injury.Brunicardi_Ch07_p0183-p0250.indd 22010/12/18 6:20 PM 221TRAUMACHAPTER 7Yes Yes NoNoMulti-Slice CTA*Surgically Accessible?Grade I Injury Antithrombotic Therapy: Heparin (PTT 40–50 sec)or Antiplatelet Therapy**NoDiscontinue AntithromboticsRepeat CTA in 7–10 days***Injury Healed? Yes NoPositive Equivocal Finding or High Clinical Suspicion ArteriogramNoYes Negative Grade II–IV Injury Grade V Injury Operative Repair Endovascular Treatment Yes StopStop Surgically Accessible?Potential arterial hemorrhage from neck/nose/mouthCervical bruit in pt <50 yrs oldExpanding cervical hematomaFocal neurologic defect: TIA, hemiparesis, vertebrobasilar symptoms, Horner’s SyndromeNeurologic deÿcit inconsistent with head CTStroke on CT or MRISigns/Symptoms of BCVIThe Denver Health Medical Center BCVI screening guideline.High energy transfer mechanismDisplaced mid-face fracture (LeFort II or III)Mandible fractureComplex skull fracture/basilar skull fracture/occipital condyle fractureSevere Traumatic Brain Injury (TBI) with GCS <6Cervical spine fracture, subluxation or ligamentous injury at any levelNear hanging with anoxic injury/ strangulations with LOCClothesline type injury or seat belt abrasion with signiÿcant swelling, pain, or altered MSTBI with thoracic injuriesScalp deglovingThoracic vascular injuriesBlunt cardiac ruptureUpper rib fractures (1–3)Risk Factors for BCVIAntithrombotics for 3–6 months and reimageConsider endovascular stenting for severe luminal narrowing, symptomatology, or markedly expanding pseudoaneurysm* CTA with multidetector-row CT, 64-channel optimal. If fewer than 16 channels, interpret CTA with caution; digital subtraction arteriogra-phy is the gold standard.** Antiplatelet therapy is typically ASA 325 mg.*** If CC fistula and symptomatic, consider angiography and endovascular therapy. If asymptomatic CC fistula, reimage with CTA at 3–4 weeks.Figure 7-55. Screening and treatment algorithm for blunt cerebrovascular injuries (BCVIs). ASA = acetylsalicylic acid; BRB = bright red blood; CHI = closed head injury; C-spine = cervical spine; CT = computed tomography; DAI = diffuse axonal injury; GCS = Glasgow Coma Scale score; MRI = magnetic resonance imaging; MS = mental status; Neg = negative; pt = patient; PTT = partial thromboplastin time; TIA = transient ischemic attack.antithrombotic treatment appear equivalent in published studies to date, and the duration of treatment is empirically recommended to be 6 months.93,94 The role of carotid stenting for grade II or III internal carotid artery injuries remain controversial; current litera-ture suggests stenting be reserved for symptomatic patients or markedly enlarging pseudoaneurysms.95 Thrombosis of the internal jugular veins caused by blunt trauma can occur unilaterally or bilaterally and is often discovered incidentally because most patients are asymptomatic. Bilateral thrombosis can aggravate cerebral edema in patients with serious head injuries; stent placement should be considered in such patients if ICP remains elevated.Brunicardi_Ch07_p0183-p0250.indd 22110/12/18 6:20 PM 222BASIC CONSIDERATIONSPART IAerodigestive. Fractures of the larynx and trachea may mani-fest as cervical emphysema. Fractures documented by CT scan are usually repaired. Common injuries include thyroid carti-lage fractures, rupture of the thyroepiglottic ligament, disrup-tion of the arytenoids or vocal cord tears, and cricoid fractures. After debridement of devitalized tissue, tracheal injuries are repaired end-to-end using a single layer of interrupted absorb-able sutures. Associated injuries of the esophagus are common in penetrating injuries due to its close proximity. After debride-ment and repair, vascularized tissue is interposed between the repaired esophagus and trachea, and a closed suction drain is placed. The sternocleidomastoid muscle or strap muscles are useful for interposition and help prevent postoperative fistulas.Chest InjuriesThe most common injuries from both blunt and penetrating thoracic trauma are hemothorax and pneumothorax. More than 85% of patients can be definitively treated with a chest tube. The indications for thoracotomy include significant initial or ongoing hemorrhage from the tube thoracostomy and specific imaging-identified diagnoses (Table 7-10). One caveat concerns the patient who presents after a delay. Even when the initial chest tube output is 1.5 L, if the output ceases and the lung is reexpanded, the patient may be managed nonoperatively if hemodynamically stable.Great Vessels. Over 90% of thoracic great vessel injuries are due to penetrating trauma, although blunt injury to the innomi-nate, subclavian, or descending aorta may cause a pseudoaneu-rysm or frank rupture.46,96,97 Simple lacerations of the ascending or transverse aortic arch can be repaired with lateral aortor-rhaphy. Repair of posterior aortic injuries, complex ascending or transverse injuries, or those requiring interposition grafting of the arch, require full cardiopulmonary bypass. Innominate artery injuries are repaired using the bypass exclusion tech-nique,97 which avoids the need for cardiopulmonary bypass. Bypass grafting from the proximal aorta to the distal innominate with a prosthetic tube graft is performed before the postinjury hematoma is entered. The PTFE graft is anastomosed end-to-side from the proximal undamaged aorta and anastomosed end-to-end to the innominate artery (Fig. 7-56). The origin of the ABCFigure 7-56. A. Angiography reveals a 1-cm pseudoaneurysm of the innominate artery origin. B. In the first stage of the bypass exclusion technique, a 12-mm polytetrafluoroethylene graft is anastomosed end to side from the proximal undamaged aorta, tunneled under the vein, and anastomosed end to end to the innominate artery. C. The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm.Table 7-10Indications for operative treatment of thoracic injuries• Initial tube thoracostomy drainage of >1000 mL (penetrating injury) or >1500 mL (blunt injury)• Ongoing tube thoracostomy drainage of >200 mL/h for 3 consecutive hours in noncoagulopathic patients• Caked hemothorax despite placement of two chest tubes• Great vessel injury (endovascular techniques may be used in selected patients)• Pericardial tamponade• Cardiac herniation• Massive air leak from the chest tube with inadequate ventilation• Tracheal or main stem bronchial injury diagnosed by endoscopy or imaging• Open pneumothorax• Esophageal perforation• Air embolisminnominate is then oversewn at its base to exclude the pseu-doaneurysm or other injury. Subclavian artery injuries can be repaired using lateral arteriorrhaphy or PTFE graft interposition; due to its multiple branches and tethering of the artery, end-to-end primary anastomosis is not advocated if there is a significant segmental loss.Descending BAI may require urgent intervention. How-ever, operative intervention for intracranial or intra-abdominal hemorrhage or unstable pelvic fractures takes precedence. To prevent aortic rupture, pharmacologic therapy with a selective β1-antagonist, esmolol, should be instituted in the trauma bay, with a target SBP of <100 mmHg and heart rate of <100/min.41,98 Endovascular stenting is now the mainstay of treatment.99,100 While endograft sizing has improved, the major question is long-term outcome in younger patients. Open repair of the descending aorta is accomplished using partial left heart bypass to prevent spinal cord and splanchnic ischemia and reduce left ventricular afterload (Fig. 7-57).101 Nonoperative management for grade I Brunicardi_Ch07_p0183-p0250.indd 22210/12/18 6:20 PM 223TRAUMACHAPTER 7LAFigure 7-57. When repairing a tear of the descending thoracic aorta, perfusion of the spinal cord while the aorta is clamped is achieved by using partial left heart bypass. The venous cannula is inserted into the left superior pulmonary vein because it is less prone to tearing than the left atrium (LA).Figure 7-58. A variety of techniques may be necessary to repair cardiac wounds. Generally, pledget support is used for the relatively thin-walled right ventricle.intimal aortic injuries is accomplished with antiplatelet agents and blood pressure control.102Heart. Blunt and penetrating cardiac injuries have widely dif-fering presentations and therefore disparate treatments. Survivable penetrating cardiac injuries consist of wounds that can be repaired operatively; most are stab wounds. Before repair of the injury is attempted, hemorrhage should be controlled; injuries to the atria can be clamped with a Satinsky vascular clamp, whereas digital pressure is used to occlude the majority of ventricular wounds. Foley catheter occlusion of larger stellate lesions is described, but even minimal traction may enlarge the original injury. Temporary control of hemorrhage, and at times definitive repair, may be accomplished with skin staples for left ventricular lacerations; the myocardial edges of the laceration must coapt in diastole for stapling to be technically feasible. Definitive repair of cardiac injuries is performed with either running 3-0 polypropylene suture or interrupted, pledgeted 2-0 polypropylene suture (Fig. 7-58).103 Use of pledgets may be particularly important in the right ventricle to prevent sutures from pulling through the thinner myocardium. Injuries adjacent to coronary arteries should be repaired using horizontal mattress sutures because use of running sutures results in coronary occlu-sion and distal infarction. Gunshot wounds may result in stellate lesions or contused, extremely friable myocardium adjacent to the wound. When the edges of such complex wounds cannot be fully approximated and hence the repair is not hemostatic, the authors have used surgical adhesive (BioGlue) to achieve hemo-stasis.104 Occasionally, interior structures of the heart may be damaged. Intraoperative auscultation or postoperative hemody-namic assessment usually identifies such injuries.105 ECHO can diagnose the injury and quantitate its effect on cardiac output. Immediate repair of valvular damage or septal defects rarely is necessary and would require cardiopulmonary bypass, but struc-tural intracardiac lesions may progress, and thus patients must have a follow-up ECHO.Patients with blunt cardiac injury typically present with persistent tachycardia or conduction disturbances, but occa-sionally present with tamponade due to atrial or right ventricu-lar rupture. There are no pathognomonic ECG findings, and cardiac enzyme levels do not correlate with the risk of cardiac complications.25 Therefore, patients for whom there is high clinical suspicion of cardiac contusion and who are hemody-namically stable should be monitored for dysrhythmias for 24 hours by telemetry. Patients with hemodynamic instability should undergo ECHO to evaluate for wall motion abnormali-ties (particularly hypokinesis of the right ventricle), pericardial fluid, valvular dysfunction, chordae rupture, or diminished ejection fraction. If such findings are noted or if vasoactive agents are required, cardiac function can be continuously moni-tored using a pulmonary artery catheter and serial SICU trans-thoracic or transesophageal ECHO.Trachea, Bronchi, and Lung Parenchyma. Less than 1% of all injured patients sustain intrathoracic tracheobronchial Brunicardi_Ch07_p0183-p0250.indd 22310/12/18 6:20 PM 224BASIC CONSIDERATIONSPART Iinjuries, and only a small number require operative intervention. Although penetrating injuries may occur throughout the tracheo-bronchial system, blunt injuries most commonly occur within 2.5 cm of the carina. For patients with a massive air leak requir-ing emergent exploration, initial control of the injury to provide effective ventilation is obtained by passing an endotracheal tube either beyond the injury or into the contralateral mainstem bron-chus. Principles of repair are similar to those for repair of cervi-cal tracheal injuries. Devitalized tissue is debrided, and primary end-to-end anastomosis with 3-0 PDS suture is performed. Dis-section should be limited to the area of injury to prevent disrup-tion of surrounding bronchial vasculature and ensuing ischemia and stricture. Suture lines should be encircled with vascularized tissue, either pericardium, intercostal muscle, or pleura. Expect-ant management is employed for bronchial injuries that are less than one-third the circumference of the airway and have no evi-dence of a persistent major air leak.11,12 In patients with periph-eral bronchial injuries, indicated by persistent air leaks from the chest tube and documented by endoscopy, bronchoscopically directed fibrin glue sealing may be useful.The majority of pulmonary parenchymal injuries are sus-pected based upon identification of a pneumothorax; the vast majority can be managed with a tube thoracostomy. Identified parenchymal injuries encountered during thoracic exploration for a massive hemothorax are managed without resection as much as possible. Bronchovenous fistula is a constant threat and should be minimized by prompt control of a major air leak. Peripheral lacerations with persistent bleeding can be managed with stapled wedge resection. For central injuries, the current treatment is pulmonary tractotomy, which permits selective ligation of individual bronchioles and bleeders, pre-vents the development of an intraparenchymal hematoma or air embolism, and reduces the need for formal lobar resection (see Fig. 7-50).106,107 A stapling device, preferably the longest stapler available (e.g., GIA-100), is inserted directly into the injury track and positioned along the thinnest section of overly-ing parenchyma. The injury track is thus filleted open, which allows direct access to the bleeding vessels and leaking bronchi. The majority of injuries are definitively managed with selective ligation, and the defect is left open. Occasionally, tractotomy reveals a more proximal vascular on bronchial injury that must be treated with formal lobectomy. Injuries severe enough to mandate pneumonectomy usually are fatal because of right heart decompensation.108One parenchymal injury that may be discovered during thoracic imaging is a posttraumatic pulmonary pseudocyst, col-loquially termed a pneumatocele.109 Traumatic pneumatoceles typically follow a benign clinical course and are treated with aggressive pain management, pulmonary toilet, and serial chest radiography to monitor for resolution of the lesion. If the patient has persistent fever or leukocytosis, however, chest CT is done to evaluate for an evolving abscess because pneumatoceles may become infected. CT-guided catheter drainage may be required in such cases because 25% of patients do not respond to anti-biotic therapy alone. Surgery, ranging from partial resection to anatomic lobectomy, is indicated for unresolving complex pneumatoceles or infected lesions refractory to antibiotic ther-apy and drainage.The most common complication after thoracic injury is development of an empyema. Management is based on CT diagnostic criteria.110 Percutaneous drainage is indicated for a single loculation without appreciable rind. While fibrinolytics are often used for empyema, there is a paucity of data to support their use. Early decortication via video-assisted thoracic surgery should be done promptly in patients with multiple loculations or a pleural rind of >1 cm.111 Antibiotic treatment is based on definitive culture results, but presumptive antibiotics should cover MRSA in the SICU.Esophagus. Due to the proximity of the structures, esophageal injuries often occur with tracheobronchial injuries, particularly in cases of penetrating trauma. Operative options are based on the extent and location of esophageal injury. With sufficient mobilization, a primary single-layer end-to-end anastomosis may be performed after appropriate debridement. As with cer-vical repairs, if there are two suture lines in close approximation (trachea or bronchi and esophagus) interposition of a vascular-ized pedicle is warranted to prevent fistula formation. Perfora-tions at the gastroesophageal junction may be treated with repair and Nissan fundoplication or, for destructive injuries, segmen-tal resection and gastric pull-up. Small esophageal injuries can be managed with stenting. With large destructive injuries or delayed presentation of injuries, esophageal exclusion with wide drainage, diverting loop esophagostomy, and placement of a gastrostomy tube should be considered.Chest Wall and Diaphragm. Virtually all chest wall injuries, consisting of rib fractures and laceration of intercostal vessels, are treated nonoperatively with pain control, pulmonary toilet or venti-latory management, and drainage of the pleural space as indicated. Early institution of effective pain control is essential. The authors advocate preemptive rib blocks with 0.25% bupivacaine hydrochlo-ride (Marcaine) in the trauma bay, followed by thoracic wall pain catheters.112 Epidural anesthesia is reserved for multiple segmen-tal fractures. Persistent hemorrhage from a chest tube after blunt trauma most often is due to injured intercostal arteries; for unusual persistent bleeding (see Table 7-10), thoracotomy with direct liga-tion or angioembolization may be required to arrest hemorrhage. In cases of extensive flail chest segments, markedly displaced bicortical rib fractures, or loss of 20% of the thoracic volume, open reduction and internal fixation of the fracture with plates may be warranted. Chest wall defects, particularly those seen with open pneumothorax, are repaired using local approximation of tissues or tissue transfer for coverage. Scapular and sternal fractures rarely require operative intervention but are markers for significant tho-racoabdominal force during injury; significant displacement may benefit from sternal plating (Fig. 7-59). Careful examination and imaging should exclude associated injuries, including blunt cardiac injury and descending BAI. On the other hand, clavicle fractures are often isolated injuries and should be managed with pain control and immobilization. The exception is posterior dislocation of the clavicular head, which may injure the subclavian vessels.Blunt diaphragmatic injuries usually result in a linear tear, and most injuries are large, whereas penetrating injuries are variable in size and location depending on the agent of injury. Regardless of the etiology, acute injuries are usually repaired through an abdominal approach to manage potential associated visceral injury. After delineation of the injury, the chest should be evacuated of all blood and particulate matter, and a thora-costomy tube placed if not previously done. Allis clamps are used to approximate the diaphragmatic edges, and the defect is closed with a running No. 1 polypropylene suture. Occasionally, large avulsions or shotgun wounds with extensive tissue loss will require polypropylene or biologic mesh to bridge the defect. Brunicardi_Ch07_p0183-p0250.indd 22410/12/18 6:20 PM 225TRAUMACHAPTER 7Alternatively, transposition of the diaphragm cephalad one to two intercostal spaces may allow repair without undue tension.73Abdominal InjuriesLiver and Extrahepatic Biliary Tract. The liver’s large size makes it the organ most susceptible to blunt trauma, and it is frequently involved in upper torso penetrating wounds. Nonop-erative management of solid organ injuries is pursued in hemo-dynamically stable patients who do not have overt peritonitis or other indications for laparotomy. Patients with >grade II injuries should be admitted to the SICU with frequent hemodynamic monitoring, determination of hemoglobin, and abdominal exam-ination. The only absolute contraindication to nonoperative management is hemodynamic instability from intraperitoneal hemorrhage. Factors such as high injury grade, large hemo-peritoneum, contrast extravasation, or pseudoaneurysms may predict complications or failure of nonoperative management. Angioembolization and endoscopic retrograde cholangiopan-creatography (ERCP) are useful adjuncts that can improve the success rate of nonoperative management.113,114 The indication for angiography to control hepatic hemorrhage is transfusion of 4 units of RBCs in 6 hours or 6 units of RBCs in 24 hours attributable to the liver.In the 15% of patients for whom emergent laparotomy is mandated, the primary goal is to arrest hemorrhage. Initial control of hemorrhage is best accomplished using perihepatic packing and manual compression. The edges of the liver laceration should be opposed for local pressure control of bleeding. Hemorrhage from most major hepatic injuries can be controlled with effec-tive perihepatic packing. The right costal margin is elevated, and the pads are strategically placed over and around the bleeding site (see Fig. 7-37). Additional pads should be placed between the liver, diaphragm, and anterior chest wall until the bleeding has been controlled. Sometimes 10 to 15 pads may be required to control the hemorrhage from an extensive right lobar injury. Packing of injuries of the left lobe is not as effective because there is insufficient abdominal and thoracic wall anterior to the left lobe to provide adequate compression with the abdomen open. Fortunately, hemorrhage from the left lobe usually can be controlled by mobilizing the lobe and compressing it between the surgeon’s hands. With extensive injuries and major hemorrhage, a Pringle maneuver should be done immediately. Intermittent release of the Pringle is helpful to attenuate hepatic cellular loss. ABFigure 7-59. Significant sternal displacement (A; arrows) can be reduced and stabilized with sternal plating (B).If the patient has persistent bleeding despite packing, injuries to the hepatic artery, portal vein, and retrohepatic vasculature should be considered. A Pringle maneuver can help delineate the source of hemorrhage. Hemorrhage from hepatic artery and portal vein injuries will halt with the application of a vascular clamp across the portal triad, whereas bleeding from the hepatic veins and the retrohepatic vena cava will continue despite a Pringle maneuver.Injuries of the portal triad vasculature should be addressed immediately. In general, ligation from the celiac axis to the level of the common hepatic artery at the gastroduodenal arterial branch is tolerated due to extensive collaterals, but the proper hepatic artery should be repaired. The right or left hepatic artery, or in urgent situations the portal vein, may be selectively ligated; occasionally, lobar necrosis will necessitate delayed anatomic resection. If the right hepatic artery is ligated, cholecystectomy also should be performed. If the vascular injury is a stab wound with clean transection of the vessels, primary end-to-end repair is done. If the injury is destructive, temporary shunting should be performed followed by interposition reversed saphenous vein graft (RSVG). Blunt avulsions of the portal structures are par-ticularly problematic if located at the hepatic plate, flush with the liver; hemorrhage control at the liver can be attempted with directed packing or Fogarty catheters. If injury to the portal triad vasculature is more proximal, at the superior border of the pancreatic body or even retropancreatic, the pancreas must be transected to gain access for hemorrhage control and repair.If massive venous hemorrhage is seen from behind the liver despite use of the Pringle maneuver, the patient likely has a hepatic vein or retrohepatic vena cava injury. If bleeding can be controlled with perihepatic packing, the packing should be left undisturbed and the patient observed in the SICU. Placement of a hepatic vein stent by interventional radiology may be considered. If bleeding continues despite repeated attempts at packing, then direct repair, with or without hepatic vascular isolation, should be attempted. Three techniques have been used to accomplish hepatic vascular isolation: (a) direct repair with suprahepatic and infrahepatic clamping of the vena cava and stapled assisted parenchymal resection115; (b) temporary shunting of the retrohe-patic vena cava; and (c) venovenous bypass (Fig. 7-60).116A number of methods for the definitive control of hepatic parenchymal hemorrhage have been developed. Minor lac-erations may be controlled with manual compression applied directly to the injury site. Topical hemostatic techniques include Brunicardi_Ch07_p0183-p0250.indd 22510/12/18 6:20 PM 226BASIC CONSIDERATIONSPART Ithe use of an electrocautery (with the device set at 100 watts), argon beam coagulator, microcrystalline collagen, thrombin-soaked gelatin foam sponge, fibrin glue, and BioGlue. Suturing of the hepatic parenchyma with a blunt tipped 0 chromic suture (e.g., a “liver suture”) can be an effective hemostatic technique. A running suture is used to approximate the edges of shal-low lacerations, whereas deeper lacerations are approximated using interrupted horizontal mattress sutures placed parallel to the edge of the laceration. When the suture is tied, tension is adequate when visible hemorrhage ceases or the liver blanches around the suture. Caution must be used to prevent hepatic necrosis. This technique of placing large liver sutures controls bleeding through reapproximation of the liver laceration rather than direct ligation of bleeding vessels. Aggressive finger frac-ture to identify bleeding vessels followed by individual clip or suture ligation was advocated previously but currently has a limited role in hemostasis. Hepatic lobar arterial ligation may be appropriate for patients with recalcitrant arterial hemorrhage from deep within the liver and is a reasonable alternative to a deep hepatotomy, particularly in unstable patients. Omen-tum can be used to fill large defects in the liver. The tongue of omentum not only obliterates potential dead space with viable tissue but also provides an excellent source of macrophages. Additionally, the omentum can provide buttressing support for parenchymal sutures.Translobar penetrating injuries are particularly challeng-ing because the extent of the injury cannot be fully visualized. As discussed in “Damage Control Surgery,” options include intraparenchymal tamponade with a Foley catheter or balloon occlusion (see Fig. 7-49).117 If tamponade is successful with either modality, the balloon is left inflated for 24 to 48 hours Figure 7-60. Venovenous bypass permits hepatic vascular isolation with continued venous return to the heart. IMV = inferior mesenteric vein; IVC = inferior vena cava; SMV = superior mesenteric vein.followed by sequential deflation and removal at a second lapa-rotomy. Hepatotomy with ligation of individual bleeders occa-sionally may be required; however, division of the overlying viable hepatic tissue may cause considerable blood loss in the coagulopathic patient. Finally, angioembolization is an effective adjunct in any of these scenarios and should be considered early in the course of treatment.Several centers have reported patients with devastat-ing hepatic injuries or necrosis of the entire liver who have undergone successful hepatic transplantation.118 Clearly this is dramatic therapy, and the patient must have all other injuries delineated, particularly those of the central nervous system, and have an excellent chance of survival excluding the hepatic injury. Because donor availability will limit such procedures, hepatic transplantation for trauma will continue to be performed only in extraordinary circumstances.Cholecystectomy is performed for injuries of the gallblad-der and after operative ligation of the right hepatic artery. Inju-ries of the extrahepatic bile ducts are a challenge due to their small size and thin walls. Because of the proximity of other portal structures and the vena cava, associated vascular inju-ries are common. These factors may preclude primary repair. Small lacerations with no accompanying loss or devitalization of adjacent tissue can be treated by the insertion of a T-tube through the wound or by lateral suturing using 6-0 monofila-ment absorbable suture. Virtually all transections and any injury associated with significant tissue loss will require a Roux-en-Y choledochojejunostomy. The anastomosis is performed using a single-layer interrupted technique with 5-0 monofilament absorbable suture. To reduce anastomotic tension, the jejunum should be sutured to the areolar tissue of the hepatic pedicle or porta hepatis. Injuries of the hepatic ducts are almost impos-sible to satisfactorily repair under emergent circumstances. One approach is to intubate the duct for external drainage and attempt a repair when the patient recovers or attempt stenting via ERC. Alternatively, the duct can be ligated if the opposite lobe is normal and uninjured.Patients undergoing perihepatic packing for extensive liver injuries typically are returned to the OR for pack removal 24 hours after initial injury. Earlier exploration may be indi-cated in patients with evidence of ongoing hemorrhage. Signs of rebleeding are usually conspicuous, and include a falling hemoglobin, accumulation of blood clots under the temporary abdominal closure device, and bloody output from drains; the magnitude of hemorrhage is reflected in ongoing hemodynamic instability and metabolic monitoring. Postoperative hemorrhage should be reevaluated in the OR once the patient’s coagulopa-thy is corrected. Alternatively, angioembolization is appropri-ate for complex injuries. Patients with hepatic ischemia due to prolonged intraoperative use of the Pringle maneuver have an expected elevation but subsequent resolution of transaminase levels, whereas patients requiring hepatic artery ligation may have frank hepatic necrosis. Although febrile patients should be evaluated for infectious complications, patients with complex hepatic injuries typically have intermittent “liver fever” for the first 5 days after injury.Aside from hemorrhage and hepatic necrosis, additional complications after significant hepatic trauma include bilomas, arterial pseudoaneurysms, and biliary fistulas (Fig. 7-61). Bilomas are loculated collections of bile, which may or may not be infected. If infected, they should be treated like an abscess via percutaneous drainage. Although small, sterile bilomas Brunicardi_Ch07_p0183-p0250.indd 22610/12/18 6:20 PM 227TRAUMACHAPTER 7Figure 7-61. Complications after hepatic trauma include bilomas (A; arrow), hepatic duct injuries (B), and hepatic necrosis after hepatic artery ligation or embolization (C).eventually will be reabsorbed, larger fluid collections should be drained. Biliary ascites, due to the disruption of a major bile duct, often requires reoperation and wide drainage. Primary repair of the injured intrahepatic duct is unlikely to be success-ful. Resectional debridement is indicated for the removal of peripheral portions of nonviable hepatic parenchyma.Pseudoaneurysms and biliary fistulas are rare complica-tions in patients with hepatic injuries. Because hemorrhage from hepatic injuries often is treated without isolating individ-ual bleeding vessels, arterial pseudoaneurysms may develop, with the potential for rupture. Rupture into a bile duct results in hemobilia, which is characterized by intermittent episodes of right upper quadrant pain, upper GI hemorrhage, and jaun-dice. If the aneurysm ruptures into a portal vein, portal venous hypertension with bleeding esophageal varices may occur. Either scenario is best managed with hepatic arteriography and embolization. Biliovenous fistulas, causing jaundice due to rapid increases in serum bilirubin levels, should be treated with ERCP and sphincterotomy. Rarely, a biliary fistulous commu-nication will form with intrathoracic structures in patients with associated diaphragm injuries, resulting in a bronchobiliary or pleurobiliary fistula. Due to the pressure differential between the biliary tract (positive) and the pleural cavity (negative), the majority require operative closure. Occasionally, endoscopic sphincterotomy with stent placement will be required to address the pressure differential, and the pleurobiliary fistula will close spontaneously.Spleen. Until the 1970s, splenectomy was considered manda-tory for all splenic injuries. Recognition of the immune function of the spleen refocused efforts on operative splenic salvage in the 1980s.119,120 After demonstrated success in pediatric patients, nonoperative management has become the preferred means of splenic salvage for all patients. The identification of contrast extravasation as a risk factor for failure of nonoperative man-agement led to liberal use of angioembolization. The role of selective angioembolization (SAE) continues to be defined, but appears warranted in high grade injuries, particularly those with contrast blush.121 It is clear, however, that up to 15% to 20% of patients with splenic trauma warrant early splenectomy and that failure of nonoperative management often represents inappro-priate patient selection.122,123 Indications for early intervention in adults include initiation of blood transfusion within the first 12 hours and hemodynamic instability. Unlike hepatic injuries, which usually rebleed within 48 hours, delayed hemorrhage or rupture of the spleen can occur up to weeks after injury.Splenic injuries are managed operatively by splenectomy, partial splenectomy, or splenic repair (splenorrhaphy), based on the extent of the injury and the physiologic condition of the patient. Splenectomy is indicated for significant hilar injuries, pulverized splenic parenchyma, or any >grade II injury in a patient with coagulopathy or multiple life-threatening inju-ries. The authors use autotransplantation of splenic implants (Fig. 7-62) to achieve partial immunocompetence in younger patients who do not have an associated enteric injury. Drains are not used. Partial splenectomy can be employed in patients in whom only the superior or inferior pole has been injured. Hem-orrhage from the raw splenic edge is controlled with horizontal mattress sutures, with gentle compression of the parenchyma (Fig. 7-63). During splenorrhaphy hemostasis is achieved by topical methods (electrocautery; argon beam coagulation; appli-cation of thrombin-soaked gelatin foam sponges, fibrin glue, or BioGlue), envelopment of the injured spleen in absorbable mesh, and pledgeted suture repair.After splenectomy or splenorrhaphy, postoperative hemor-rhage may be due to an improperly ligated or unrecognized short gastric artery, or recurrent bleeding from the splenic parenchyma if splenic repair was used. An immediate postsplenectomy Brunicardi_Ch07_p0183-p0250.indd 22710/12/18 6:20 PM 228BASIC CONSIDERATIONSPART Iincrease in platelets and WBCs is normal; however, beyond postoperative day 5, a WBC count above 15,000/mm3 and a platelet/WBC ratio of <20 are associated with sepsis and should prompt a thorough search for underlying infection.124 A com-mon infectious complication after splenectomy is a subphrenic abscess, which should be managed with percutaneous drain-age. Additional sources of morbidity include a concurrent or unrecognized iatrogenic injury to the pancreatic tail during rapid splenectomy resulting in pancreatic ascites or fistula, or gastric perforation during short gastric vessel ligation. Enthusiasm for splenic salvage was driven by the rare, but often fatal, compli-cation of overwhelming postsplenectomy sepsis. Overwhelm-ing postsplenectomy sepsis is caused by encapsulated bacteria, Streptococcus pneumoniae, Haemophilus influenzae, and Neis-seria meningitidis, which are resistant to antimicrobial treat-ment. In patients undergoing splenectomy, prophylaxis against these bacteria is provided via vaccines administered optimally at >14 days postinjury.125Stomach and Small Intestine. Little controversy exists regarding the repair of injuries to the stomach or small bowel because of a rich blood supply. Gastric wounds can be oversewn with a running single-layer suture line or closed with a stapler. If a single-layer closure is chosen, full-thickness bites should be taken to ensure hemostasis from the well-vascularized gastric Figure 7-63. Interrupted pledgeted sutures may effectively control hemorrhage from the cut edge of the spleen.Figure 7-62. Autologous splenic transplantation is performed by placing sections of splenic parenchyma, 40 × 40 × 3 mm in size, into pouches in the greater omentum.wall. The most commonly missed gastric injury is the posterior wound of a through and through penetrating injury. Injuries also can be overlooked if the wound is located within the mesen-tery of the lesser curvature or high in the fundus. To delineate a questionable injury, the stomach can be digitally occluded at the pylorus while methylene blue-colored saline is instilled via a nasogastric (NG) tube. Alternatively, air can be introduced via the NG tube with the abdomen filled with saline. Partial gastrectomy may be required for destructive injuries, with resec-tions of the distal antrum or pylorus reconstructed using a Bill-roth procedure. Patients with injuries that damage both Latarjet nerves or vagi should undergo a drainage procedure (see Chap-ter 26). Small intestine injuries can be repaired using a trans-verse running 3-0 PDS suture if the injury is less than one-third the circumference of the bowel. Destructive injuries or multiple penetrating injuries occurring close together are treated with segmental resection followed by end-to-end anastomosis using a continuous, single-layer 3-0 polypropylene suture.55 Mesenteric injuries may result in an ischemic segment of intestine, which mandates resection.Following repair of GI tract injuries, patients may develop a postoperative ileus. Return of bowel function is indicated by a decrease in gastrostomy or nasogastric tube output. The topic of nutrition is well covered in other chapters (see Chapter 2), but a few issues warrant mention. Multiple studies have con-firmed the importance of early total enteral nutrition (TEN) in the trauma population, particularly its impact in reducing septic complications.126 The route of enteral feedings (stomach vs. small bowel) tends to be less important because gut toler-ance appears equivalent unless there is upper GI tract pathol-ogy. Although early enteral nutrition is the goal, evidence of bowel function should be apparent before advancing to goal tube feedings. Overzealous jejunal feeding can lead to small bowel necrosis in the patient recovering from profound shock. Patients undergoing monitoring for nonoperative manage-ment of grade III or higher solid organ injuries should receive nothing by mouth for at least 48 hours in case they require an operation. Although there is general reluctance to initiate TEN in patients with an open abdomen, a recent multicenter trial demonstrates that TEN in the postinjury open abdomen is feasible.127 For those patients without a bowel injury, TEN was associated with higher fascial closure rates, decreased Brunicardi_Ch07_p0183-p0250.indd 22810/12/18 6:21 PM 229TRAUMACHAPTER 7complications, and decreased mortality. TEN in patients with bowel injuries does not appear to alter fascial closure rates, complications, or mortality; hence, EN appears to be neither advantageous nor detrimental in these patients. Once resuscita-tion is complete, initiation of TEN, even at trophic levels (20 mL/h), should be considered in all injured patients with an open abdomen.Duodenum and Pancreas. The spectrum of injuries to the duodenum includes hematomas, perforation (blunt blow-outs, lacerations from stab wounds, or blast injury from gunshot wounds), and combined pancreaticoduodenal injuries. The majority of duodenal hematomas are managed nonoperatively with nasogastric suction and parenteral nutrition. Patients with suspected associated perforation, suggested by clinical deterio-ration or imaging with retroperitoneal free air or contrast extrav-asation, should undergo operative exploration. A marked drop in nasogastric tube output heralds resolution of the hematoma, which typically occurs within 2 weeks; repeat imaging to con-firm these clinical findings is optional. If the patient shows no clinical or radiographic improvement within 3 weeks, operative evaluation is warranted.Small duodenal perforations or lacerations should be treated by primary repair using a running single-layer suture of 3-0 monofilament.128 The wound should be closed in a direc-tion that results in the largest residual lumen. Challenges arise when there is a substantial loss of duodenal tissue. Extensive injuries of the first portion of the duodenum (proximal to the duct of Santorini) can be repaired by debridement and end-to-end anastomosis because of the mobility and rich blood supply of the distal gastric atrium and pylorus. In contrast, the second portion is tethered to the head of the pancreas by its blood supply and the ducts of Wirsung and Santorini; therefore, no more than 1 cm of duodenum can be mobilized away from the pancreas. Moreover, suture repair using an end-to-end anastomosis in the second portion often results in an unacceptably narrow lumen. Therefore, defects in the second portion of the duodenum should be “patched” with a Roux-en-Y duodenojejunostomy. Duodenal injuries with tissue loss distal to the papilla of Vater and proximal to the superior mesenteric vessels are best treated by Roux-en-Y duodenojejunostomy with the distal portion of the duodenum oversewn (Fig. 7-64). In particular, injuries in the distal third and fourth portions of the duodenum (behind the mesenteric vessels) should be resected, and a duodenojejunostomy should be per-formed on the D3 side of the superior mesenteric vessels.Optimal management of pancreatic trauma is determined by where the parenchymal damage is located and whether the intra-pancreatic common bile duct and main pancreatic duct remain intact. Patients with pancreatic contusions (defined as injuries that leave the ductal system intact) can be treated nonoperatively or with closed suction drainage if undergoing laparotomy for other indications. Patients with proximal pancreatic injuries, defined as those that lie to the right of the superior mesenteric vessels, are also managed with closed suction drainage.129 In contrast, distal pancreatic injuries are managed based upon ductal integrity. Pan-creatic duct disruption can be identified through direct exploration of the parenchymal laceration, operative pancreatography, ERCP, or magnetic resonance cholangiopancreatography. Patients with distal ductal disruption undergo distal pancreatectomy, preferably with splenic preservation.Injuries to the pancreatic head add substantial complex-ity because the intrapancreatic portion of the common bile duct Figure 7-64. Roux-en-Y duodenojejunostomy is used to treat duo-denal injuries between the papilla of Vater and superior mesenteric vessels when tissue loss precludes primary repair.traverses this area and often converges with the pancreatic duct. In contrast to diagnosis of pancreatic duct injuries, identifica-tion of intrapancreatic common bile duct disruption is relatively simple. The first method is to squeeze the gallbladder and look for bile leaking from the pancreatic wound. Otherwise, cholan-giography, optimally via the cystic duct, is diagnostic. Definitive treatment of this injury entails division of the common bile duct superior to the first portion of the duodenum, with ligation of the distal duct and reconstruction with a Roux-en-Y choledochojeju-nostomy. For injuries to the head of the pancreas that involve the main pancreatic duct but not the intrapancreatic bile duct, there are few options. Distal pancreatectomy alone is rarely indicated due to the extended resection of normal gland and the resultant risk of pancreatic insufficiency. Central pancreatectomy pre-serves the common bile duct, and mobilization of the pancreatic body permits drainage into a posterior wall pancreaticogas-trostomy or a Roux-en-Y pancreaticojejunostomy (Fig. 7-65). Although this approach avoids a pancreaticoduodenectomy (Whipple procedure), the complexity may make the pancre-aticoduodenectomy more appropriate in patients with multiple injuries and is usually done in a damage control scenario. Some injuries of the pancreatic head do not involve either the pancre-atic or common bile duct; if no clear ductal injury is present, drains are placed. Rarely, patients sustain destructive injuries to the head of the pancreas or combined pancreaticoduodenal inju-ries that require pancreaticoduodenectomy. Examples of such injuries include transection of both the intrapancreatic bile duct and the main pancreatic duct in the head of the pancreas, avul-sion of the papilla of Vater from the duodenum, and destruction Brunicardi_Ch07_p0183-p0250.indd 22910/12/18 6:21 PM 230BASIC CONSIDERATIONSPART Iof the entire second portion of the duodenum. In these cases of extensive injuries, damage control principles are often employed.In contrast to proximal injuries, pancreatic resection con-tinues to be advocated for major ductal disruption in the more distal pancreas. Several options exist for treating injuries of the pancreatic body and tail. In stable patients, spleen-preserving distal pancreatectomy should be performed. An alternative, which preserves both the spleen and distal transected end of the pancreas, is either a Roux-en-Y pancreaticojejunostomy or pan-creaticogastrostomy. If the patient is physiologically compro-mised, distal pancreatectomy with splenectomy is the preferred approach. Regardless of the choice of definitive procedure, the pancreatic duct in the proximal edge of transected pancreas should be individually ligated or occluded with a TA stapler. Application of fibrin glue over the stump may be advantageous.Pyloric exclusion may be used to divert the GI stream after high-risk, complex duodenal repairs, particularly with adjacent pancreatic injuries (Fig. 7-66).130 If the duodenal repair breaks down, the resultant fistula is an end fistula, which is easier to manage and more likely to close than a lateral fistula. To per-form a pyloric exclusion, first a gastrostomy is made on the greater curvature near the pylorus. The pylorus is then grasped with a Babcock clamp, via the gastrostomy, and oversewn with an O polypropylene suture. A gastrojejunostomy restores GI tract continuity. Vagotomy is not necessary because a risk of marginal ulceration has not been documented. Perhaps surpris-ingly, the sutures maintain diversion for only 3 to 4 weeks. Alternatively, the most durable pyloric closure is a double exter-nal staple line across the pylorus using a TA stapler.Complications should be expected after major pancre-aticoduodenal injuries.131 Delayed hemorrhage is rare but may Figure 7-65. For injuries of the pancreatic head that involve the pancreatic duct but spare the common bile duct, central pancreatic resection with Roux-en-Y pancreaticojejunostomy prevents pancreatic insufficiency.occur with pancreatic necrosis or abdominal infection; this usu-ally can be managed by angioembolization. If closed suction drains have been inserted for major pancreatic trauma, these should remain in place until the patient is tolerating an oral diet or enteral nutrition. Pancreatic fistula is diagnosed after post-operative day 5 in patients with drain output of >30 mL/d and a drain amylase level three times the serum value. Pancreatic fistula develops in over 20% of patients with combined injuries and should be managed similar to fistulas after elective surgery (see Chapter 33). Similarly, a duodenal fistula, presumptively an end fistula if a pyloric exclusion has been done, will typi-cally heal in 6 to 8 weeks with adequate drainage and control of intra-abdominal sepsis. Pancreatic pseudocysts in patients man-aged nonoperatively suggest a missed injury, and ERCP should be done to evaluate the integrity of the pancreatic duct. Late pseudocysts may be a complication of operative management and are treated much like those in patients with pancreatitis (see Chapter 33). Intra-abdominal abscesses are common and rou-tinely managed with percutaneous drainage.Colon and Rectum. Currently, three methods for treating colonic injuries are used: primary repair, end colostomy, and primary repair with diverting loop ileostomy. Primary repairs include lateral suture repair or resection of the damaged seg-ment with reconstruction by ileocolostomy or colocolostomy. All suturing and anastomoses are performed using a running single-layer technique (Fig. 7-67).55 The advantage of defini-tive treatment must be balanced against the possibility of anas-tomotic leakage if suture lines are created under suboptimal conditions. Alternatively, although use of an end colostomy requires a second operation, an unprotected suture line with Brunicardi_Ch07_p0183-p0250.indd 23010/12/18 6:21 PM 231TRAUMACHAPTER 7Figure 7-66. A. Pyloric exclusion is used to treat combined injuries of the duodenum and the head of the pancreas as well as isolated duodenal injuries when the duodenal repair is less than optimal. B and C. The pylorus is oversewn through a gastrotomy, which is subsequently used to create a gastrojejunostomy. The authors frequently use operatively placed feeding jejunostomy tube feedings for these patients.Figure 7-67. Technique for bowel repair and anastomosis. A. The running, single-layer suture is started at the mesenteric border. B. Stitches are spaced 3 to 4 mm from the edge of the bowel and advanced 3 to 4 mm, including all layers except the mucosa. C. The continuous suture is tied near the antimesenteric border.Brunicardi_Ch07_p0183-p0250.indd 23110/12/18 6:21 PM 232BASIC CONSIDERATIONSPART IFigure 7-68. Loop colostomy will completely divert the fecal flow, allowing the low rectal injury to heal. For extensive wounds, presacral drains are inserted through a perianal incision (box) and advanced along Waldeyer’s fascia (dashed line).the potential for breakdown is avoided. Numerous large ret-rospective and several prospective studies have now clearly demonstrated that primary repair is safe and effective in virtu-ally all patients with penetrating wounds.132 Colostomy is still appropriate in a few patients, but the current dilemma is how to select which patients should undergo the procedure. Cur-rently, the overall physiologic status of the patient, rather than local factors, directs decision making. Patients with devastating left colon injuries requiring damage control have a leak rate of over 40%, and may be candidates for temporary colostomy.133 Diverting ileostomy with colocolostomy is another option for these high-risk patients.Rectal injuries are similar to colonic injuries with respect to the ecology of the luminal contents, overall structure, and blood supply of the wall, but access to extraperitoneal injuries is limited due to the surrounding bony pelvis. Therefore, indirect treatment with intestinal diversion usually is required. The current options are loop ileostomy and sigmoid loop colostomy. The latter is preferred because it is quick and easy to perform, and provides essentially total fecal diversion. For sigmoid colostomy, technical elements include: (a) adequate mobilization of the sigmoid colon so that the loop will rest on the abdominal wall without tension, (b) maintenance of the spur of the colostomy (the common wall of the proximal and distal limbs after maturation) above the level of the skin with a one-half-inch Penrose drain or similar device, (c) longitudinal incision in the tenia coli, and (d) immediate matu-ration in the OR (Fig. 7-68). If the injury is accessible (e.g., in the posterior intraperitoneal portion of the rectum), repair of the injury should also be attempted. However, it is not necessary to explore the extraperitoneal rectum to repair a distal perforation. If the rectal injury is extensive, another option is to divide the rectum at the level of the injury, oversew or staple the distal rec-tal pouch if possible, and create an end colostomy (Hartmann’s procedure). Extensive injuries may warrant presacral drainage with Penrose drains placed along Waldeyer’s fascia via a peri-anal incision (see Fig. 7-68), but routine presacral drainage and rectal washout is no longer practiced. In rare instances in which destructive injuries are present, an abdominoperineal resection may be necessary to avert lethal pelvic sepsis.Complications related to colorectal injuries include intra-abdominal abscess, fecal fistula, wound infection, and stomal complications. Intra-abdominal abscesses occur in approxi-mately 10% of patients, and most are managed with percu-taneous drainage. Fistulas occur in 1% to 3% of patients and usually present as an abscess or wound infection with subse-quent continuous drainage of fecal output; the majority will heal spontaneously with routine care (see Chapter 29). Stomal com-plications (necrosis, stenosis, obstruction, and prolapse) occur in 5% of patients and may require either immediate or delayed reoperation. Stomal necrosis should be carefully monitored because spread beyond the mucosa may result in septic compli-cations, including necrotizing fasciitis of the abdominal wall. Penetrating injuries that involve both the rectum and adjacent bony structures are prone to development of osteomyelitis. Bone biopsy is performed for diagnosis and bacteriologic analysis, and treatment entails long-term IV antibiotic therapy and occa-sionally debridement.Abdominal and Pelvic Vasculature. Injury to the major arter-ies and veins in the abdomen can be a technical challenge.132-137 Although penetrating trauma indiscriminately affects all blood vessels, blunt trauma most commonly involves renal vasculature and occasionally the abdominal aorta. Patients with a penetrat-ing aortic wound who survive to reach the OR frequently have a contained hematoma within the retroperitoneum. Due to lack of mobility of the abdominal aorta, few injuries are amenable to primary repair. Supraceliac aortic wounds are particularly challenging due to the need for proximal control. Small lateral perforations may be controlled with 4-0 polypropylene suture or a PTFE patch, but end-to-end interposition grafting with a PTFE tube graft is the most common repair. Blunt injuries are typi-cally extensive intimal tears of the infrarenal aorta with resultant thrombosis, and are exposed via a direct approach; most require an interposition graft. To avoid future vascular-enteric fistulas, the vascular suture lines should be covered with omentum.Brunicardi_Ch07_p0183-p0250.indd 23210/12/18 6:21 PM 233TRAUMACHAPTER 7Penetrating wounds to the superior mesenteric artery (SMA) are typically encountered after exploration for a gun-shot wound, with “black bowel” and associated supramesocolic hematoma being pathognomonic. Blunt avulsions of the SMA are rare but should be considered in patients with a seat belt sign who have midepigastric pain or tenderness and associated hypotension. For injuries of the SMA, temporary damage con-trol with a Pruitt-Inahara shunt can prevent extensive bowel necrosis. For definitive repair, end-to-end interposition RSVG from the proximal SMA to the SMA past the point of injury can be performed if there is no associated pancreatic injury. Alterna-tively, if the patient has an associated pancreatic injury, the graft should be tunneled from the distal aorta beneath the duodenum to the distal SMA. For proximal SMV injuries, digital compres-sion for hemorrhage control is followed by attempted venorrha-phy; ligation is an option in a life-threatening situation, but the resultant bowel edema requires aggressive fluid resuscitation. Temporary abdominal closure and a second-look operation to evaluate bowel viability should be done.Transpelvic gunshot wounds or blunt injuries with associ-ated pelvic fractures are the most common scenarios in patients with iliac artery injuries. As with abdominal vascular injuries, a Pruitt-Inahara shunt can be used for temporary shunting of the vessel for damage control. Definitive interposition graft-ing with excision of the injured segment is appropriate (see “Vascular Repair Techniques”). Careful monitoring for distal embolic events and reperfusion injury necessitating fasciotomy is imperative.In general, outcome after pelvic vascular injuries is related to (a) the technical success of the vascular reconstruction and (b) associated soft tissue and nerve injuries. Vascular repairs rarely fail after the first 12 hours, whereas soft tissue infection is a limb threat for several weeks. Following aortic interposition grafting, the patient’s SBP should not exceed 120 mmHg for at least the first 72 hours postoperatively. Patients requiring ligation of an inferior vena cava injury often develop marked bilateral lower extremity edema. To limit the associated morbidity, the patient’s legs should be wrapped with elastic bandages from the toes to the hips and elevated. For superior mesenteric vein injuries, either ligation or thrombosis after venorrhaphy results in marked bowel edema; fluid resuscitation should be aggressive and abdominal pressure monitoring routine in these patients. Prosthetic graft infections are rare complications, but prevention of bacteremia is imperative82; administration of antibiotics perioperatively and treatment of secondary infections is indicated. Long-term arte-rial graft complications such as stenosis or pseudoaneurysms are uncommon, and routine graft surveillance rarely is performed. Consequently, long-term administration of antiplatelet agents or antithrombotics is not routine.Genitourinary Tract. Historically, when undergoing lapa-rotomy for trauma, all penetrating wounds to the kidneys were explored; recently, routine exploration of Gerota’s fascia has been questioned.138,139 Parenchymal renal injuries are treated with hemostatic and reconstructive techniques similar to those used for injuries of the liver and spleen: topical methods (electrocautery; argon beam coagulation; application of thrombin-soaked gela-tin foam sponge, fibrin glue, or BioGlue) and pledgeted suture repair. However, two caveats are recognized: the collecting sys-tem should be closed separately, and the renal capsule should be preserved to close over the repair of the collecting system (Fig. 7-69). Renal vascular injuries are common after penetrat-ing trauma and may be deceptive due to tamponade by Gerota’s Figure 7-69. When renorrhaphy is undertaken, effective repair is assisted by attention to several key points: A. Vascular occlusion controls bleeding and permits adequate visualization. B. The renal capsule is carefully preserved. C. The collecting system is closed separately with absorbable suture. D. The preserved capsule is closed over the collecting system repair.Brunicardi_Ch07_p0183-p0250.indd 23310/12/18 6:21 PM 234BASIC CONSIDERATIONSPART Ifascia, which results in delayed hemorrhage. Arterial reconstruc-tion using graft interposition should be attempted within 5 hours of injury for renal preservation. For destructive parenchymal or irreparable renovascular injuries, nephrectomy may be the only option; a normal contralateral kidney must be palpated because unilateral renal agenesis occurs in 0.1% of patients.Over 90% of blunt renal injuries are treated nonoperatively. Hematuria typically resolves within a few days with bed rest, although rarely bleeding is so persistent that bladder irrigation to dispel blood clots is warranted. Persistent gross hematuria may require embolization, whereas urinomas can be drained percutane-ously. Operative intervention after blunt trauma is limited to reno-vascular injuries and destructive parenchymal injuries that result in hypotension. The renal arteries and veins are uniquely susceptible to traction injury caused by blunt trauma. As the artery is stretched, the inelastic intima and media may rupture, which causes throm-bus formation and resultant stenosis or occlusion. The success rate for renal artery repair is limited, but an attempt is reasonable if the injury is <5 hours old or if the patient has a solitary kidney or bilat-eral injuries.140 Image-guided endoluminal stent placement is now employed for many of these injuries recognized by CT scanning. Reconstruction after blunt renal injuries may be difficult, however, because the injury is typically at the level of the aorta. If repair is not possible within this time frame, leaving the kidney in situ does not necessarily lead to the late sequelae of hypertension or abscess formation. The renal vein may be torn or completely avulsed from the vena cava due to blunt trauma. Typically, the large hematoma causes hypotension, which leads to operative intervention. During laparotomy for blunt trauma, expanding or pulsatile perinephric hematomas should be explored. If necessary, emergent vascular control can be obtained by placing a curved vascular clamp across the hilum from an inferior approach. Techniques of repair and hemostasis are similar to those described earlier.Injuries to the ureters are uncommon but may occur in patients with pelvic fractures and penetrating trauma. An injury may not be identified until a complication (i.e., a urinoma) becomes apparent. If an injury is suspected during operative exploration but is not clearly identified, methylene blue or indigo carmine is administered IV with observation for extrava-sation. Injuries are repaired using 5-0 absorbable monofilament, and mobilization of the kidney may reduce tension on the anas-tomosis. Distal ureteral injuries can be treated by reimplanta-tion facilitated with a psoas hitch and/or Boari flap. In damage control circumstances, the ureter can be ligated on both sides of the injury and a nephrostomy tube placed.Bladder injuries are subdivided into those with intraperito-neal extravasation and those with extraperitoneal extravasation. Ruptures or lacerations of the intraperitoneal bladder are opera-tively closed with a running, single-layer, 3-0 absorbable mono-filament suture. Laparoscopic repair is becoming common in patients not requiring laparotomy for other injuries. Extraperito-neal ruptures are treated nonoperatively with bladder decompres-sion for 2 weeks. Urethral injuries are managed by bridging the defect with a Foley catheter, with or without direct suture repair. Strictures are not uncommon but can be managed electively.Female Reproductive Tract. Gynecologic injuries are rare. Occasionally the vaginal wall will be lacerated by a bone frag-ment from a pelvic fracture. Although repair is not mandated, it should be performed if physiologically feasible. More impor-tant, however, is recognition of the open fracture, need for possible drainage, and potential for pelvic sepsis. Penetrating injuries to the vagina, uterus, fallopian tubes, and ovaries are also uncommon, and routine hemostatic techniques are used. Repair of a transected fallopian tube can be attempted but prob-ably is unjustified because a suboptimal repair will increase the risk of tubal pregnancy. Transection at the injury site with proximal ligation and distal salpingectomy is a more prudent approach.Pelvic Fracture Hemorrhage ControlPatients with pelvic fractures who are hemodynamically unsta-ble are a diagnostic and therapeutic challenge for the trauma team. These injuries often occur in conjunction with other life-threatening injuries, and there is no universal agreement among clinicians on management. Current management algorithms in the United States incorporate variable time frames for bony stabilization and fixation, as well as hemorrhage control by preperitoneal pelvic packing and/or angioembolization. Early institution of a multidisciplinary approach with the involvement of trauma surgeons, orthopedic surgeons, interventional radiolo-gists, the director of the blood bank, and anesthesiologists is imperative due to high associated mortality rates (Fig. 7-70).Evaluation in the ED focuses on identification of injuries mandating operative intervention (e.g., massive hemothorax or hemoperitoneum) and injuries related to the pelvic fracture that alter management (e.g., injuries to the iliac artery, rectum, ure-thra, or bladder). Immediate temporary stabilization with sheeting of the pelvis or application of commercially available compres-sion devices should be performed in hemodynamically unstable patients. In patients with profound shock who are at high risk based upon mechanism (e.g., autopedestrian accident), pelvic sta-bilization should be done before radiographic confirmation. If the patient’s primary source of bleeding is the fracture-related pelvic hematoma, several options exist for hemorrhage control. Because 85% of bleeding due to pelvic fractures is venous or bony in ori-gin, the authors advocate immediate external fixation and pre-peritoneal pelvic packing.141 Anterior external fixation decreases pelvic volume, which promotes tamponade of venous bleeding and prevents secondary hemorrhage from the shifting of bony ele-ments. Pelvic packing, in which six laparotomy pads (four in chil-dren) are placed directly into the paravesical space through a small anterior suprapubic incision, provides tamponade for the bleeding (Fig. 7-71). Pelvic packing also eliminates the often difficult deci-sion by the trauma surgeon: OR vs. interventional radiology? All patients can be rapidly transported to the OR, and packing can be accomplished in under 30 minutes. In the authors’ experience, this results in hemodynamic stability and abrupt cessation of the need for ongoing blood transfusion in the majority of cases.141 Patients also can undergo additional procedures such as laparotomy, tho-racotomy, external fixation of extremity fractures, fasciotomy, revascularization, or craniotomy. Following pelvic packing, angi-ography is reserved for patients with evidence of ongoing pelvic bleeding after admission to the SICU (>4 units of RBCs in the first 12 postoperative hours after the coagulopathy is corrected). Patients undergo standard posttrauma resuscitative SICU care, and the pelvic packs are removed within 48 hours; prior to unpacking, however, the patient’s coagulopathy should be corrected to pre-vent the need for repacking of the pelvic space. Repacking of the pelvic space is associated with an infection rate of 47% and should be avoided; directed hemostasis with topical agents, suture repair, or electrocautery at pelvic pack removal should be performed.Another clinical challenge is the open pelvic fracture. In many instances, the wounds are located in the perineum, and the risk of pelvic sepsis and osteomyelitis is high. To reduce Brunicardi_Ch07_p0183-p0250.indd 23410/12/18 6:21 PM 235TRAUMACHAPTER 7the risk of infection, performance of a diverting sigmoid colos-tomy is recommended. The pelvic wound is manually debrided and then irrigated daily with a high-pressure pulsatile irrigation system until granulation tissue covers the wound. The wound is then left to heal by secondary intention with a wound vacuum-assisted wound closure (VAC) device.Extremity Vascular Injuries, Fractures, and Compartment SyndromesPatients with injured extremities often require a multidisci-plinary approach with involvement of trauma, orthopedic, and plastic surgeons to address vascular injuries, fractures, soft tis-sue injuries, and compartment syndromes. Immediate stabili-zation of fractures or unstable joints is done in the ED using Hare traction, knee immobilizers, or plaster splints. In patients with open fractures, the wound should be covered with povido-neiodine (Betadine)-soaked gauze and antibiotics administered. Options for fracture fixation include external fixation or open reduction and internal fixation with plates or intramedullary nails. Vascular injuries, either isolated or in combination with fractures, require emergent repair. Common combined injuries include clavicle/first rib fractures and subclavian artery injuries, dislocated shoulder/proximal humeral fractures and axillary artery injuries, supracondylar fractures/elbow dislocations and brachial artery injuries, femur fracture and superficial femoral artery injuries, and knee dislocation and popliteal vessel inju-ries. On-table angiography in the OR facilitates rapid interven-tion and is warranted in patients with evidence of limb threat on arrival. Arterial access for on-table lower extremity angiography can be obtained percutaneously at the femoral vessels with a standard arterial catheter, via femoral vessel exposure and direct cannulation, or with superficial femoral artery (SFA) exposure just above the medial knee. Controversy exists regarding which should be done first, fracture fixation or arterial repair. The authors prefer placement of temporary intravascular shunts first to reestablish arterial flow and minimize ischemia during frac-ture treatment, with definitive vascular repair following. Rarely, immediate amputation may be considered due to the severity of orthopedic and neurovascular injuries. This is particularly true if primary nerve transection is present in addition to fracture and arterial injury.142 Collaborative decision making by the trauma, orthopedic, and plastic/reconstructive team is essential.FAST ExamPositiveNegative2 units RBCs/ED trauma bayHD StableHD StableHD StableHD UnstableHD UnstableResuscitate in the SICU + CT scansOperating Room:Exploratory LaparotomyIf Pelvic Hematoma Evident ˜Pelvic Fixation and Pelvic PackingHD UnstableOngoing Transfusion Requirements after Pelvic Packing?(>4 units RBCs from pelvic source with normal coags in 12 hours)NoAngiographySICUYesDenver Health Unstable Pelvic Fracture ManagementResuscitate with 2 L crystalloid – measure base deÿcit – rule out thoracic source – sheet the pelvis.Transfuse fresh frozen plasma (FFP) and RBC 1:2; 1 apheresis unit of platelets for each 5 units RBCs; perform thromboelastography.Immediate notiÿcation: Attending Trauma Surgeon, Attending Orthopedic Surgeon, Operating Room, Blood BankPlace 7Fr Terumo arterial sheath if SBP <90 mmHg; consider REBOA if SBP <80 mmHg Operating Room:Pelvic Fixation and Pelvic PackingReultrasound AbdomenFigure 7-70. Management algorithm for patients with pelvic fractures with hemodynamic instability. CT = computed tomography; ED = emergency department; FAST = focused abdominal sonography for trauma; HD = hemodynamic; PLT = platelets; PRBCs = packed red blood cells; SICU = surgical intensive care unit.Brunicardi_Ch07_p0183-p0250.indd 23510/12/18 6:21 PM 236BASIC CONSIDERATIONSPART IOperative intervention for vascular injuries should follow standard principles of repair (see “Vascular Repair Techniques”). For subclavian or axillary artery repairs, 6-mm PTFE graft or RSVG are used depending on the location. Because associated injuries of the brachial plexus are common, a thorough neuro-logic examination of the extremity is mandated before operative intervention. Operative approach for a brachial artery injury is via a medial upper extremity longitudinal incision; proximal control may be obtained at the axillary artery, and an S-shaped exten-sion through the antecubital fossa provides access to the distal brachial artery. The injured vessel segment is excised, and an end-to-end interposition RSVG graft is performed. Upper extremity fasciotomy is rarely required because of the rich collateral per-fusion via the profunda. For SFA injuries, external fixation of the femur typically is performed, followed by end-to-end RSVG of the injured SFA segment. Close monitoring for calf compart-ment syndrome is mandatory. Preferred access to the popliteal space for an acute injury is the medial, one-incision approach with detachment of the semitendinosus, semimembranosus, and gracilis muscles (Fig. 7-72). Another option is a medial approach Figure 7-71. A. Pelvic packing is performed through a 6to 8-cm midline incision made from the pubic symphysis cephalad, with division of the midline fascia. B. The pelvic hematoma often dissects the preperitoneal and paravesical space down to the presacral region, which facilitates packing; alternatively, blunt digital dissection opens the preperitoneal space for packing. C. Three standard surgical laparotomy pads are placed on each side of the bladder, deep within the preperitoneal space; the fascia is closed with an O polydioxanone monofilament suture and the skin with staples.Figure 7-72. A. The popliteal space is commonly accessed using a single medial incision (the detached semitendinosus, semimembranosus, and gracilis muscles are identified by different suture types). B. Alternatively, a medial approach with two incisions may be used. Insertion of a Pruitt-Inahara shunt (arrow) provides temporary restoration of blood flow, which prevents ischemia during fracture treatment.Brunicardi_Ch07_p0183-p0250.indd 23610/12/18 6:21 PM 237TRAUMACHAPTER 7Table 7-11Arterial vasospasm treatment guidelineStep 1: Intra-arterial alteplase (tissue plasminogen activator) 5 mg/20 mL bolusIf spasm continues, proceed to step 2.Step 2: Intra-arterial nitroglycerin 200 μg/20 mL bolusRepeat same dose once as needed.If spasm continues, proceed to step 3.Step 3: Interarterial verapamil 10 mg/10 mL bolusIf spasm continues, proceed to step 4.Step 4: Interarterial papaverine drip 60 mg/50 mL given over 15 minwith two incisions using a longer RSVG, but this requires interval ligation of the popliteal artery and geniculate branches. Rarely, with open wounds a straight posterior approach with an S-shaped incision can be used. If the patient has an associated popliteal vein injury, this should be repaired first with a PTFE interposition graft while the artery is shunted. For an isolated popliteal artery injury, RSVG is performed with an end-to-end anastomosis. Compart-ment syndrome is common, and presumptive four-compartment fasciotomies are warranted in patients with combined arterial and venous injury. Once the vessel is repaired and restoration of arte-rial flow documented, completion angiography should be done in the OR if there is no palpable distal pulse. Vasoparalysis with verapamil, nitroglycerin, and papaverine may be used to treat vasoconstriction (Table 7-11).Compartment syndromes, which can occur anywhere in the extremities, involve an acute increase in pressure inside a closed space, which impairs blood flow to the structures within. Causes of compartment syndrome include arterial hemorrhage into a compartment, venous ligation or thrombosis, crush inju-ries, and reperfusion injury. In conscious patients, pain is the prominent symptom, and active or passive motion of muscles in the involved compartment increases the pain. Paresthesias may also be described. In the lower extremity, numbness between the first and second toes is the hallmark of early compartment syndrome in the exquisitely sensitive anterior compartment and its enveloped deep peroneal nerve. Progression to paralysis can occur, and loss of pulses is a late sign. In comatose or obtunded patients, the diagnosis is more difficult to secure. In patients with a compatible history and a tense extremity, compartment pressures should be measured with a hand-held Stryker device. Fasciotomy is indicated in patients with a gradient of <30 mmHg (gradient = diastolic pressure − compartment pressure), an abso-lute compartment pressure >30 mmHg, ischemic periods of >6 hours, or combined arterial and venous injuries. The lower extremity is most frequently involved, and compartment release is performed using a two-incision, four-compartment fasciotomy (Fig. 7-73). Of note, the soleus muscle must be detached from the tibia to decompress the deep flexor compartment.SURGICAL INTENSIVE CARE MANAGEMENTPostinjury ResuscitationICU management of the trauma patient, either with direct admis-sion from the ED or after emergent operative intervention, is considered in distinct phases because there are differing goals and priorities. The period of acute resuscitation, typically last-ing for the first 12 to 24 hours after injury, combines several key principles: optimizing tissue perfusion, ensuring normother-mia, and restoring coagulation status.143 There are a multitude of management algorithms aimed at accomplishing these goals, the majority of which involve goal-directed resuscitation with initial volume loading to attain adequate preload, followed by judicious use of inotropic agents or vasopressors.144 Although the optimal hemoglobin level remains debated, during shock resuscitation a hemoglobin level of >10 g/dL is generally accepted to optimize hemostasis and ensure adequate oxygen delivery. After the first 24 hours of resuscitation, a more judicious transfusion trigger of a hemoglobin level of <7 g/dL in the euvolemic patient limits the adverse inflammatory effects of stored RBCs. Recent trends have focused on limiting crystalloid loading. In fact, optimiz-ing crystalloid administration is a challenging aspect of early care (i.e., balancing cardiac performance against generation of an abdominal compartment syndrome and generalized tissue edema). Although early colloid administration is appealing, evi-dence to date does not support this concept.Invasive monitoring with pulmonary artery catheters has been supplanted with specialized catheters that measure arte-rial pulse contour analysis; in mechanically ventilated patients, stroke volume (SV) and continuous cardiac output can be mea-sured. A patient’s volume status may be ascertained by measur-ing the SV following either 10 cc/kg volume bolus or following a passive leg raise, which augments preload by 250 to 500 mL. A change in SV of ≥10% suggests preload responsiveness, and additional resuscitation fluid should be given. Although norepi-nephrine is the agent of choice for patients with low systemic vascular resistance who are unable to maintain a mean arterial pressure of >60 mmHg, patients may have an element of myo-cardial dysfunction requiring inotropic support. The role of rela-tive adrenal insufficiency is another controversial area.Optimal early resuscitation is mandatory and determines when the patient can (a) undergo additional necessary imaging, and (b) be returned to the OR after initial damage control surgery for definitive repair of injuries. Specific goals of resuscitation before repeated “semi-elective” transport include a core tempera-ture of >35°C (95°F), base deficit of <6 mmol/L, and normal coagulation indices. Although correction of metabolic acidosis is desirable, how quickly this should be accomplished requires careful consideration. Adverse sequelae of excessive crystalloid resuscitation include increased intracranial pressure, worsening pulmonary edema, and intra-abdominal visceral and retroperi-toneal edema resulting in secondary abdominal compartment syndrome. Therefore, it should be the overall trend of the resus-citation rather than a rapid reduction of the base deficit that is the goal. The goal is to normalize lactate within 24 hours.145In general, wounds sustained from trauma should be examined daily for progression of healing and signs of infection. Complex soft tissue wounds of the abdomen, such as degloving injuries after blunt trauma (termed Morel-Lavallee lesions146), shotgun wounds, and other destructive blast injuries, are par-ticularly difficult to manage. Following initial debridement of devitalized tissue, wound care includes wet-to-dry dressing changes twice daily or application of a VAC device. Repeated operative debridement may be necessary, and early involvement of the reconstructive surgery service for possible flap cover-age is advised. Midline laparotomy wounds are inspected 48 hours postoperatively by removing the sterile surgical dressing. If an ileostomy or colostomy is required, one should inspect it Brunicardi_Ch07_p0183-p0250.indd 23710/12/18 6:21 PM 238BASIC CONSIDERATIONSPART IFigure 7-73. A. The anterior and lateral compartments are approached from a lateral incision, with identification of the fascial raphe between the two compartments. Care must be taken to avoid the superficial peroneal nerve running along the raphe. B. To decompress the deep flexor compartment, which contains the tibial nerve and two of the three arteries to the foot, the soleus muscle must be detached from the tibia.daily to ensure that it is viable. If the patient develops a high-grade fever, the wound should be inspected sooner to exclude an early necrotizing infection. If a wound infection is identified—as evidenced by erythema, pain along the wound, or purulent drainage—the wound should be widely opened by removing skin staples. After ensuring that the midline fascia is intact with digital palpation, the wound is initially managed with wet-to-dry dressing changes. The most common intra-abdominal complica-tions are anastomotic failure and abscess. The choice between percutaneous and operative therapy is based on the location, timing, and extent of the collection.Abdominal Compartment SyndromeThe abdominal compartment syndrome is classified as patho-logic intra-abdominal hypertension due to intra-abdominal injury (primary) or splanchnic reperfusion after massive resus-citation (secondary). Secondary abdominal compartment syn-drome may result from any condition requiring extensive crystalloid resuscitation, including extremity trauma, chest trauma, or even postinjury sepsis. The sources of increased intra-abdominal pressure include bowel edema, ascites, bleed-ing, and packs. A diagnosis of intra-abdominal hypertension cannot reliably be made by physical examination; therefore, it is obtained by measuring the intraperitoneal pressure. The most common technique is to measure the patient’s bladder pressure. Fifty milliliters of saline is instilled into the bladder via the aspi-ration port of the Foley catheter with the drainage tube clamped, and a three-way stopcock and water manometer is placed at the level of the pubic symphysis. Bladder pressure is then measured on the manometer in centimeters of water (Table 7-12) and 10Brunicardi_Ch07_p0183-p0250.indd 23810/12/18 6:21 PM 239TRAUMACHAPTER 7Table 7-12Abdominal compartment syndrome grading systemBLADDER PRESSUREGRADEmmHgcmH2OI10–1513–20II16–2521–35III26–3536–47IV >35   >48˜ Renal blood flow˜ UOPHypoxemia ˛ Airway pressures ˜ Compliance ˛ PA pressures ˛ CVP readings˜ CO˜ VEDV˜ SV˛ SVR˛ ICPSplanchnicischemiaExtremityischemiaIncreased abdominal pressureIntrathoracic pressure˛Venous return˜Compression of kidneysFigure 7-74. Abdominal compartment syndrome is defined by the end organ sequelae of intra-abdominal hypertension. CO = cardiac output; CVP = central venous pressure; ICP = intracranial pressure; PA = pulmonary artery; SV = stroke volume; SVR = systemic vascular resistance; UOP = urine output; VEDV = ventricular end diastolic volume.correlated with the physiologic sequelae. Conditions in which the bladder pressure is unreliable include bladder rupture, exter-nal compression from pelvic packing, neurogenic bladder, and adhesive disease.Increased abdominal pressure affects multiple organ systems (Fig. 7-74). Abdominal compartment syndrome, as noted earlier, is defined as intra-abdominal hypertension suf-ficient to produce physiologic deterioration and manifests via such end-organ sequelae as decreased urine output, increased pulmonary inspiratory pressures, decreased cardiac preload, and decreased cardiac output. Because any of these clinical symptoms of abdominal compartment syndrome may be attributed to the primary injury, a heightened awareness of this syndrome must be maintained. Organ fail-ure can occur over a wide range of recorded bladder pres-sures. Generally, no specific bladder pressure prompts therapeutic intervention, except when the pressure is >35 mmHg. Rather, emergent decompression is carried out when intra-abdominal hypertension reaches a level at which end-organ dysfunction occurs. Mortality is directly affected by the timing of decompression, with 70% mortality in patients with a delay in decompression, and nearly uniform mortality in those not undergoing decompression. Decompression is usually performed operatively, either in the ICU if the patient 11is hemodynamically unstable or in the OR. ICU bedside lapa-rotomy is easily accomplished, avoids transport of hemody-namically compromised patients, and requires minimal equipment (e.g., scalpel, suction device, cautery, and dress-ings for temporary abdominal closure). In patients with sig-nificant intra-abdominal fluid as the primary component of abdominal compartment syndrome, rather than bowel or ret-roperitoneal edema, decompression can be accomplished effectively via a percutaneous drain. These patients are iden-tified by bedside ultrasound, and the morbidity of a laparot-omy is avoided. When operative decompression is required with egress of the abdominal contents, temporary coverage is obtained using a fenestrated subfascial 45 × 60 cm sterile drape and Ioban application (see Fig. 7-49).The performance of damage control surgery and recogni-tion of abdominal compartment syndrome have dramatically improved patient survival, but at the cost of an open abdomen. Several management points deserve attention. Despite having a widely open abdomen, patients can develop recurrent abdomi-nal compartment syndrome, which increases their morbidity and mortality; therefore, bladder pressure should be monitored every 4 hours, with significant increases in pressures alerting the clini-cian to the possible need for repeat operative decompression. Patients with an open abdomen lose between 500 and 2500 mL per day of abdominal effluent. Appropriate volume compensa-tion for this albumin-rich fluid remains controversial, with regard to both the amount administered (replacement based on clinical indices vs. routine 0.5 mL replacement for every milliliter lost) as well as the type of replacement (crystalloid vs. colloid).Following resuscitation and management of specific inju-ries, the goal of the operative team is to close the abdomen as quickly as possible. Multiple techniques have been introduced to obtain fascial closure of the open abdomen to minimize mor-bidity and cost of care. Historically, for patients who could not be closed at repeat operation, approximation of the fascia with mesh (prosthetic or biologic) was used, with planned reopera-tion. Another option was split-thickness skin grafts applied directly to the exposed bowel for coverage; removal of the skin Brunicardi_Ch07_p0183-p0250.indd 23910/12/18 6:21 PM 240BASIC CONSIDERATIONSPART Igrafts was planned 9 to 12 months after the initial surgery, with definitive repair of the hernia by component separation. How-ever, delayed abdominal wall reconstruction was resource inva-sive, with considerable patient morbidity. The advent of VAC technology has revolutionized fascial closure. The authors cur-rently use a sequential closure technique with the wound VAC device that is based on constant fascial tension and return to the OR every 48 hours until closure is complete (Fig. 7-75).147 The authors’ success rate with this approach exceeds 95%. This is important because among patients not attaining fascial closure, 20% suffer GI tract complications that prolong their hospital course. These include intra-abdominal abscess, enteric fistula, and bowel perforations (Fig. 7-76). Management requires fre-quent operative or percutaneous drainage of abscesses, control of fistulas, and prolonged nutritional support.SPECIAL POPULATIONSPregnant PatientsDuring pregnancy, 7% of women are injured. Motor vehicle col-lisions and falls are the leading causes of injury, accounting for 70% of cases. Fetal death after trauma most frequently occurs after motor vehicle collisions, but only 11% of fetal deaths are due to the death of the mother; therefore, early trauma resusci-tation and management is directed not only at the mother but also at the fetus. Domestic violence is also common, affecting between 10% and 30% of pregnant women and resulting in fetal mortality of 5%.Pregnancy results in physiologic changes that may impact postinjury evaluation (Table 7-13). Heart rate increases by 10 to 15 beats per minute during the first trimester and remains elevated until delivery. Blood pressure diminishes during the first two trimesters due to a decrease in systemic vascular resis-tance and rises again slightly during the third trimester (mean values: first = 105/60, second = 102/55, third = 108/67). Intra-vascular volume is increased by up to 8 L, which results in a relative anemia but also a relative hypervolemia. Consequently, a pregnant woman may lose 35% of her blood volume before exhibiting signs of shock. Pregnant patients have an increase in tidal volume and minute ventilation but a decreased functional residual capacity; this results in a diminished PCO2 and respi-ratory alkalosis. Also, pregnant patients may desaturate more rapidly, particularly in the supine position and during intuba-tion. Supplemental oxygen is always warranted in the trauma patient but is particularly critical in the injured pregnant patient because the oxygen dissociation curve is shifted to the left for the fetus compared to the mother (i.e., small changes in maternal oxygenation result in larger changes for the fetus because the fetus is operating in the steep portion of the dissociation curve). Anatomic changes contribute to these pulmonary functional alterations and are relevant in terms of procedures. With the gravid uterus enlarged, DPL should be performed in a supra-umbilical site with the catheter directed cephalad. In addition, the upward pressure on the diaphragm calls for caution when placing a thoracostomy tube; standard positioning may result in an intra-abdominal location or perforation of the diaphragm.Other physiologic changes during pregnancy affect the GI, renal, and hematologic systems. The lower esophageal sphincter has decreased competency, which increases the risk for aspira-tion. Liver function test values increase, with the alkaline phos-phatase level nearly doubling. The high levels of progesterone impair gallbladder contractions, which results in bile stasis and an increased incidence of gallstone formation; this may not affect the trauma bay evaluation but becomes important in a pro-longed ICU stay. Plasma albumin level decreases from a normal of around 4.3 g/dL to an average of 3.0 g/dL. Renal blood flow increases by 30% during pregnancy, which causes a decrease in serum level of blood urea nitrogen and creatinine. The uterus may also compress the ureters and bladder, causing hydronephro-sis and hydroureter. Finally, as noted earlier there is a relative anemia during pregnancy, but a hemoglobin level of <11 g/dL is considered abnormal. Additional hematologic changes include a moderate leukocytosis (up to 20,000 mm3) and a rela-tive hypercoagulable state due to increased levels of factors VII, VIII, IX, X, and XII and decreased fibrinolytic activity.During evaluation in the ED, the primary and secondary surveys commence, with mindfulness that the mother always receives priority while conditions are still optimized for the fetus.148 This management includes provision of supplemental oxygen (to prevent maternal and fetal hypoxia), fluid resuscita-tion (the hypervolemia of pregnancy may mask signs of shock), and placement of the patient in the left lateral decubitus posi-tion (or tilting of the backboard to the left) to avoid caval com-pression. Assessment of the fetal heart rate is the most valuable information regarding fetal viability. Fetal monitoring should initially be assessed with bedside FAST ultrasound to document the heart rate of the fetus; subsequent monitoring should be per-formed with a cardiotocographic device that measures both con-tractions and fetal heart tones (FHTs). Because change in heart rate is the primary response of the fetus to hypoxia or hypo-tension, anything above an FHT of 160 is a concern, whereas bradycardia (FHT of <120) is considered fetal distress. Indica-tions for emergent cesarean section include: (a) severe mater-nal shock or impending death (if the fetus is delivered within 5 minutes, survival is estimated at 70%), (b) uterine injury or significant fetal distress (anticipated survival rates of >70% if FHTs are present and fetal gestational age is >28 weeks).149If possible, a member of the obstetrics team should be present during initial evaluation. Vaginal bleeding can signal early cervical dilation and labor, abruptio placentae, or placenta previa. Amniotic sac rupture can result in prolapse of the umbil-ical cord with fetal compromise. Strong contractions are associ-ated with true labor and should prompt consideration of delivery and resuscitation of the neonate. Focused prenatal history-taking should elicit a history of pregnancy-induced hypertension, ges-tational diabetes, congenital heart disease, preterm labor, or placental abnormalities. Asking the patient when the baby first moved and if she is currently experiencing movement of the fetus is important. Determining fetal age is key for consider-ations of viability. Gestational age may be estimated by noting fundal height, with the fundus approximating the umbilicus at 20 weeks and the costal margin at 40 weeks. Discrepancy in dates and size may be due to uterine rupture or hemorrhage.Initial evaluation for abdominopelvic trauma in pregnant patients should proceed in the standard manner. Ultrasound (FAST) of the abdomen should evaluate the four windows (pericardial, right and left upper quadrant, and bladder) and additionally assess FHTs, fetal movement, and sufficiency of amniotic fluid. DPL can be performed in pregnant women via a supraumbilical, open technique. Trauma radiography of pregnant patients presents a conundrum. Radiation damage has three distinct phases of damage and effect: preimplantation, dur-ing the period of organogenesis from 3 to 16 weeks, and after 16 weeks. Generally, it is accepted that “safe” doses of radiation Brunicardi_Ch07_p0183-p0250.indd 24010/12/18 6:21 PM 241TRAUMACHAPTER 7Figure 7-75. The authors’ sequential closure technique for the open abdomen. A. Multiple white sponges (solid arrow), stapled together, are placed on top of the bowel underneath the fascia. Interrupted No. 1 polydioxanone sutures are placed approximately 5 cm apart (dashed arrow), which puts the fascia under moderate tension over the white sponge. B. After the sticky clear plastic vacuum-assisted closure (VAC) dressing is placed over the white sponges and adjacent 5 cm of skin, the central portion is removed by cutting along the wound edges. C and D. Black VAC sponges are placed on top of the white sponges and plastic-protected skin with standard occlusive dressing and suction. E. On return to the operating room (OR) 48 hours later, fascial sutures are placed from both the superior and inferior directions until tension precludes further closure; skin is closed over the fascial closure with skin staples. F. White sponges (fewer in number) are again applied and fascial retention sutures are placed with planned return to the OR in 48 hours.Brunicardi_Ch07_p0183-p0250.indd 24110/12/18 6:22 PM 242BASIC CONSIDERATIONSPART IFigure 7-76. Complications after split-thickness skin graft closure of the abdomen include enterocutaneous fistulas (intubated here with a red rubber catheter) (A; arrow), rupture of the graft with exposure of the bowel mucosa (B), enteroatmospheric fistulas with a large ventral hernias and loss of abdominal domain (C).from radiography are <5 rad.150 A chest radiograph results in a dose of 0.07 mrad; CT scan of the chest, <1 rad; and CT scan of the abdomen, 3.5 rad. It is important, therefore, to limit radio-graphs to those that are essential and to shield the pelvis with a lead apron when possible. If clinically warranted, however, a radiograph should be obtained.The vast majority of injuries are treated similarly whether the patient is pregnant or not. Following standard protocols for nonoperative management of blunt trauma avoids the risks associated with general anesthesia. A particular challenge in the pregnant trauma patient is a major pelvic fracture. Because uter-ine and retroperitoneal veins may dilate to 60 times their origi-nal size, hemorrhage from these vessels may be torrential. Fetal loss may be related to both maternal shock and direct injury to the uterus or fetal head. Penetrating injuries in this patient population also carry a high risk. The gravid uterus is a large target, and any penetrating injury to the abdomen may result in fetal injury depending on trajectory and uterine size. Gunshot wounds to the abdomen are associated with a 70% injury rate to the uterus and 35% mortality rate of the fetus. If the bul-let traverses the uterus and the fetus is viable, cesarean section should be performed. On the other hand, stab wounds do not often penetrate the thick wall of the uterus.Any patient with a viable pregnancy should be monitored after trauma, with the length of monitoring determined by the injury mechanism and patient physiology. Patients who are Brunicardi_Ch07_p0183-p0250.indd 24210/12/18 6:22 PM 243TRAUMACHAPTER 7symptomatic, defined by the presence of uterine irritability or contractions, abdominal tenderness, vaginal bleeding, or blood pressure instability, should be monitored in the hospital for at least 24 hours. In addition, patients at high risk for fetal loss (those experiencing vehicle ejection or involved in motorcycle or pedestrian collisions and those with maternal tachycardia, Injury Severity Score of >9, gestational period of >35 weeks, or history of prior assault) also warrant careful monitoring.151 Patients without these risk factors who are asymptomatic can be monitored for 6 hours in the ED and sent home if no problems develop. They should be counseled regarding warning signs that mandate prompt return to the ED.Geriatric PatientsElderly trauma patients (>65 years of age) are hospitalized twice as often as those in any other age group, and this population accounts for one quarter of all trauma admissions. Although the physiology of aging separates older trauma patients from the younger generation (Table 7-14), treatment must remain indi-vidualized (some octogenarians look and physiologically act 50 years old, whereas others appear closer to 100 years). No chronologic age is associated with a higher morbidity or mor-tality, but a patient’s comorbidities do impact the individual’s postinjury course and outcome. For example, recognition that a patient is taking β-blockers affects the physician’s evaluation of vital signs in the ED and impacts treatment course in the ICU. Early monitoring of arterial blood gas values will identify occult shock. A base deficit of >6 mmol/L is associated with a twofold higher risk of mortality in patients over the age of 55 than in younger patients (67% vs. 30%).152Although the published literature on geriatric traumatic brain injury is relatively sparse and uncontrolled with regard to management, some interesting points are noted. First, as anticipated, outcomes are worse in this age group than in their younger counterparts. Based on data from the Traumatic Coma Databank, mortality in patients with severe head injury more than doubles after the age of 55. Moreover, 25% of patients with a normal GCS score of 15 had intracranial bleeding, with an associated mortality of 50%.140 Just as there is no absolute age that predicts outcome, admission GCS score is a poor predictor of individual outcome. Therefore, the majority of trauma centers advocate an initial aggressive approach with reevaluation at the 72-hour mark to determine subsequent care.One of the most common sequelae of blunt thoracic trauma is rib fractures. In the aging population, perhaps due to osteo-porosis, less force is required to cause a fracture. In fact, in one study, 50% of patients >65 years old sustained rib fractures from a fall of <6 ft, compared with only 1% of patients <65 years of age. Concurrent pulmonary contusion is noted in up to 35% of patients, and pneumonia complicates the injuries in 10% to 30% of patients with rib fractures, not surprisingly leading to longer ICU stays.153,154 Additionally, mortality increases linearly with the number of rib fractures. Patients who sustain more than six rib fractures have pulmonary morbidity rates of >50% and over-all mortality rates of >20%.Chronologic age is not the best predictor of outcome, but the presence of preexisting conditions, which affect a patient’s physiologic age, is associated with increased mortality rates. Injury Severity Score is probably the best overall predictor of patient outcome in the elderly; however, for any given individ-ual its sensitivity may not be precise, and there is a time delay in obtaining sufficient information to calculate the final score. In addition to preexisting conditions and severity of injury, the occurrence of complications compounds the risk for mortality.Table 7-13Physiologic effects of pregnancyCardiovascularIncrease in heart rate by 10–15 bpm(a) Decreased systemic vascular resistance resulting in:(b) Increased intravascular volumeDecreased blood pressure during the first two trimestersPulmonaryElevated diaphragmIncreased tidal volumeIncreased minute ventilationDecreased functional residual capacityHematopoieticRelative anemiaLeukocytosisHypercoagulability(a) Increased levels of factors VII, VIII, IX, X, XII(b) Decreased fibrinolytic activityOtherDecreased competency of lower esophageal sphincterIncreased enzyme levels on liver function testsImpaired gallbladder contractionsDecreased plasma albumin levelDecreased blood urea nitrogen and creatinine levelsHydronephrosis and hydroureterTable 7-14Physiologic effects of agingCardiovascularAtherosclerotic disease that limits cardiac response to stressProgressive stiffening and loss of elasticity of the myocardiumDiminished stroke volume, systolic contraction, and diastolic relaxationDecrease in cardiac output of 0.5% per yearThickening and calcification of the cardiac valves, which results in valvular incompetencePulmonaryLoss of complianceProgressive loss of alveolar size and surface areaAir trapping and atelectasisIntracranialLoss of cerebral volume, resulting in:(a) Increased risk of tearing of bridging veins with smaller injuries(b) Accumulation of a significant amount of blood before symptoms occur(c) muscle lossSenescence of the sensesOtherDecline in creatinine clearance by 80%–90%Osteoporosis, which causes a greater susceptibility to fracturesBrunicardi_Ch07_p0183-p0250.indd 24310/12/18 6:22 PM 244BASIC CONSIDERATIONSPART IPediatric PatientsTwenty million children, or almost one in four children, are injured each year, with an associated cost of treating the injured child of $16 billion per year. Injury is the leading cause of death among children over the age of 1 year, with 15,000 to 25,000 pediatric deaths per year. Disability after traumatic injury is more devastating, with rates 3 to 10 times that of the death rate. Pediatric trauma involves different mechanisms, different constellations of injury, and the potential for long-term problems related to growth and development. As with adult trauma, over 85% of pediatric trauma has a blunt mecha-nism, with boys injured twice as often as girls.155 Falls are the most common cause of injury in infants and toddlers. In chil-dren, bicycle mishaps are the most common cause of severe injury, whereas motor vehicle-related injury predominates in adolescence. Although unintentional injuries are by far the most common type of injuries in childhood, the number of intentional injuries, such as firearm-related injury and child abuse, is increasing.ED preparation for the pediatric trauma patient includes assembling age-appropriate equipment (e.g., intubation equip-ment; IV catheters, including intraosseous needles and 4F single-lumen lines), laying out the Broselow Pediatric Emergency Tape (which allows effective approximation of the patient’s weight, medication doses, size of endotracheal tube, and chest tube size), and turning on heat lamps. Upon the pediatric patient’s arrival, the basic tenets of the ABCs apply, with some caveats. In children, the airway is smaller and more cephalad in position compared with that of adults, and in children younger than 10 years, the larynx is funnel shaped rather than cylindrical as in adults. Addi-tionally, the child’s tongue is much larger in relation to the oro-pharynx. Therefore, a small amount of edema or obstruction can significantly reduce the diameter of the airway (thus increasing the work of breathing), and the tongue may posteriorly obstruct the airway, causing intubation to be difficult. During intubation, a Miller (straight) blade rather than a Macintosh (curved) blade may be more effective due to the acute angle of the cephalad, funnel-shaped larynx. Administration of atropine before rapid-sequence intubation will prevent bradycardia. Adequate ventila-tion is critical because oxygen consumption in infants and young children is twice that in adults; onset of hypoxemia, followed by cardiac arrest, may be precipitous. Because gastric distension can inhibit adequate ventilation, placement of a nasogastric tube may facilitate effective gas exchange. Approximately one-third of pre-ventable deaths in children are related to airway management; therefore, if airway control cannot be obtained using a standard endotracheal method, surgical establishment of an airway should be considered. In children older than 11 years, standard crico-thyroidotomy is performed. Due to the increased incidence of subglottic stenosis in younger patients, needle cricothyroidotomy with either a 14or 16-gauge catheter is advocated, although it is rarely used. Alternatively, tracheostomy may be performed. In children, the standard physiologic response to hypovolemia is peripheral vasoconstriction and reflex tachycardia; this may mask significant hemorrhagic injury because children can compensate for up to a 25% loss of circulating blood volume with minimal external signs. “Normal” values for vital signs should not neces-sarily make one feel more secure about the child’s volume status. Volume restoration is based on the child’s weight; two to three boluses of 20 mL/kg of crystalloid is appropriate. Hypotension in children may be due to TBI rather than hypovolemia and should be considered in the appropriate clinic scenario.156After initial evaluation based on the trauma ABCs, iden-tification and management of specific injuries proceeds. Acute traumatic brain injury is the most common cause of death and disability in any pediatric age group. Although falls are the most common mechanism overall, severe brain injury most often is due to child abuse (in children <2 years) or motor vehicle col-lisions (in those >2 years). Head CT should be performed to determine intracranial pathology, followed by skull radiogra-phy to diagnose skull fractures. As in adults, CPP is monitored, and appropriate resuscitation is critical to prevent the second-ary insults of hypoxemia and hypovolemia. Although some data indicate that the pediatric brain recovers from traumatic injury better than the adult brain, this advantage may be eliminated if hypotension is allowed to occur.As is true in adults, the vast majority of thoracic trauma is also blunt. However, because a child’s skeleton is not completely calcified, it is more pliable. Significant internal organ damage may occur without overlying bony fractures. For example, adult patients with significant chest trauma have a 70% incidence of rib fractures, whereas only 40% of children with significant chest trauma do. Pneumothorax is treated similarly in the pediatric population; patients who are asymptomatic with a pneumothorax of <15% are admitted for observation, whereas those who have a pneumothorax of >15% or who require positive pressure ventilation undergo tube decompression. Presence of a hemothorax in this age group may be particularly problematic because the child’s chest may contain his or her entire blood volume. If the chest tube output is initially 20% of the patient’s blood volume (80 mL/kg) or is persistently >1 to 2 mL/kg per hour, thoracotomy should be considered. Aortic injuries are rare in children, and tracheobronchial injuries are more amenable to nonoperative management. Penetrating thoracic trauma, although uncom-mon, has 35% operative intervention rate, which is consid-erably higher than that of the adult population.157 Thoracic injuries are second only to brain injuries as the main cause of death according to the National Pediatric Trauma Registry; however, the overall mortality rate of 15% correlates with the levels in many adult studies.The evaluation for abdominal trauma in the pediatric patient is similar to that in the adult. FAST is valid in the pedi-atric age group to detect intra-abdominal fluid. The mecha-nism of injury often correlates with specific injury patterns. A child sustaining a blow to the epigastrium (e.g., hitting the handlebars during a bike accident) should be evaluated for a duodenal hematoma and/or a pancreatic transection. After a motor vehicle collision in which the patient was wearing a passenger restraint, injuries comprising the “lap belt com-plex” or “seat belt syndrome” (i.e., abdominal wall contusion, small bowel perforation, flexion-distraction injury of the lumbar spine, diaphragm rupture, and occasionally abdomi-nal aortic dissection) may exist. Nonoperative management of solid organ injuries, first used in children, is the current standard of care in the hemodynamically stable patient. If the patient shows clinical deterioration or hemodynamic lability, has a hollow viscus injury, or requires >40 mL/kg of packed RBCs, continued nonoperative management is not an option. Success rates of nonoperative management approach 95%,158 with an associated 10% to 23% transfusion rate. Findings of a hepatic or splenic blush on CT imaging does not uniformly require intervention; patient physiology should dictate embo-lization or operative intervention.159Brunicardi_Ch07_p0183-p0250.indd 24410/12/18 6:22 PM 245TRAUMACHAPTER 7REFERENCESEntries highlighted in bright blue are key references. 1. Minino AM, Heron MP, Murphy SL, et al. Deaths: final data for 2004. Natl Vital Stat Rep. 2007 Aug 21;55(19):1-120. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr65/nvsr65_04.pdf. Accessed June 8, 2017. 2. National Center for Injury Prevention and Control. CDC Injury Fact Book. Atlanta: Centers for Disease Control and Preven-tion, November 2006. Available at: http://www.cdc.gov/ncipc/fact_book/InjuryBook2006.pdf. Accessed October 29, 2012. 3. Brasel KJ. Epidemiology. In: Moore EE, Mattox KL, Feliciano DV, eds. Trauma. 8th ed. New York: McGraw-Hill; 2017. 4. Eastman AB. Wherever the dart lands: toward the ideal trauma system. J Am Coll Surg. 2010;211(2):153-168. 5. 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Single-layer con-tinuous vs. two-layer interrupted intestinal anastomosis—a prospective randomized study. Ann Surg. 2000;231:832-837. 56. Moore EE. Thomas G. Orr Memorial Lecture. Staged lapa-rotomy for the hypothermia, acidosis, and coagulopathy syn-drome. Am J Surg. 1996;172:405-410. 57. Morrison JJ, Galgon RE, Jansen JO, Cannon JW, Rasmussen TE, Eliason JL. A systematic review of the use of resuscita-tive endovascular balloon occlusion of the aorta in the man-agement of hemorrhagic shock. J Trauma Acute Care Surg. 2016;80(2):324-334. 58. Moore LJ, Brenner M, Kozar RA, et al. Implementation of resuscitative endovascular balloon occlusion of the aorta as an alternative to resuscitative thoracotomy for noncom-pressible truncal hemorrhage. J Trauma Acute Care Surg. 2015;79(4):523-530; discussion 530-532. 59. Gonzalez E, Moore EE, Moore HB. Management of trauma-induced coagulopathy with thrombelastography. Crit Care Clin. 2017;33(1):119-134. Review. 60. 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Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented research core-standard operating procedures for clinical care. IV. Guidelines for transfusion in the trauma patient. J Trauma. 2006;61:436-439. 66. Tariket S, Sut C, Hamzeh-Cognasse H, et al. Transfusion-related acute lung injury: transfusion, platelets and biological response modifiers. Expert Rev Hematol. 2016;9(5):497-508. 67. Moore FA, Moore EE, Sauaia A. Blood transfusion: an inde-pendent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132:620-624. 68. Kashuk JL, Moore EE, Sauaia A, et al. Postinjury life-threat-ening coagulopathy: is 1:1 fresh frozen plasma: packed red blood cells the answer? J Trauma. 2008;65:261-270. 69. Davenport R, Curry N, Manson J, et al. Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70(1):90-95. 70. Stanworth SJ, Morris TP, Gaarder C, et al. Reappraising the concept of massive transfusion in trauma. Crit Care. 2010;14(6):R239. 71. Dzik WH, Blajchman MA, Fergusson D, et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products–Massive transfusion consensus conference 2011: report of the panel. Crit Care. 2011;15(6):242. 72. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482. 73. Menaker J, Stein DM, Scalea TM. Incidence of early pulmo-nary embolism after injury. J Trauma. 2007;63:620-624. 74. Harr JN, Moore EE, Chin TL, et al. Platelets are dominant contributors to hypercoagulability after injury. J Trauma Acute Care Surg. 2013;74(3):756-762; discussion 762-765. 75. Prager M, Polterauer P, Böhmig HJ, et al. Collagen vs. gelatin-coated Dacron vs. stretch polytetrafluoroethylene in abdominal aortic bifurcation graft surgery: results of a seven-year prospective, randomized multicenter trial. Surgery. 2001;130(3):408-414. 76. Asensio JA, Feliciano DV. Abdominal vascular injury. In: Moore EE, Mattox KL, Feliciano DV, eds. Trauma. 8th ed. New York: McGraw-Hill; 2017. 77. Coleman JJ, Brewer BL, Feliciano DV. Trauma damage con-trol. In: Moore EE, Mattox KL, Feliciano DV, eds. Trauma. 8th ed. New York: McGraw-Hill; 2017. 78. Mathew S, Smith BP, Cannon JW, Reilly PM, Schwab CW, Seamon MJ. Temporary arterial shunts in damage Brunicardi_Ch07_p0183-p0250.indd 24610/12/18 6:22 PM 247TRAUMACHAPTER 7control: experience and outcomes. J Trauma Acute Care Surg. 2017;82(3):512-517. 79. Lubitz AL, Sjoholm LO, Goldberg A, et al. Acute right heart failure after hemorrhagic shock and trauma pneumonectomy—a management approach: a blinded randomized controlled ani-mal trial using inhaled nitric oxide. J Trauma Acute Care Surg. 2017;82(2):243-251. 80. Smith JW, Matheson PJ, Franklin GA, Harbrecht BG, Richardson JD, Garrison RN. Randomized controlled trial evaluating the efficacy of peritoneal resuscitation in the man-agement of trauma patients undergoing damage control sur-gery. J Am Coll Surg. 2017;224(4):396-404. 81. Dawes AJ, Sacks GD, Cryer HG, et al; Los Angeles County Trauma Consortium. Intracranial pressure monitoring and inpatient mortality in severe traumatic brain injury: a pro-pensity score-matched analysis. J Trauma Acute Care Surg. 2015;78(3):492-501; discussion 501-502. 82. Nirula R, Millar D, Greene T, et al. Decompressive craniectomy for medical management for refractory intracranial hyperten-sion: an AAST-MITC propensity score analysis. J Trauma Acute Care Surg. 2014;76(4):944-952; discussion 952-955. 83. Cooper DJ, Rosenfeld JV, Murray L, et al; DECRA Trial Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniec-tomy in diffuse traumatic brain injury. N Engl J Med. 2011;364(16):1493-1502. 84. Rinker C, McMurry F, Groeneweg V, et al. Emergency craniotomy in a rural level III trauma center. J Trauma. 1998;44:984-989. 85. Hutchison JS, Ward RE, Lacroix J, et al; Hypothermia Pedi-atric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008;358(23):2447-2456. 86. Kramer C, Freeman WD, Hoffman-Snyder C, et al. Therapeu-tic hypothermia for severe traumatic brain injury: a critically appraised topic. Neurologist. 2012;18(3):173-177. 87. Cogbill T, Cothren CC, Ahearn MK, et al. Management of severe hemorrhage associated with maxillofacial injuries: a multicenter perspective. J Trauma. 2008;64:250. 88. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesyl-ate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Ran-domized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA. 1997;277:1597-1604. 89. Stahel PF, Vanderheiden T, Finn MA. Management strategies for acute spinal cord injury: current options and future per-spectives. Curr Opin Crit Care. 2012;18(6):651-660. 90. Fehlings MG, Perrin RG: The timing of surgical intervention in the treatment of spinal cord injury: a systematic review of recent clinical evidence. Spine. 2006;31:S28-S35. 91. Biffl WL, Moore EE, Offner PJ, et al. Blunt carotid arte-rial injuries: implications of a new grading scale. J Trauma. 1999;47:845-853. 92. Burlew CC, Biffl WL, Moore EE, Barnett CC, Johnson JL, Bensard DD. Blunt cerebrovascular injuries: redefining screen-ing criteria in the era of noninvasive diagnosis. J Trauma Acute Care Surg. 2012;72(2):330-335. 93. Cothren CC, Moore EE, Biffl WL, et al. Anticoagulation is the gold standard therapy for blunt carotid injuries to reduce stroke rate. Arch Surg. 2004;139:540-545. 94. Shahan CP, Croce MA, Fabian TC, Magnotti LJ. Impact of continuous evaluation of technology and therapy: 30 years of research reduces stroke and mortality from blunt cerebrovas-cular injury. J Am Coll Surg. 2017;224(4):595-599. 95. Burlew CC, Biffl WL, Moore EE, et al. Endovascular stenting is rarely necessary for the management of blunt cerebrovascu-lar injuries. J Am Coll Surg. 2014;218(5):1012-1017. 96. Weinberg JA, Moore AH, Magnotti LJ, et al. Contemporary management of civilian penetrating cervicothoracic arterial injuries. J Trauma Acute Care Surg. 2016;81(2):302-306. 97. Johnston RH, Wall MJ, Mattox KL. Innominate artery trauma: a thirty-year experience. J Vasc Surg. 1993;17:134-139. 98. Shalhub S, Starnes BW, Brenner ML, et al. Blunt abdominal aortic injury: a Western Trauma Association multicenter study. J Trauma Acute Care Surg. 2014;77(6):879-885; discussion 885. 99. Harris DG, Rabin J, Starnes BW, et al. Evolution of lesion-specific management of blunt thoracic aortic injury. J Vasc Surg. 2016;64(2):500-505. 100. Fox N, Schwartz D, Salazar JH, et al. Evaluation and man-agement of blunt traumatic aortic injury: a practice manage-ment guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2015;78(1):136-146. 101. Moore EE, Burch JM, Moore JB. Repair of the torn descend-ing thoracic aorta using the centrifugal pump with partial left heart bypass. Ann Surg. 2004;240:38-43. 102. Rabin J, DuBose J, Sliker CW, O’Connor JV, Scalea TM, Griffith BP. Parameters for successful nonoperative manage-ment of traumatic aortic injury. J Thorac Cardiovasc Surg. 2014;147(1):143-149. 103. Wall MJ, Tsai PI, Mattox KL. Heart and thoracic vascular injury. In: Moore EE, Mattox KL, Feliciano DV, eds. Trauma. 8th ed. New York: McGraw-Hill; 2017. 104. Jones EL, Burlew CC, Moore EE. BioGlue hemostasis of penetrating cardiac wounds in proximity to the left ante-rior descending coronary artery. J Trauma Acute Care Surg. 2012;72(3):796-798. 105. Cothren CC, Moore EE. Traumatic ventricular septal defect. Surgery. 2007;142:776-777. 106. Wall MJ Jr, Hirshberg A, Mattox KL. Pulmonary tractotomy with selective vascular ligation for penetrating injuries to the lung. Am J Surg. 1994;168:665-669. 107. Cothren C, Moore EE, Biffl WL, et al. Lung-sparing tech-niques are associated with improved outcome compared with anatomic resection for severe lung injuries. J Trauma. 2002;53:483-487. 108. Cryer HG, Mavroudis C, Yu J, et al. Shock, transfusion, and pneumonectomy. Death is due to right heart failure and increased pulmonary vascular resistance. Ann Surg. 1990;212:197-201. 109. Luo L, Yin L, Liu Z, Xiang Z. Posttraumatic pulmonary pseudocyst: computed tomography findings and man-agement in 33 patients. J Trauma and Acute Care Surg. 2012;73(5):1225-1228. 110. Moore HB, Moore EE, Burlew CC, et al. Western Trauma Association critical decisions in trauma: management of parapneumonic effusion. J Trauma Acute Care Surg. 2012;73:1372-1379. 111. de Souza A, Offner PJ, Moore EE, et al. Optimal management of complicated empyema. Am J Surg. 2000;180:507-511. 112. Truitt MS, Murry J, Amos J, et al. Continuous intercostal nerve blockade for rib fractures: ready for primetime? J Trauma. 2011;71(6):1548-1552. 113. Kozar RA, Moore FA, Cothren CC, et al. Risk factors for hepatic morbidity following nonoperative management: mul-ticenter study. Arch Surg. 2006;141:451-458. 114. Malhotra AK, Fabian TC, Croce MA, et al. Blunt hepatic injury: a paradigm shift from operative to nonoperative man-agement in the 1990s. Ann Surg. 2000;231:804-813. 115. Peitzman AB, Marsh JW. Advanced operative techniques in the management of complex liver injury. J Trauma Acute Care Surg. 2012;73(3):765-770. 116. Biffl WL, Moore EE, Franciose RJ. Venovenous bypass and hepatic vascular isolation as adjuncts in the repair of destruc-tive wounds to the retrohepatic inferior vena cava. J Trauma. 1998;45:400-403.Brunicardi_Ch07_p0183-p0250.indd 24710/12/18 6:22 PM 248BASIC CONSIDERATIONSPART I 117. Poggetti RS, Moore EE, Moore FA, et al. Balloon tampon-ade for bilobar transfixing hepatic gunshot wounds. J Trauma. 1992;33:694-697. 118. Delis SG, Bakoyiannis A, Selvaggi G, et al. Liver transplanta-tion for severe hepatic trauma: experience from a single center. World J Gastroenterol. 2009;15(13):1641-1644. 119. Pickhardt B, Moore EE, Moore FA, et al. Operative splenic salvage in adults: a decade perspective. J Trauma. 1989;29:1386-1391. 120. Feliciano DV, Spjut-Patrinely V, Burch JM, et al. Splenorrha-phy: the alternative. Ann Surg. 1990;211:569-580. 121. Bhullar IS, Tepas JJ 3rd, Siragusa D, Loper T, Kerwin A, Frykberg ER. To nearly come full circle: nonoperative man-agement of high-grade IV-V blunt splenic trauma is safe using a protocol with routine angioembolization. J Trauma Acute Care Surg. 2017;82(4):657-664. 122. McIntyre LK, Schiff M, Jurkovich GJ. Failure of nonopera-tive management of splenic injuries: causes and consequences. Arch Surg. 2005;140:563-568. 123. Lopez JM Jr, McGonagill PW, Gross JL, et al. Subcapsular hematoma in blunt splenic injury: a significant predictor of failure of nonoperative management. J Trauma Acute Care Surg. 2015;79(6):957-959; discussion 959-960. 124. Toutouzas KG, Velmahos GC, Kaminski A, et al. Leukocytosis after posttraumatic splenectomy: a physiologic event or sign of sepsis? Arch Surg. 2002;137:924-928. 125. Howdieshell TR, Heffernan D, Dipiro JT; Therapeutic Agents Committee of the Surgical Infection Society. Surgical infec-tion society guidelines for vaccination after traumatic injury. Surg Infect (Larchmt). 2006;7(3):275-303. 126. Todd SR, Kozar RA, Moore FA. Nutrition support in adult trauma patients. Nutr Clin Pract. 2006;21:421-429. 127. Burlew CC, Moore EE, Cuschieri J, et al; the WTA Study Group. Who should we feed? Western Trauma Asso-ciation multi-institutional study of enteral nutrition in the open abdomen after injury. J Trauma Acute Care Surg. 2012;73:1380-1387. 128. Schroeppel TJ, Saleem K, Sharpe JP, et al. Penetrating duode-nal trauma: a 19-year experience. J Trauma Acute Care Surg. 2016;80(3):461-465. 129. Biffl WL, Moore EE, Croce M, et al. Western Trauma Asso-ciation critical decisions in trauma: management of pancreatic injuries. J Trauma Acute Care Surg. 2013;75(6):941-946. 130. Vaughn GD, Frazier OH, Graham D, et al. The use of pyloric exclusion in the management of severe duodenal injuries. Am J Surg. 1977;134:785. 131. Krige JE, Kotze UK, Setshedi M, Nicol AJ, Navsaria PH. Surgical management and outcomes of combined pancreati-coduodenal injuries: analysis of 75 consecutive cases. J Am Coll Surg. 2016;222(5):737-749. 132. Nelson R, Singer M. Primary repair for penetrating colon inju-ries. Cochrane Database Syst Rev. 2003;(3):CD002247. 133. Burlew CC, Moore EE, Cuschieri J, et al; WTA Study Group. Sew it up! A Western Trauma Association multi-institutional study of enteric injury management in the postinjury open abdomen. J Trauma. 2011;70(2):273-277. 134. Asensio JA, Britt LD, Borzotta A, et al. Multi-institutional experience with the management of superior mesenteric artery injuries. J Am Coll Surg. 2001;193:354-356. 135. Burch JM, Richardson RJ, Martin RR, et al. Penetrating iliac vascular injuries: experience with 233 consecutive patients. J Trauma. 1990;30:1450-1459. 136. Mullins RJ, Lucas CE, Ledgerwood AM. The natural his-tory following venous ligation for civilian injuries. J Trauma. 1980;20:737-743. 137. Jurkovich GJ, Hoyt DB, Moore FA, et al. Portal triad injuries. J Trauma. 1995;39:426-434. 138. Voelzke BB, McAninch JW. Renal gunshot wounds: clinical management and outcome. J Trauma. 2009;66(3):593-600. 139. Rostas J, Simmons JD, Frotan MA, Brevard SB, Gonzalez RP. Intraoperative management of renal gunshot injuries: is man-datory exploration of Gerota’s fascia necessary? Am J Surg. 2016;211(4):783-786. 140. Knudson MM, Harrison PB, Hoyt DB, et al. Outcome after major renovascular injuries: a Western Trauma Association multicenter report. J Trauma. 2000;49:1116-1122. 141. Burlew CC, Moore EE, Stahel PF, et al. Preperitoneal pelvic packing reduces mortality in patients with life-threatening hemorrhage due to unstable pelvic fractures. J Trauma Acute Care Surg. 2017;82(2):233-242. 142. Bosse MJ, MacKenzie EJ, Kellam JF, et al. An analysis of outcomes of reconstruction or amputation of leg-threatening injuries. N Engl J Med. 2002;347:1924-1931. 143. Einersen PM, Moore EE, Chapman MP, et al. Rapid throm-belastography thresholds for goal-directed resuscitation of patients at risk for massive transfusion. J Trauma Acute Care Surg. 2017;82(1):114-119. 144. Moore FA, McKinley BA, Moore EE, et al. Inflammation and the host response to injury, a large-scale collaborative proj-ect: patient-oriented research core—standard operating proce-dures for clinical care. III. Guidelines for shock resuscitation. J Trauma, 2006;61:82-89. 145. Dezman ZD, Comer AC, Smith GS, Narayan M, Scalea TM, Hirshon JM. Failure to clear elevated lactate predicts 24-hour mortality in trauma patients. J Trauma Acute Care Surg. 2015;79(4):580-585. 146. Nickerson TP, Zielinski MD, Jenkins DH, Schiller HJ. The Mayo Clinic experience with Morel-Lavallée lesions: estab-lishment of a practice management guideline. J Trauma Acute Care Surg. 2014;76(2):493-497. 147. Burlew CC, Moore EE, Biffl WL, Bensard DD, Johnson JL, Barnett CC. One hundred percent fascial approximation can be achieved in the postinjury open abdomen with a sequential clo-sure protocol. J Trauma Acute Care Surg. 2012;72(1):235-241. 148. Sela HY, Weiniger CF, Hersch M, Smueloff A, Laufer N, Einav S. The pregnant motor vehicle accident casualty: adher-ence to basic workup and admission guidelines. Ann Surg. 2011;254(2):346-352. 149. Drukker L, Hants Y, Sharon E, Sela HY, Grisaru-Granovsky S. Perimortem cesarean section for maternal and fetal salvage: concise review and protocol. Acta Obstet Gynecol Scand. 2014;93(10):965-972. 150. ACOG Committee on Obstetric Practice. ACOG Commit-tee Opinion. Number 299, September 2004. Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol. 2004;104:647-651. 151. Curet MJ, Schermer CR, Demarest GB, et al. Predictors of outcome in trauma during pregnancy: identification of patients who can be monitored for less than 6 hours. J Trauma. 2000;49:18-24. 152. Bruijns SR, Guly HR, Bouamra O, Lecky F, Lee WA. The value of traditional vital signs, shock index, and age-based markers in predicting trauma mortality. J Trauma Acute Care Surg. 2013;74(6):1432-1437. 153. Bulger EM, Arneson MA, Mock CN, et al. Rib fractures in the elderly. J Trauma. 2000;48:1040-1046. 154. Pieracci FM, Lin Y, Rodil M, et al. A prospective, controlled clinical evaluation of surgical stabilization of severe rib frac-tures. J Trauma Acute Care Surg. 2016;80(2):187-194. 155. Tepas JJ. The national pediatric trauma registry: a legacy of commitment to control childhood injury. Semin Pediatr Surg. 2004;13:126-132. 156. Gardner AR, Diz DI, Tooze JA, Miller CD, Petty J. Injury pat-terns associated with hypotension in pediatric trauma patients: Brunicardi_Ch07_p0183-p0250.indd 24810/12/18 6:22 PM 249TRAUMACHAPTER 7a national trauma database review. J Trauma Acute Care Surg. 2015;78(6):1143-1148. 157. Mollberg NM, Tabachnick D, Lin FJ, et al. Age-associated impact on presentation and outcome for penetrating thoracic trauma in the adult and pediatric patient populations. J Trauma Acute Care Surg. 2014;76(2):273-277; discussion 277-278. 158. Linnaus ME, Langlais CS, Garcia NM, et al. Failure of non-operative management of pediatric blunt liver and spleen injuries: a prospective Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium study. J Trauma Acute Care Surg. 2017;82(4):672-679. 159. Ingram MC, Siddharthan RV, Morris AD, et al. Hepatic and splenic blush on computed tomography in children fol-lowing blunt abdominal trauma: is intervention necessary? J Trauma Acute Care Surg. 2016;81(2):266-270.Brunicardi_Ch07_p0183-p0250.indd 24910/12/18 6:22 PM

Brunicardi_Ch07_p0183-p0250.indd 25010/12/18 6:22 PMThis page intentionally left blankBurnsJeffrey H. Anderson, Samuel P. Mandell, and Nicole S. Gibran 8chapterSurgical care of the burned patient has evolved into a special-ized field incorporating the interdisciplinary skills of burn sur-geons, nurses, burn therapists, and other healthcare specialists. However, recent mass casualty events have been a reminder that healthcare systems may be rapidly pressed to care for large numbers of burn patients. Naturally, general surgeons may be at the forefront in these events, so it is crucial that they are com-fortable with the care of burned patients and well equipped to provide the standard of care.BACKGROUNDBurn injury historically carried a poor prognosis. With advances in fluid resuscitation1 and the advent of early excision of the burn wound,2 survival has become an expectation even for patients with severe burns.3 Continued improvements in critical care and progress in skin bioengineering herald a future in which func-tional and psychologic outcomes are equally important as sur-vival alone. With this shift in priority, the American Burn Association (ABA) has emphasized referral to specialized burn centers after early stabilization. Specific criteria should guide transfer of patients with more complex injuries or other medical needs to a burn center (Table 8-1). The ABA has published stan-dards of care4 and created a verification process to ensure that burn centers meet those standards.5 Because of increased prehospital safety measures, burn patients are trans-ferred longer distances for definitive care at regional burn centers6; data from one burn center with a particularly wide catch-ment area confirmed that even transport times averaging several hours did not affect the long-term outcomes of burn patients.7INITIAL EVALUATIONInitial evaluation of the burned patient should follow the same initial priorities of all trauma patients and involves four crucial assessments: airway management, evaluation of other injuries, 1estimation of burn size, and diagnosis of CO and cyanide poi-soning. With direct thermal injury to the upper airway or smoke inhalation, rapid and severe airway edema is potentially lethal. Anticipating the need for intubation and establishing an early airway are critical. Signs of impending respiratory compromise include a hoarse voice, wheezing, or stridor; subjective dyspnea is a particularly concerning symptom and should trigger prompt elective endotracheal intubation. Perioral burns and singed nasal hairs alone do not indicate an upper airway injury, but are signs that the oral cavity and pharynx should be further evaluated for mucosal injury. Orotracheal intubation is the preferred method for securing the airway. Nasotracheal intubation may be use-ful for patients with associated facial trauma when experienced providers are present, but it should be avoided if oral intubation is safe and easy.Burned patients are trauma patients and evaluated with a primary survey in accordance with Advanced Trauma Life Sup-port guidelines. Concurrently with the primary survey, large-bore peripheral intravenous (IV) catheters should be placed and fluid resuscitation should be initiated; for a burn larger than 40% total body surface area (TBSA), two large-bore IVs are ideal. IV place-ment through burned skin is safe and effective but requires atten-tion to securing the catheters. Central venous access and intraosseous (IO) access should be considered when peripheral access cannot be easily obtained. Rarely, IV resuscitation is indi-cated in patients with burns smaller than 15% who can usually hydrate orally. Pediatric patients with burns larger than 15% may require IO access in emergent situations if venous access cannot be attained. An early and comprehensive secondary survey must be performed on all burn patients, but especially those with a his-tory of associated mechanical trauma such as a motor vehicle collision. Also, patients from structural fires in which the manner of egress is not known should be carefully evaluated for injuries from a possible jump or fall. Urgent radiology studies, such as a chest X-ray, should be performed in the emergency department, but nonurgent skeletal evaluation (i.e., extremity X-rays) can be Background 251Initial Evaluation 251Burn Classification 252Burn Depth 253Prognosis 254Resuscitation 254Inhalation Injury and Ventilator Management 255Treatment of The Burn Wound 257Nutrition 257Complications in Burn Care 258Surgery 259Wound Coverage 259Rehabilitation 260Late Complications: Hypertrophic Scar, Contractures, and Heterotopic Ossification 260Psychological Recovery 261Prevention 261Burn Disasters 261Future Areas of Study 262Brunicardi_Ch08_p0251-p0270.indd 25128/12/18 11:51 AM 252Table 8-1Guidelines for referral to a burn centerPartial-thickness burns greater than 10% TBSABurns involving the face, hands, feet, genitalia, perineum, or major jointsThird-degree burns in any age groupElectrical burns, including lightning injuryChemical burnsInhalation injuryBurn injury in patients with complicated preexisting medical disordersPatients with burns and concomitant trauma in which the burn is the greatest risk. If the trauma is the greater immediate risk, the patient may be stabilized in a trauma center before transfer to a burn center.Burned children in hospitals without qualified personnel for the care of childrenBurn injury in patients who will require special social, emotional, or rehabilitative interventionTBSA = total body surface area.done in the intensive care unit (ICU) to avoid hypothermia and delayed resuscitation. Hypothermia is a common prehospital complication that contributes to resuscitation failure. Patients should be wrapped with clean blankets in transport. Cooling should be avoided in patients with moderate or large (>20% TBSA) burns. Patients with acute burn injuries should never receive prophylactic antibiotics. This intervention has been clearly demonstrated to promote development of fungal infections and resistant organisms and was abandoned in the mid-1980s.8 A tetanus booster should be administered in the emergency department depending on patient immunization status.The importance of pain management for these patients has been widely recognized over the past 25 years. While pain man-agement is a priority for burn patients, it is important to acknowl-edge the opioid crisis and the recent push toward decreasing opiate use in general.9 In order to limit opiate-related morbidity, we recommend responsible opiate use in conjunction with mul-timodal pain control and development of a weaning plan start-ing at opioid commencement. Clear expectations around pain medication use should be set with patients. Anxiety is another component of the psychological response of burn patients, seen with both wound care and general postinjury hospital course. Benzodiazepines are a staple in the treatment of acute anxiety; however, they can contribute significantly to hospital delirium.10 We recommend conservative benzodiazepine use to mitigate the effects of anxiety while minimizing deliriogenic effects of benzodiazepines.2Most burn resuscitation formulas estimate fluid require-ments based on burn size measured as a percentage of TBSA (%TBSA). The “rule of nines” is a crude but quick and effec-tive method of estimating burn size (Fig. 8-1). In adults, the anterior and posterior trunk each account for 18%, each lower extremity is 18%, each upper extremity is 9%, and the head is 9%. In children under 3 years old, the head accounts for a larger relative surface area and should be taken into account when esti-mating burn size. For smaller or odd-shaped burns, the “rule of the palm” where the palmar surface of the hand, including the digits, is 1% TBSA is useful. Diagrams such as the Lund and Browder chart give a more accurate accounting of the true burn size in children and adults. The importance of an accurate burn size assessment cannot be overemphasized. Superficial or first-degree burns should not be included when calculating burn size, and thorough cleaning of soot and debris is mandatory to avoid confusing soiled skin with burns. Examination of referral data suggests that physicians inexperienced with burns tend to overestimate the size of small burns and underestimate the size of large burns, with potentially detrimental effects on pretrans-fer resuscitation.11BURN CLASSIFICATIONBurns are commonly classified as thermal, electrical, or chemi-cal burns, with thermal burns consisting of flame, contact, or scald burns. Flame burns are the most common cause for hos-pital admission of burns, and have the highest mortality. This is primarily related to their association with structural fires and the accompanying inhalation injury and/or CO poisoning.12Electrical burns make up 3% of U.S. hospital admissions but have special concerns,12 including cardiac arrhythmia and compartment syndrome with concurrent rhabdomyolysis. A baseline ECG is recommended in all patients with an electrical injury, and a normal ECG in a low-voltage injury (<1000 V) may preclude hospital admission. Because compartment syn-drome and rhabdomyolysis are common in high-voltage elec-trical injuries, vigilance must be maintained for neurologic or vascular compromise, and fasciotomies should be performed even in cases of moderate clinical suspicion. Long-term neuro-logic symptoms13 and cataract development14 are not uncommon with high-voltage electrical injuries, and neurologic and oph-thalmologic consultation should be obtained to define baseline patient function.15Chemical burns also comprise 3% of admitted burn patients12 and result in potentially severe burns. Typically, acid chemical burns result in coagulation necrosis and alkali chemical burns cause liquefactive necrosis (with an exception of hydrofluoric acid, which also causes liquefactive necrosis).16,17 Key Points1 Follow American Burn Association criteria for referral of a patient to a regional burn center.2 Never administer prophylactic antibiotics other than tetanus vaccination.3 Early excision and grafting of full-thickness and deep partial-thickness burns improve outcomes.4 Intravenous fluid resuscitation for patients with burns >20% of total body surface area (children with burns >15% of total body surface area) should be titrated to mean arterial pres-sure (MAP) >60 mmHg and appropriate urine output.Brunicardi_Ch08_p0251-p0270.indd 25228/12/18 11:51 AM 253BURNSCHAPTER 8The most important components of initial therapy are careful removal of the toxic substance from the patient and irrigation of the affected area with water for a minimum of 30 minutes. In cases of exposure to dry chemicals, such as concrete or pow-dered forms of lye, the substance should be swept from the patient to avoid a thermal reaction with water. The offending agents in chemical burns can be systemically absorbed and may cause specific metabolic derangements. Formic acid has been known to cause hemolysis and hemoglobinuria, and hydroflu-oric acid causes hypocalcemia. Hydrofluoric acid is a particu-larly common offender due to its widespread industrial uses. Calcium-based therapies are the mainstay of treating hydroflu-oric acid burns, with topical application of calcium gluconate onto wounds18 and IV administration of calcium gluconate for systemic hypocalcemia symptoms. Intra-arterial calcium gluco-nate infusion provides effective treatment of progressive tissue injury and intense pain.19,20 Patients undergoing intra-arterial therapy need continuous cardiac monitoring. Persistent refrac-tory hypocalcemia with electrocardiac abnormalities may signal the need for emergent excision of the burned areas.21BURN DEPTHBased on the original burn depth classification by Dupuytren in 1832,22 burn wounds are commonly classified as superficial (first-degree), partial-thickness (second-degree), full-thickness (third-degree), and fourth-degree burns, which affect underlying soft tissue. Fifth-degree burns (through muscle to bone) and sixth degree burns (charring bone) were also described although are less common. Partial-thickness burns are classified as either superficial or deep partial-thickness burns by depth of involved dermis. Clinically, first-degree burns are painful but do not blis-ter, second-degree burns have dermal involvement and are extremely painful with weeping and blisters, and third-degree burns are leathery, painless, and nonblanching. Jackson described three zones of tissue injury following burn injury.23 The zone of coagulation is the most severely burned portion and is typically in the center of the wound. As the name implies, the affected tissue is coagulated and sometimes frankly necrotic, much like a full thickness burn, and will need excision and graft-ing. Peripheral to that is a zone of stasis, with variable degrees of vasoconstriction and resultant ischemia, much like a second-degree burn. Appropriate resuscitation and wound care may pre-vent conversion to a deeper wound, but infection or suboptimal perfusion may result in an increase in burn depth. This is clini-cally relevant because many superficial partial-thickness burns will heal with nonoperative management, and the majority of deep partial-thickness burns benefit from excision and skin grafting. The outermost area of a burn is called the zone of hyperemia, which will heal with minimal or no scarring and is most like a superficial partial thickness burn or first-degree burn.Unfortunately, even experienced burn surgeons have lim-ited ability to accurately predict the healing potential of partial-thickness burns soon after injury; one reason is that burn wounds evolve over the 48 to 72 hours after injury. Numerous burn depth assessment tools have been developed with the idea that 39%4.5%4.5%9%9%18%1%1%18%18%18%FrontBackFigure 8-1. The “rule of nines” can be used as a quick reference for estimating a patient’s burn size by dividing the body into regions to which total body surface area is allocated in multiples of nine.Brunicardi_Ch08_p0251-p0270.indd 25328/12/18 11:51 AM 254BASIC CONSIDERATIONSPART Iearlier burn depth definition will expedite appropriate surgical decision-making. One of the most effective ways to determine burn depth is full-thickness biopsy, but this has several limita-tions; not only is the procedure painful and potentially scar-ring, but accurate interpretation of the histopathology requires a specialized pathologist and may have slow turnaround times.24 Laser Doppler can measure skin perfusion to predict burn depth with sensitivities and specificity of up to 83% and 97%, respectively.25 Noncontact ultrasound has been postulated as a painless modality to predict nonhealing wounds and has the advantage of easily performed serial measurements.26 Unfortu-nately, none of these newer therapies have proven adequately superior to justify their cost and as yet have not substituted serial examination by experienced burn surgeons.PROGNOSISThe Baux score (mortality risk equals age plus %TBSA) was used for many years to predict mortality in burns. Analysis of multiple risk factors for burn mortality has validated age and burn size as the strongest predictors of mortality.27 Advance-ments in burn care have lowered overall mortality to the point that the original Baux score may no longer be accurate. How-ever, the Revised Baux Score, which accounts for age, burn size, and inhalation injury, has been found to be independently associated with mortality.28 As such, age, burn size, and inhala-tion injury continue to be the most robust indicators for burn mortality.29 Age even as a single variable strongly predicts mortality in burns,30 and in-hospital mortality in elderly burn patients is a function of age regardless of other comorbidities.31 In nonelderly patients, comorbidities such as preinjury human immunodeficiency virus (HIV), metastatic cancer, and kidney or liver disease may influence mortality and length of stay.32 A large database study of 68,661 burn patients found that the vari-ables with the highest predictive value for mortality were age, %TBSA, inhalation injury, coexistent trauma, and pneumonia.33 A more recent study analyzing 506,628 burn inpatients between 1998 and 2008 demonstrated an association between burn size, age, inhalation injury, and mortality. Other factors associated with mortality included African American race, female gender, and treatment in urban private hospitals (as opposed to urban academic hospitals).34Mortality is not the only outcome of interest in the burn population. Burn injury can significantly impact the subsequent quality of life for survivors, including but not limited to appear-ance, mobility, functional status, and ability to work. One study found that burn injury reduces short term quality of life by 30% and long-term quality of life by approximately 11%.35 Predic-tors of poorer physical and mental health 12 months removed from burn injury include older age, female gender, and greater %TBSA burn size.36 One factor impacting quality of life is itching—a late and bothersome consequence of burn injury that affects both adult and pediatric population.37,38 Other factors dis-cussed later in this chapter include hypertrophic scarring, con-tracture, and heterotopic ossification. Finally, return to work or school has been a useful tool to evaluate recovery and prognosis. A recent meta-analysis found that approximately 28% of burn survivors never return to work.39 A recent study using an inter-ventional bundle involving the patient, the employee, worker’s compensation, and burn clinic staff demonstrated a return to work rate of 93%.40 The return to school for pediatric patients is actually very prompt, averaging about 10 days after discharge. However, further study is needed to determine whether atten-dance and performance suffer despite early reentry to school.41 It is important to recognize these potential quality-of-life issues in burn patients and take necessary steps to diminish the impact that burn injury has on quality of life both in the hospital and following discharge.RESUSCITATIONA myriad of formulas exist for calculating fluid needs during burn resuscitation, suggesting that no one formula benefits all patients. The most commonly used formula, the Parkland or Baxter formula, consists of 3 to 4 mL/kg per % burn of Lac-tated Ringer’s, of which half is given during the first 8 hours after burn and the remaining half is given over the subsequent 16 hours.1 The most recent American Burn Association con-sensus formula recommends 2 mL/kg per % burn of Lactated Ringers given the tendency toward excessive fluid administra-tion with the traditional formulas.42 The concept behind continu-ous fluid requirements is simple. The burn (and/or inhalation injury) drives an inflammatory response that leads to capillary leak; as plasma leaks into the extravascular space, crystalloid administration maintains the intravascular volume. Therefore, if a patient receives a large fluid bolus in a prehospital setting or emergency department, the fluid has likely leaked into the interstitium, and the patient still requires ongoing burn resusci-tation according to the estimates. Continuation of fluid volumes should depend on the time since injury, urine output, and mean arterial pressure (MAP). As the capillary leak closes, the patient will require less volume to maintain these two resuscitation endpoints. Children under 20 kg have the additional require-ment that they do not have sufficient glycogen stores to main-tain an adequate glucose level in response to the inflammatory response. Specific pediatric formulas have been described, but the simplest approach is to deliver a weight-based maintenance IV fluid with glucose supplementation in addition to the calcu-lated resuscitation with lactated Ringer’s.It is important to remember that any formula for burn resuscitation is merely a guideline, and fluid must be titrated based on appropriate response to therapy. A number of parame-ters are widely used to gauge burn resuscitation, but the most common remain the simple outcomes of blood pressure and urine output. As in any critically ill patient, a target MAP of 60 mmHg ensures optimal end-organ perfusion. Goals for urine out-put should be 30 mL/h in adults and 1 to 1.5 mL/kg per h in pediatric patients. Because blood pressure and urine output may not correlate perfectly with true tissue perfusion, the search continues for other adjunctive parameters that may more accu-rately reflect adequate resuscitation. Some centers have found serum lactate to be a better predictor of mortality in severe burns,43,44 and others have found that base deficit predicts even-tual organ dysfunction and mortality.45,46 Because burned patients with normal blood pressure and serum lactate levels may have compromised gastric mucosal perfusion, continuous measurement of mucosal pH with its logistical difficulties has garnered limited popularity.47,48 Invasive monitoring with pul-monary artery catheters typically results in significant excessive fluid administration without improved cardiac output or preload measurements; use of invasive monitoring seems to have vari-able effects on long-term outcomes.49Actual administrated fluid volumes typically exceed vol-umes predicted by standard formulas.50 One survey of burn 4Brunicardi_Ch08_p0251-p0270.indd 25428/12/18 11:51 AM 255BURNSCHAPTER 8centers showed that 58% of patients end up getting more fluids than would be predicted by Baxter’s formula.51 Comparison of modern-day patients with historical controls shows that over-resuscitation may be a relatively recent trend.52 One theory is that increased opioid analgesic use results in peripheral vaso-dilation and hypotension and the need for greater volumes of bolused resuscitative fluids.53 A classic study by Navar et al showed that burned patients with inhalation injury required an average of 5.76 mL/kg per % burn, vs. 3.98 mL/kg per % burn for patients without inhalation injury, and this has been corroborated by subsequent studies.54,55 Prolonged mechanical ventilation may also play a role in increased fluid needs.56 A multicenter study found that age, weight, %TBSA, and intu-bation on admission were significant predictors of more fluid delivery during the resuscitation period. Those patients receiv-ing higher fluid volumes were at increased risk of complications and death.57 Common complications include abdominal com-partment syndrome, extremity compartment syndrome, intraoc-ular compartment syndrome, and pleural effusions. Monitoring bladder pressures can provide valuable information about devel-opment of intra-abdominal hypertension.The use of colloid as part of the burn resuscitation has gen-erated much interest over the years. In late resuscitation when the capillary leak has closed, colloid administration may decrease overall fluid volumes and potentially may decrease associated complications such as intra-abdominal hypertension.58 A recent meta-analysis accounting for statistical heterogeneity among studies included demonstrated a trend toward mortality ben-efit for patients receiving albumin.59 However, albumin use has never been shown to definitively improve mortality in burn patients and has controversial effects on mortality in critically ill patients.60-63 Still, many burn centers including ours continue to use albumin as an adjunct during burn resuscitation.64 Attempts to minimize fluid volumes in burn resuscitation have included study of hypertonic solutions. A recent meta-analysis evaluating hyperosmotic vs. isoosmotic fluid resuscitation demonstrates decreased total fluid load (vol/%TBSA per weight) over the first 24 hours with use of hyperosmotic fluid with no difference in total fluid, urine output, creatinine, or mortality.65 A described downside of hypertonic fluid administration is hyperchloremic acidosis.66Other adjuncts are being increasingly used during initial burn resuscitation. High-dose ascorbic acid (vitamin C) may decrease fluid volume requirements and ameliorate respira-tory embarrassment during resuscitation, although no mortality benefit has been noted thus far in two trials.67,68 Plasmapheresis has also been associated with decreased fluid requirements and increased urine output in patients who require higher resuscita-tive volumes than predicted to maintain adequate urine output and MAP.69 It is postulated that plasmapheresis may filter out inflammatory mediators, thus decreasing ongoing vasodilation and capillary leak.70One adjunct that has found increasing utility in surgi-cal ICUs has been the application of bedside ultrasound.71 Ultrasound offers the potential to make rapid, noninvasive assessments during acute changes in clinical condition. For burn patients, bedside ultrasonography may be indicated for evalu-ation of volume status, gross assessment of cardiac function, and diagnosis of pneumothorax. Determining patient cardiac function and volume status may guide fluid resuscitation. Car-diac function can be evaluated with three common heart views: the parasternal long axis, parasternal short axis, and apical four-chamber views.72 Whereas no study has used ultrasound to guide fluid resuscitation in burn patients, volume status can be estimated by examination of cardiac function and evaluation of the inferior vena cava (IVC) diameter with changes in respira-tion, as has been done in patients with hemorrhage and shock.73 Ultrasound also allows timely diagnosis of pneumothorax.74 A high-frequency probe with an adequate window between ribs permits identification of lung parenchyma against the chest well. A pneumothorax appears as a transition on ultrasound between lung parenchyma, which has a heterogeneous appear-ance, and air, which has a hypoechoic appearance. Further stud-ies are warranted to identify indications for the use of ultrasound in burned patients.Machine learning and bedside computer decision support are other adjuncts gaining traction in caring for burn patients. These modalities can enhance patient care and aid in diagnosis, treatment, and research.75 The use of bedside computer decision support has been particularly appealing for resuscitation of burn patients in the first 48 hours and has been shown to improve fluid management during initial resuscitation.76The role of blood transfusion in critically injured patients has undergone a reevaluation in recent years.77,78 Blood transfu-sions are considered to be immunomodulatory and potentially immunosuppressive, which is one explanation to the links between blood transfusions and increased infection and shorter time to recurrence after oncologic surgery.79,80 A large multi-center study of blood transfusions in burn patients found that increased numbers of transfusions were associated with increased infections and higher mortality in burn patients, even when cor-recting for burn severity.81 A follow-up study implementing a restrictive transfusion policy in burned children showed that a hemoglobin threshold of 7 g/dL had no more adverse outcomes vs. a traditional transfusion trigger of 10 g/dL. In addition, costs incurred to the institution were significantly less.82 A recent ran-domized control trial in patients with >20% TBSA compared outcomes of a restrictive to a liberal red blood cell transfusion strategy (hemoglobin 7–8 vs. 10–11, respectively). There were no differences in blood stream infection, organ dysfunction, ven-tilator days, time to wound healing, or 30-day mortality between both groups.83 These data, in concert with other reported compli-cations such as transfusion-related lung injury,84 have led to rec-ommendations that blood transfusions be used only when there is an apparent physiologic need. Attempts to minimize blood transfusion in nonburned critically ill patients have led to use of erythropoietin by some centers. However, burn patients often have elevated erythropoietin levels, and a randomized study in burn patients showed that recombinant human erythropoietin did not effectively prevent anemia or decrease the number of transfusions given.85 Promising animal studies demonstrating erythropoietin-mediated prevention of secondary burn progres-sion have yet to be validated in humans.86INHALATION INJURY AND VENTILATOR MANAGEMENTInhalation injuries are commonly seen in tandem with burn inju-ries and are known to increase mortality in burned patients.87,88 Smoke inhalation is present in as many as 35% of hospital-ized burn patients and may triple the hospital stay compared to isolated burn injuries.89 Mortality for inhalation injury has been reported to be as high as 25%, with this increasing to 50% in patients with ≥20% TBSA burns.90 The pneumonia rate in Brunicardi_Ch08_p0251-p0270.indd 25528/12/18 11:51 AM 256BASIC CONSIDERATIONSPART Ipatients with inhalation injury has been reported to be three times higher than those without inhalation injury, and it has been associated with increased length of stay, increased ven-tilator days, and need for tracheostomy.91,92 The combination of burns, inhalation injury, and pneumonia increases mortal-ity by up to 60% over burns alone.93 Subsequent development of the adult respiratory distress syndrome (ARDS) is common in these patients and may be caused in part by recruitment of alveolar leukocytes with an enhanced endotoxin-activated cyto-kine response.94 When ARDS complicates burns and inhalation injury, mortality approaches 66%; in one study, patients with burns ≥60% TBSA in combination with inhalation injury and ARDS had 100% mortality.95Smoke inhalation causes injury in two ways: by direct heat injury to the upper airways and inhalation of combustion prod-ucts into the lower airways. Direct injury to the upper airway causes airway swelling that typically leads to maximal edema in the first 24 to 48 hours after injury and often requires a short course of endotracheal intubation for airway protection. Com-bustion products found in smoke, most commonly from syn-thetic substances in structural fires, cause lower airway injury. These irritants cause direct mucosal injury, which in turn leads to mucosal sloughing, edema, reactive bronchoconstriction, and finally obstruction of the lower airways. Injury to both the epi-thelium and pulmonary alveolar macrophages causes release of prostaglandins, chemokines, and other inflammatory mediators; neutrophil migration; increased tracheobronchial blood flow; and, finally, increased capillary permeability. All of these com-ponents of acute lung injury increase the risk of pneumonia and ARDS following an inhalation injury.The physiologic effects of smoke inhalation are numerous. Inhalation injury decreases lung compliance96 and increases air-way resistance work of breathing.97 Inhalation injury in the pres-ence of burns also increases overall metabolic demands.98 The most common physiologic derangement seen with inhalation injury is increased fluid requirement during resuscitation. Since severe inhalation injury may result in mucosal sloughing with obstruction of smaller airways, bronchoscopy findings including carbon deposits, erythema, edema, bronchorrhea, and a hemor-rhagic appearance may be useful for staging inhalation injury. The Abbreviated Injury Score—a scale from 0 to 4, with 0 representing no injury and 4 representing massive injury—is commonly used for grading inhalation injury. Higher grades of bronchoscopic inhalation injury have been associated with increased incidence of ARDS, increased ventilator days, higher rate of multiple organ dysfunction syndrome, and higher mortality.99 Bronchoscopic evaluation can also help isolate organisms early in the course of a potential pneumonia. Bronchoalveolar lavage (BAL) within 24 hours after an inhalation injury demonstrates a high rate of positive quantitative cultures,100 suggesting that pneumonia develops soon after the acute lung injury. Bacterial contamina-tion from urgent intubation may contribute to early development of pneumonia in patients with inhalation injury.100 Early evalu-ation with bronchoscopy can identify causative organisms and guide appropriate antibiotic therapy.Because bronchoscopy is an invasive test, attempts have been made to utilize other diagnostic modalities, such as tho-racic computed tomography (CT) scans101 and xenon ventilationperfusion scanning.102,103 However, these are generally not uti-lized unless otherwise indicated, and the best tools available for diagnosing inhalation injury remain clinical presentation and bronchoscopic evaluation. Decreased PaO2:FiO2 ratio (<350) on admission may not only predict inhalation injury but also indi-cate increased fluid needs more accurately than bronchoscopic grading of the severity of inhalation.104Treatment of inhalation injury consists primarily of support-ive care. Aggressive pulmonary toilet and routine use of nebulized bronchodilators such as albuterol are recommended. Nebulized N-acetylcysteine is an antioxidant free radical scavenger designed to decrease the toxicity of high oxygen concentrations. Aero-solized heparin aims to prevent formation of fibrin plugs and decrease the formation of airway casts and has been associated with increased number of ventilator-free days.105 A recent meta-analysis demonstrated improved mortality with the use of inhaled anticoagulation regimens.106 Aerosolized tissue plasminogen activator107 and recombinant human antithrombin108 have shown promise in sheep models but have not yet seen widespread clinical use. Administration of intrabronchial surfactant has been used as a salvage therapy in patients with severe burns and inhalation injury.109 Inhaled nitric oxide may also be useful as a last effort in burn patients with severe lung injury who are failing other means of ventilator support.110 The use of steroids has traditionally been avoided due to the worse outcomes in burn patients111; however, some data demonstrate selectively improved outcomes with septic shock requiring vasopressor circulatory.112An important contributor to early mortality in burn patients and often seen in patients with inhalation injury is carbon mon-oxide (CO) poisoning. This clear, odorless gas has an affinity for hemoglobin is approximately 200 to 250 times more than that of oxygen. Carboxyhemoglobin decreases the levels of nor-mal oxygenated hemoglobin and can quickly lead to anoxia and death.113 CO also causes uncoupling of oxidative phosphory-lation in mitochondria, free radical generation, and increased systemic inflammatory response via platelet activation—all of which may increase cardiac and neurologic morbidity and mortality in CO toxicity.114 Unexpected neurologic or cardiac symptoms should raise the level of suspicion, and an arterial carboxyhemoglobin level must be obtained because pulse oxim-etry can be falsely elevated. Administration of 100% normo-baric oxygen is the gold standard for treating CO poisoning and reduces the half-life of CO from 250 minutes in room air to 40 to 60 minutes.115 Some authors have proposed hyperbaric oxygen as an adjunctive therapy for CO poisoning.116 However, a recent meta-analysis offers mixed results regarding the suc-cess and long-term outcomes of hyperbaric oxygen, and its asso-ciated logistical difficulties and complications have limited its usefulness for patients with moderate or large burns.117 Patients who sustain a cardiac arrest as a result of their CO poisoning have an extremely poor prognosis regardless of the success of initial resuscitation attempts.118Hydrogen cyanide toxicity may also be a component of an overwhelming smoke inhalation injury. Cyanide inhibits cyto-chrome oxidase, which is required for oxidative phosphorylation.119 Afflicted patients may have a persistent, severe lactic acidosis, neurologic symptoms, pulmonary edema, or cardiac sequelae (ST elevation on electrocardiogram).120,121 Classic signs of cya-nide poisoning—including bitter almond breath and cherry-red skin changes—are rare and should not be used as the sole diagnostic criteria. Treatment consists of sodium thiosulfate, hydroxocobalamin, and 100% oxygen. Sodium thiosulfate works as a substrate for the metabolism cyanide into a nontoxic deriva-tive, but it works slowly and is not effective for acute therapy.121 Hydroxocobalamin—a vitamin B12 precursor—quickly Brunicardi_Ch08_p0251-p0270.indd 25628/12/18 11:51 AM 257BURNSCHAPTER 8complexes with cyanide, is excreted by the kidney, and is rec-ommended for immediate therapy.122 In the majority of patients, lactic acidosis will resolve with ventilation, and sodium thio-sulfate treatment becomes unnecessary.123 Given the unknown side-effects of hydroxocobalamin administration, it should be reserved only for patients with a strong suspicion of cyanide poisoning.New ventilator strategies have contributed to the improved mortality with ARDS. Although ARDS still contributes to mor-tality in burn patients, treatments have improved so that mor-tality is primarily from multisystem organ failure rather than isolated respiratory causes.124 The ARDS Network Study find-ing that low tidal volume (6 cc/kg) or “lung-protective ventila-tion” had a 22% lower mortality than patients with traditional tidal volumes (12 cc/kg)124 has dramatically changed the man-agement of patients with acute lung injury. A similar approach had previously been shown to improve outcomes in pediatric burn patients.125 In patients with refractory hypoxemia despite lung-protective ventilation, prone positioning may improve oxygenation and mortality.126,127 No specific studies have exam-ined prone positioning in burned patients, and in fact exclusion criteria from a large prone positioning trial included patients with ≥20% TBSA.127 Select reports demonstrate the feasibility of prone positioning in burn patients,128 although they pres-ent logistical challenges and caution must be used in patients with frontal and facial burns who are already at risk for loss of the grafts, invasive catheters, and the endotracheal tube. Highfrequency percussive ventilation (HFPV) has shown early promise in patients with inhalation injury.129 One study showed notable decreases in both morbidity and mortality with HFPV, especially in patients with burns <40% TBSA and inhalation injury.130 A randomized controlled trial between low-tidal vol-ume ventilation and HFPV in burn patients requiring mechani-cal ventilation demonstrated no significant difference in primary clinical outcomes.131 A related technique is high-frequency oscillatory ventilation (HFOV), which has been used primarily as a salvage modality in patients refractory to more conventional measures.132 However, two recent studies and a recent metaanalysis have concluded that HFOV yields no mortality benefit and in fact may actually increase patient mortality in patients with ARDS.133-135 Extracorporeal membrane oxygenation (ECMO) is typically reserved for salvage situations, although utilization of ECMO for burn patients is increasing and out-comes have been shown to be similar to other ECMO patients.136TREATMENT OF THE BURN WOUNDMultitudes of topical therapies exist for the treatment of burn wounds, many of which contain antimicrobial properties. A recent Cochrane Database Review nicely summarizes the data surrounding antisepsis for burns; however, much of the data is inconclusive.137 Silver sulfadiazine is one of the most widely used in clinical practice. Silver sulfadiazine has a wide range of antimicrobial activity, primarily as prophylaxis against burn wound infections rather than treatment of existing infec-tions. It has the added benefits of being inexpensive, being easily applied, and having soothing qualities. It is not signifi-cantly absorbed systemically and thus has minimal metabolic derangements. Silver sulfadiazine has a reputation for causing neutropenia, but this association is more likely due to neutro-phil margination from the inflammatory response following burn injury. True allergic reactions to the sulfa component of silver sulfadiazine are rare, and at-risk patients can have a small test patch applied to identify a burning sensation or rash. Silver sulfadiazine destroys skin grafts and is contraindicated on burns or donor sites in proximity to newly grafted areas. Also, silver sulfadiazine may retard epithelial migration in healing partial-thickness wounds.Mafenide acetate, either in cream or solution form, is an effective topical antimicrobial. It is effective even in the pres-ence of eschar and can be used in both treating and prevent-ing wound infections; the solution formulation is an excellent antimicrobial for fresh skin grafts. Use of mafenide acetate may be limited by pain with application to partial-thickness burns. As mafenide is a carbonic anhydrase inhibitor, a his-torically described side effect is metabolic acidosis. However, multiple studies have been performed using mafenide to treat burn wounds without any significant incidence of metabolic acidosis.138,139Silver nitrate has broad-spectrum antimicrobial activity as a topical solution. The solution used must be dilute (0.5%), and prolonged topical application leads to electrolyte extravasation with resulting hyponatremia. A rare complication is methemo-globinemia.140 Although inexpensive, silver nitrate solution causes black stains, and laundry costs may offset any fiscal benefit to the hospital. Although there is no definitive evidence regarding use in the burn population, Dakin’s solution (0.5% sodium hypochlorite solution) is an acceptable alternative as an inexpensive topical antimicrobial.For smaller burns or larger burns that are nearly healed, topical ointments such as bacitracin, neomycin, and polymyxin B can be used. These are also useful for superficial partial-thickness facial burns as they can be applied and left open to air without dressing coverage. Meshed skin grafts in which the interstices are nearly closed are another indication for use of these agents, preferably with greasy gauze to help retain the ointment in the affected area. All three have been reported to cause nephrotoxicity and should be used sparingly in large burns. Recent media coverage of methicillin-resistant Staphy-lococcus aureus (MRSA) has led to widespread use by commu-nity practitioners of mupirocin for new burns. Unless the patient has known risk factors for MRSA, mupirocin should only be used in culture-positive burn wound infections to prevent emer-gence of further resistance.Silver-impregnated dressings are increasingly being used for donor sites, skin grafts, and partial-thickness burns because of their potential to avoid daily dressing changes. These may be more comfortable for the patient, reduce the number of dressing changes, and shorten hospital length of stay, but they limit serial wound examinations. Biologic membranes such as Biobrane (Smith & Nephew Global Products) provide a prolonged barrier under which wounds may heal. Because of the occlusive nature of these dressings, these are typically used only on fresh, super-ficial, partial-thickness burns that are clearly not contaminated.NUTRITIONNutritional support may be more important in patients with large burns than in any other patient population. Not only does adequate nutrition play a role in acute issues such as immune responsiveness, but the hypermetabolic response in burn injury may raise baseline metabolic rates by as much as 200%.141 This can lead to catabolism of muscle proteins and decreased lean body mass that may delay functional recovery.142 Early enteral Brunicardi_Ch08_p0251-p0270.indd 25728/12/18 11:51 AM 258BASIC CONSIDERATIONSPART Ifeeding for patients with burns >20% TBSA is safe and may reduce loss of lean body mass,143 slow the hypermetabolic response,144 and result in more efficient protein metabolism.145,146 Early enteral feeds have also been associated with shorter dura-tion of ICU stay and decreased rates of wound infection.147 If the enteral feeds are started within the first few hours after admis-sion, gastric ileus may be avoided. Adjuncts such as metoclo-pramide promote gastrointestinal motility; if other measures for gastric feeding are unsuccessful, advancing the tube into the small bowel with nasojejunal feeding can be attempted.148 In endotracheally intubated patients, trips to the operating room do not necessitate holding enteral feedings.149 Immune-modulating supplements such as glutamine may decrease infectious com-plications in burn patients,150,151 although the effect on mortality and wound closure remains unknown. One proposed mechanism for glutamine’s immune modulating properties is via preven-tion of T-cell suppression in mesenteric lymph nodes.152 There is currently a multicenter randomized control trial recruiting to determine the effect of glutamine on mortality, blood stream infections, and health-related quality of life (https://clinicaltri-als.gov/ct2/show/NCT00985205). Micronutrient supplementa-tion with antioxidant vitamins (vitamin E and ascorbic acid) and trace minerals (selenium, zinc, and copper) optimizes wound healing, enhances immune function, and fights oxida-tive stress.153Calculating the appropriate caloric needs of the burn patient can be challenging. A commonly used formula in non-burned patients is the Harris-Benedict equation, which calcu-lates caloric needs using factors such as gender, age, height, and weight. This formula uses an activity factor for specific inju-ries, and for burns, the basal energy expenditure is multiplied by two. The Harris-Benedict equation may be inaccurate in burns of <40% TBSA, and in these patients, the Curreri formula may be more appropriate. This formula estimates caloric needs to be 25 kcal/kg per d plus 40 kcal/%TBSA per d. Indirect calorim-etry can also be used to calculate resting energy expenditure, but in burn patients, a “metabolic cart” has not been documented to be more beneficial than the predictive equations.154 Titrating caloric needs closely is important because overfeeding patients will lead to storage of fat instead of muscle anabolism.155Modifying the hypermetabolic response is an area of intense study. β-Blocker use in pediatric patients decreases heart rate and resting energy expenditure and abrogates protein catabolism, even in long-term use.156 There may be benefits to β-blockade in adult patients,157 and many centers use β-blockers routinely in the adult population with limited safety and efficacy data.158 Some data suggests that β-blocker use in the adult burn population has a greater incidence of iatrogenic hypotension and bradycardia. As such, it is important to monitor hemodynamic status when starting β-blockers in these populations.159The anabolic steroid oxandrolone has been extensively studied in burn patients as well and has demonstrated improve-ments in lean body mass and bone density in severely burned children.160 The weight gain and functional improvements seen with oxandrolone may persist even after stopping administration of the drug.161,162 A double-blind, randomized study of oxandro-lone showed decreased length of stay, improved hepatic pro-tein synthesis, and no adverse effects on endocrine function, although the authors noted a rise in transaminases with unclear clinical significance.163 Oxandrolone therapy has also been asso-ciated with overall decreased mortality in patients with large burns.164Hyperglycemia has been associated with increased mortal-ity after burn injury,165 and intensive insulin therapy in critically ill patients has shown benefit, presumably from avoidance of hyperglycemia.166 However, in burn patients, the insulin itself may have a metabolic benefit, with improvements in lean body mass and amelioration of the inflammatory response to burn injury.167,168 Oral hypoglycemic agents such as metformin also help to avoid hyperglycemia and may contribute to prevention of muscle catabolism.169COMPLICATIONS IN BURN CAREThere are several complications commonly associated with treatment of burn patients. Though not always avoidable, main-taining vigilance for typical complications and using appro-priate techniques for prevention may limit the frequency and severity of complications. Ventilator-associated pneumonia, as in all critically ill patients, is a significant problem in burned patients. However, it is so common in patients with inhalation injury that a better nomenclature may be postinjury pneumonia. Unfortunately, commonly used scores in critical illness such as the Clinical Pulmonary Infection Score (CPIS) have not been shown to be reliable in burn patients. Quantitative broncho-scopic cultures in the setting of clinical suspicion of pneumo-nia should guide treatment of pneumonia.170 Simple measures such as elevating the head of the bed and maintaining excel-lent oral hygiene and pulmonary toilet are recommended to help decrease the risk of postinjury pneumonia. There is some question as to whether early tracheostomy decreases infectious morbidity in burn patients and whether it improves long-term outcomes. There do not seem to be any major differences in the rates of pneumonia with early tracheostomy, though there may be reduced development of subglottic stenosis compared with prolonged endotracheal intubation.171,172 Practical consid-erations such as protection of facial skin grafts may influence the decision for tracheostomy placement. One major consider-ation in deciding whether to perform a tracheostomy has been the presence of eschar at the insertion site, which complicates tracheostomy site care and increases the risk of airway infec-tion. Bedside percutaneous dilatational tracheostomy is a facile method for performing tracheostomy and is reported to be as safe as open tracheostomy in the burn population.173Massive resuscitation of burned patients may lead to an abdominal compartment syndrome characterized by increased airway pressures with hypoventilation and decreased urine output and hemodynamic compromise. Decompressive lapa-rotomy is the standard of care for refractory abdominal com-partment syndrome but carries an especially poor prognosis in burn patients.174 Adjunctive measures such as minimizing fluid, performing torso escharotomies, decreasing tidal volumes, and chemical paralysis should be initiated before resorting to decompressive laparotomy. Patients undergoing massive resus-citation also develop elevated intraocular pressures and may require lateral canthotomy.175Deep vein thrombosis (DVT) and prophylaxis in the burn population has received increasing attention in the literature recently. Up to 25% of burn patients develop DVT, and fatal pulmonary emboli have been reported in burn patients.176,177 A recent prospective trial demonstrated an 8% incidence of DVT in patients with 30% to 60% TBSA burns not receiving low molecular weight heparin prophylaxis with no evidence of DVT in patients receiving prophylaxis. There were no complications Brunicardi_Ch08_p0251-p0270.indd 25828/12/18 11:51 AM 259BURNSCHAPTER 8from low molecular weight heparin prophylaxis.178 Thus, it appears that heparin prophylaxis is safe in burn patients and may help prevent thrombotic complications.Unfortunately, the use of both prophylactic and therapeu-tic heparin may be associated with heparin-associated throm-bocytopenia (HIT). One study of HIT in burn patients showed an incidence of 1.6% in heparinized burn patients. Thrombotic complications included DVT, pulmonary embolus, and even arterial thrombosis requiring limb amputation. Nonheparin anticoagulation for HIT commonly caused bleeding complica-tions requiring transfusion.179 Although rare, a high index of suspicion for HIT should be maintained in thrombocytopenic burn patients, particularly if the platelet counts drop at hospital days 7 to 10.Burn patients often require central venous access for fluid resuscitation and hemodynamic monitoring. Because of the ana-tomic relation of their burns to commonly used access sites, burn patients may be at higher risk for catheter-related blood-stream infections. The 2012 Centers for Disease Control and Prevention National Healthcare Safety Network report indicates that American burn centers have higher infectious complica-tion rates than any other ICUs.180 Because burn patients may commonly exhibit leukocytosis with a documented bloodstream infection, practice has been to rewire lines over a guide wire and to culture the catheter tip. However, this may increase the risk of catheter-related infections in burned patients, and a new site should be used if at all possible.181SURGERYFull-thickness burns with a rigid eschar can form a tourniquet effect as the edema progresses, leading to compromised venous outflow and eventually arterial inflow. The resulting compart-ment syndrome is most common in circumferential extremity burns, but abdominal and thoracic compartment syndromes also occur. Warning signs of impending compartment syndrome may include paresthesias, pain, decreased capillary refill, and progression to loss of distal pulses; in an intubated patient, the surgeon should anticipate the compartment syndrome and perform frequent neurovascular evaluations. Abdominal com-partment syndrome should be suspected with decreased urine output, increased ventilator airway pressures, and hypotension. Hypoventilation, increased airway pressures, and hypotension may also characterize thoracic compartment syndrome. Escha-rotomies are rarely needed within the first 8 hours following injury and should not be performed unless indicated because of the terrible aesthetic sequelae. When indicated, they are usu-ally performed at the bedside, preferably with electrocautery to minimize blood loss. Extremity incisions are made on the lateral and medial aspects of the limbs in an anatomic position and may extend onto thenar and hypothenar eminences of the hand. Digital escharotomies do not usually result in any meaningful salvage of functional tissue and are not recommended. Inad-equate perfusion despite proper escharotomies may indicate the need for fasciotomy, but this procedure should not be routinely performed as part of the eschar release. Thoracic escharotomies should be placed along the anterior axillary lines with bilateral subcostal and subclavicular extensions. Extension of the ante-rior axillary incisions down the lateral abdomen typically will allow adequate release of abdominal eschar.The strategy of early excision and grafting in burned patients revolutionized survival outcomes in burn care. Not only did it improve mortality, but early excision also decreased reconstruction surgery, hospital length of stay, and costs of care.182-184 Once the initial resuscitation is complete and the patient is hemodynamically stable, attention should be turned to excising the burn wound. Burn excision and wound coverage should ideally start within the first several days, and in larger burns, serial excisions can be performed as patient condition allows. Excision is performed with repeated tangential slices using a Watson or Goulian blade until viable, diffusely bleeding tissue remains. It is appropriate to leave healthy dermis, which will appear white with punctate areas of bleeding. Excision to fat or fascia may be necessary in deeper burns. The downside of tangential excision is a high blood loss, though this may be ame-liorated using techniques such as instillation of an epinephrine tumescence solution underneath the burn. Pneumatic tourni-quets are helpful in extremity burns, and compresses soaked in a dilute epinephrine solution are necessary adjuncts after excision. A fibrinogen and thrombin spray sealant (Tisseel Fibrin Sealant; Baxter, Deerfield, IL) also has beneficial effects on both hemo-stasis and graft adherence to the wound bed. The use of these techniques has markedly decreased the number of blood trans-fusions given during burn surgery.185 For patients with clearly deep burns and concern for excessive blood loss, fascial exci-sion may be employed. In this technique, electrocautery is used to excise the burned tissue and the underlying subcutaneous tis-sue down to muscle fascia. This technique markedly decreases blood loss but results in a cosmetically inferior appearance due to the loss of subcutaneous tissue. For excision of burns in dif-ficult anatomic areas, such as the face, eyelids, or hands, a pres-surized water dissector may offer more precision but is time consuming, has a steep learning curve, and is expensive.186WOUND COVERAGESince full-thickness burns are impractical for most burn wounds, split-thickness sheet autografts harvested with a power dermatome make the most durable wound coverings and have a decent cosmetic appearance. In larger burns, meshed auto-grafted skin provides a larger area of wound coverage. This also allows drainage of blood and serous fluid to prevent accumula-tion under the skin graft with subsequent graft loss. Areas of cosmetic importance such as the face, neck, and hands should be grafted with nonmeshed sheet grafts to ensure optimal appear-ance and function. Unfortunately, even extensive meshing of skin grafts in patients with limited donor sites may not provide adequate amounts of skin. One emerging technique for large burns with limited donor sites is the Meek micrografting tech-nique, or “postage-stamp” technique, where expansion ratios of up to 9:1 are able to be achieved. This technique has a con-siderable learning curve and requires further investigation to determine whether it is the optimal technique for large surface area burns with limited donor sites.187 Options for temporary wound coverage include human cadaveric allograft, which is incorporated into the wound but is rejected by the immune sys-tem and must be eventually replaced. This allows temporary biologic wound coverage until donor sites heal enough so that they may be reharvested. Xenograft appears to function as well as allograft for temporary wound coverage and is considerably less expensive.The search for a perfect permanent synthetic skin sub-stitute remains elusive. Integra (Integra LifeSciences Cor-poration, Plainsboro, NJ) is a bilayer product with a porous Brunicardi_Ch08_p0251-p0270.indd 25928/12/18 11:51 AM 260BASIC CONSIDERATIONSPART Icollagen-chondroitin 6-sulphate inner layer that is attached to an outer silastic sheet, which helps prevent fluid loss and infection as the inner layer becomes vascularized, creating an artificial neodermis. At approximately 2 weeks after placement, the silas-tic layer can be removed and a thin autograft can be placed over the neodermis. This results in faster healing of the more superfi-cial donor sites and has been increasingly utilized for treatment of complex wounds and injuries.188 Alloderm (LifeCell Corpo-ration, The Woodlands, TX) is a dermal substitute consisting of cryopreserved acellular human dermis. NovoSorb™ Biode-gradable Temporizing Matrix (PolyNovo Limited, Melbourne, Australia) is a biodegradable polyurethane dermal substitute newly available and recently approved by the United States Food and Drug Administration (FDA). These dermal substitutes should also be used in combination with thin split-thickness skin grafts for final wound coverage.189Epidermal skin substitutes such as cultured epithelial auto-grafts are an option in patients with massive burns and very limited donor sites.190,191 Their clinical use has been limited by a long turnaround time for culturing, as well as the fragility of the cultured skin, which creates great difficulty with intraopera-tive handling and graft take. There are promising developments in skin culturing techniques and engineered skin development, but no other products are FDA approved and commercially available.188Thighs make convenient anatomic donor sites; they are eas-ily harvested and relatively hidden from an aesthetic standpoint. The thicker skin of the back is useful in older patients, who have thinner skin elsewhere and may have difficulty with healing of donor sites. The buttocks are an excellent donor site in infants and toddlers; silver sulfadiazine can be applied to the donor site with a diaper as coverage. The scalp is also an excellent donor site; the skin is thick and the many hair follicles allow rapid heal-ing, with the added advantage of being completely hidden once hair regrows. Epinephrine tumescence is necessary for harvest-ing the scalp, for both hemostasis of this hypervascular area and also to create a smooth contoured surface for harvesting.The list of commonly used donor site dressings is long and includes simple transparent films to hydrocolloids, petrolatum gauzes, and silver-impregnated dressings. Donor sites close to fresh grafts may be dressed with a porous nonadherent gauze, and both the donors and grafts are soaked with an antimicrobial solution. Principles behind choosing a dressing should balance ease of care, comfort, infection control, and cost. The choice of donor site dressing is largely institution dependent, and few data support the clear superiority of any single treatment plan.REHABILITATIONRehabilitation is an integral part of the clinical care plan for the burn patient and should be initiated on admission. Immediate and ongoing physical and occupational therapy is mandatory to prevent functional loss. Patients who are unable to actively participate should have passive range-of-motion exercises done at least twice a day. This includes patients with burns over joints, such as with hand burns. Patients should be taught exer-cises they can do themselves to maintain full range of motion. Patients with foot and extremity burns should be instructed to walk independently without crutches or other assistive devices to prevent extremity swelling, desensitize the burned areas, and prevent disuse atrophy; when patients are not ambulating, they must elevate the affected extremity to minimize swelling. If postoperative immobilization is used for graft protection, the graft should be evaluated early and at frequent intervals so that active exercise can be resumed at the earliest possible occasion. The transition to outpatient care should also include physical and occupational therapy, with introduction of exercises designed to accelerate return to activities of daily living as well as specific job-related tasks. Tight-fitting pressure garments provide vascu-lar support in burns that are further along in the healing process. Whether they prevent hypertrophic scar formation has been long debated. However, they do provide vascular support that many patients find more comfortable.LATE COMPLICATIONS: HYPERTROPHIC SCAR, CONTRACTURES, AND HETEROTOPIC OSSIFICATIONOnce patients have recovered from their acute burns, many face management of the hypertrophic burn scars. In patients with healed burns or donor sites, hypertrophic scar-related morbid-ity includes pruritus, erythema, pain, thickened tight skin, and even contractures. Within these scars, there is believed to be an increased inflammatory response, irregular neovascularization, aberrant cytokine and Toll-like receptor expression, abundant collagen production, and abnormal extracellular matrix struc-ture. Treatment for these scars has included nonsurgical therapies such as compression garments, silicone gel sheeting, massage, physical therapy, and corticosteroid. Surgical excision and scar revision represent more invasive scar management approaches that are often necessary for functional and aesthetic recovery.192Laser-based therapies provide additional treatment options for symptomatic hypertrophic scars. Two of the most common ones are the pulsed dye laser (PDL) and the ablative carbon dioxide (CO2) laser. The PDL causes photothermolysis of hemoglobin, resulting in coagulative necrosis.193 It obliterates small capillaries close to the skin and has had success treating congenital, cutaneous vascular malformations. The CO2 laser has been used for treatment of acne and recently has been gain-ing acceptance for its use to treat hypertrophic burn scars.194 It works by ablating microscopic columns of tissue to flatten scars and is also believed to stimulate matrix metalloproteinases and other signaling pathways to induce collagen reorganization. Lasers are ultimately believed to help with scar remodeling and collagen reorganization. CO2 laser therapy has been shown to decrease symptoms associated with hypertrophic scarring, including scar appearance, pliability, contracture, neuropathic pain, and pruritus. A recent prospective study utilizing PDL and CO2 laser therapy demonstrated improved signs and symptoms of hypertrophic scars based on the Vancouver Scar Scale and the University of North Carolina 4P Scar Scale.195 Outpatient and office-based treatment sessions are tolerated well by most patients. There is wide practice variation on when to start ther-apy and the number of treatments, but the literature has general support for starting treatment at 6 to 12 months and offering three treatments. More research is needed to determine the full potential of laser therapy to provide burn survivors a less inva-sive treatment of hypertrophic scars with improved symptoms and quality of life.Contractures are another long-term complication of burn injury that can result in significant morbidity. Contractures result from both wound contracture and scar contracture and prevents range of motion of a particular joint. Factors influenc-ing contracture development include burn depth and activation Brunicardi_Ch08_p0251-p0270.indd 26028/12/18 11:51 AM 261BURNSCHAPTER 8of dermal fibroblasts, myofibroblasts, fibrocytes, and helper T cells.196 Despite aggressive physiotherapy, contractures have been reported to develop in as many as one-third of burn patients. A recent study of 1865 patients demonstrated that the shoulder is the most affected joint, followed by the elbow, wrist, ankle, and knee.197 A similar study in the pediatric population yielded similar results. Gender, race, and %TBSA were associated with contracture development in the adult population. Age and length of stay in the ICU were associated with contracture develop-ment, severity of contracture, and total number of contractures in the pediatric population. Treatment of contractures includes both nonsurgical and surgical options, ranging from pressure garments and splints to laser therapy and contracture excision.Heterotopic ossification (HO) is another long-term mor-bidity associated with burn injury. HO is the pathologic devel-opment of lamellar bone in peripheral tissue. Its incidence has been reported to be between 1% and 3% of burn patients.198 Symptoms include decreased range of motion, pain, and swell-ing overlying the affected joints. Often times, the pathologic bone formation can be visualized radiographically with plain X-rays. Risk factors include >30% TBSA, arm burns, arm grafts, ventilator days, and number of trips to the operat-ing room.199 Treatment includes aggressive physiotherapy, NSAIDs, bisphosphonates, radiation therapy, and rarely surgi-cal excision. A risk scoring system has been developed to pre-dict which burn patients are at risk of developing HO based on admission criteria; however, further validation is warranted.200PSYCHOLOGICAL RECOVERYPsychological rehabilitation is equally important in the burn patient. Depression, posttraumatic stress disorder (PTSD), concerns about image, and anxiety about returning to society constitute predictable barriers to progress in both the inpa-tient and outpatient setting. Psychological distress occurs in as many as 38% of burn patients and persists in severity long after discharge.201 Rates of depression vary between 4% and 54% following injury, although these numbers vary dramatically based on the methodology used to diagnose depression.202 Still, depressive symptoms have been documented in up to 43% of patients 2 years following injury and have been associated with the female gender. Factors such as gender, extraversion, capac-ity for forgiveness, the event as a disaster or nondisaster, alcohol use, and peritraumatic emotional response have been identified as contributing factors to PTSD.203 Despite the psychological impact of burn injury, many patients will be able to quickly return to work or school, and goals should be set accordingly. The involvement of clinical psychologists and psychiatrists is invaluable in providing guidance and coping techniques to lessen the significant psychological burden of burn injury.PREVENTIONDespite many areas of progress in prevention over the past cen-tury, burns continue to be a common source of injury. The cor-nerstone for burn prevention programs has been “The Five Step Process,” a systematic method of assessing, implementing, and evaluating burn hazards and subsequent intervention impact, and The Five E’s—engineering/environment, enforcement, education, emergency response, and economic initiative.204 It has been shown that patients who live in environments opti-mal for sustaining burn injury have decreased knowledge of burn prevention strategies.205 Some successful initiatives have included school-based education and community-based inter-ventions targeting simple home safety measures. A 6-year study of second-graders demonstrated both shortand long-term retainment of information related to burn, fire, and life safety following multiple educational sessions. Smoke alarms are known to decrease mortality from structural fires, but not all homes are equipped with proper smoke alarms, particularly in low-income households. Mandatory smoke alarm installa-tion via community initiatives can be successful but seems to be contingent on close, long-term follow-up to ensure proper maintenance and function.206,207 Regulation of hot water heater temperatures has had some success and may be even more effec-tive in conjunction with community-based programs emphasiz-ing education and in-home inspections.208,209 A recent systematic review of prevention in lowand middle-income countries iden-tified multiple successful prevention programs.210 Burn profes-sionals have also demonstrated incomplete knowledge on best practices for fire safety and burn prevention.211 As such, appro-priate education of burn professionals participating in preven-tion programs is necessary.BURN DISASTERSAlthough rare, burn disasters can be devastating to those involved due to the sudden nature of the event, the difficulty of managing personnel and resources,212 a deficit of staff expe-rience in burn management, and relatively small resource availability for a potentially large number of patients.213 The American Burn Association has estimated that up to 30% of patients in mass casualty incidents suffer from burn injury.214 A recent review of the literature between 1990 and 2016 identi-fied 752 burn disasters world-wide, defined as an incident with ≥50 burn injuries and/or ≥30 burn-related deaths. The major-ity occurred in Asia and the Middle East and are thought to be secondary to rapid industrialization, inadequate fire-prevention strategies, and poor building codes. There was a significant increase in terrorist-related incidences from 2000 to 2015. Finally, the authors demonstrated that international adoption of the U.S. Health and Human Services guidelines on bed avail-ability for burns and trauma dramatically underestimated the number of beds needed for burn disasters.215Preparedness is paramount for reacting quickly, efficiently, and effectively to a burn disaster. General surgeons not trained in burn care may feel uncomfortable longitudinally caring for severely burned patients following a burn disaster. However, due to resource limitations, they should be prepared to care for burn patients for the first 72 hours of resuscitation or until the patients can be transferred to a center that specializes in burn care. This will involve initial evaluation, resuscitation, and potential inter-ventions including central line placement, intubation, and escha-rotomies. Coordination for burn disasters should take place at three levels: institutional/intrafacility, interfacility/intrastate, and interstate/regional. It is important to have multiple stakeholders involved in the development of a disaster plan, from the burn surgeons to the emergency department personnel to the emer-gency medical personnel who are first responders.216 Resource utilization can be guided by The American Burn Association Age/TBSA survival grid, which stratifies patients into benefit-to-resource categories (outpatient, high, low, and expectant) based on age and %TBSA.3 This allows providers to allocate resources during burn disasters based on the severity of injury Brunicardi_Ch08_p0251-p0270.indd 26128/12/18 11:51 AM 262BASIC CONSIDERATIONSPART Iand expected survival.214 Another important consideration is the involvement of nonburn hospitals in the planning for burn disas-ters as burn centers do not possess enough resources to be sole providers in these events. Multiple strategies have been adopted by local burn centers, including the development of a consortium of hospitals surrounding one burn center in New Jersey to allow transfer of patients when resource capacity is in jeopardy.217Interest in mass burn casualty disaster planning invariably includes a discussion of radiation burns. Radioactive material results in both acute injury from immediate exposure and more prolonged injury from delayed exposure to radioactive fallout or contamination. When a 10-kiloton nuclear bomb is deto-nated, people at a distance 0.7 miles from ground zero absorb 4.5 Gy. At 60 days, the median lethal radiation dose (LD50) is 3.5 Sv; with aggressive medical care, this dose might be doubled to nearly 7 Sv. To put this in context, radiation expo-sure from a diagnostic CT of the chest or abdomen is 5 mSv, and the average annual background absorbed radiation dose is 3.6 mSv. Radiation is known to impact several organ systems and result in several syndromes based on increasing exposure doses. These syndromes include hematologic (1–8 Sv expo-sure), gastrointestinal (8–30 Sv exposure), and cardiovascular/neurologic syndromes (>30 Sv exposure), with the latter two being nonsurvivable.218-220After initial evaluation and decontamination by removing clothing, a useful way to estimate exposure is by determining the time to emesis. Patients who do not experience emesis within 4 hours of exposure are unlikely to have severe clinical effects. Emesis within 2 hours suggests a dose of at least 3 Sv, and emesis within 1 hour suggests at least 4 Sv. The hematologic system follows a similar dose-dependent temporal pattern for predicting radiation exposure, mortality, and treatment. These have been determined based on the Armed Forces Radiobiology Research Institute’s Biodosimetry Assessment Tool, which can be downloaded from www.afrri.usuhs.mil.The combination of radiation exposure and burn wounds has the potential to increase mortality compared with traditional burns. Early closure of wounds before radiation depletes circu-lating lymphocytes may be needed for wound healing (which occurs within 48 hours). Also, in radiation injuries combined with burn or trauma, laboratory lymphocyte counts may be unreliable.218-221 A significant difference between burn/traumatic injuries and radiation injures is that burn/traumatic injuries can result in higher mortality when not treated within hours.Decontamination and triage are vital to maximize the num-ber of survivors. Initial decontamination requires removal of clothing and washing wounds with water. Irrigation fluid should be collected to prevent radiation spread into the water supply. Work by many professional organizations, including the ABA, has focused on nationwide triage for disasters and will be vital to save as many lives as possible. Yet, it is likely that expectant or comfort care could be offered to more patients than typically seen in civilian hospitals, due to resource availability after the disaster.Finally, agents used in warfare—including white phos-phorus and sulfur mustard—can cause significant morbidity and mortality. White phosphorus oxidizes when exposed to the atmosphere, creating the highly corrosive phosphorus pentox-ide. Absorption of even small amounts of white phosphorus can result in hypocalcemia and hyperphosphatemia and their subse-quent cardiac side effects. Treatment consists of removal of all clothing, irrigation with cool liquid (as phosphorus pentoxide liquidizes above 44°C), application of saline soaked gauze to prevent drying out and reignition, and potential surgical excision.222,223 Sulfur mustard, more commonly known as mus-tard gas, is another chemical warfare agent that can cause lesions similar to burn lesions. The gas infiltrates the skin surface, caus-ing degranulation of mast cells, leukocyte invasion, and sub-sequent blistering of the skin. Treatment includes scrubbing to relieve the remaining skin of sulfur mustard, irrigation, and traditional burn therapy depending on the depth of the lesion.FUTURE AREAS OF STUDYIt has long been anecdotally noted that two patients of simi-lar ages and burn size may have very divergent responses to their burn injuries. Attention is being increasingly turned to identifying genetic differences among burn patients and how they affect response to injury. Specific allele variants have been linked with increased mortality in burned patients.224 It may be that genetic differences may predispose burn patients to severe sepsis,225 perhaps by downregulating the immune response.226 The Inflammation and the Host Response to Injury trial was a prospective, multicenter, federally funded study that aimed to define specific genetic pathways that differ in the response to both burns and traumatic injury.227 Blood and tissue samples from a strictly defined patient population were analyzed using gene arrays to determine whether differential expression in cer-tain genetic pathways affects clinical outcomes.228 Although data from this study are still being analyzed, some interesting findings suggest that sepsis, trauma, and burn patients share common gene expression patterns, starting early after injury.229 These genes can upregulate proinflammatory pathways as well as disrupt antigen presentation pathways. A better understand-ing of these common genomic responses may allow for the tar-geted treatment of immunologic and signal pathways to help improve patient survival from burn injuries.Another area of increasing interest includes integration of technology to burn size estimation and resuscitation. These include the use of smart device applications to assist with esti-mation of burn size and resuscitation recommendations.230-232 Further investigation is needed to determine the applicability of these models to burn estimation and resuscitation. However, as these models can include hourly updates and recommendations, they nudge clinicians to frequently reconsider fluid parameters during the critical stages of resuscitation.With the dramatic progress in improving survival follow-ing a major burn injury during the twentieth century, under-standing and addressing functional and psychological outcomes is critical to the well-being of burn survivors. Since 1993, the National Institute of Disability and Rehabilitation Research has funded four burn model systems to identify long-term sequelae of burn injuries and to develop ways to improve outcomes for survivors. Ongoing outcome studies are crucial for dismantling barriers that our patients face in returning to their communities and to the workplace or to school.REFERENCESEntries highlighted in bright blue are key references. 1. Baxter CR, Shires T. Physiological response to crystal-loid resuscitation of severe burns. Ann N Y Acad Sci. 1968;150(3):874-894. doi:10.1111/j.1749-6632.1968.tb14738.xBrunicardi_Ch08_p0251-p0270.indd 26228/12/18 11:51 AM 263BURNSCHAPTER 8 2. Janzekovic Z. A new concept in the early excision and imme-diate grafting of burns. J Trauma. 1970;10(12):1103-1108. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4921723. Accessed May 7, 2018. 3. Taylor S, Curri T, Lawless M, Sen S, Greenhalgh DG, Palm-ieri TL. Predicting resource utilization in burn treatment. 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Brunicardi_Ch08_p0251-p0270.indd 27028/12/18 11:51 AMThis page intentionally left blankWound HealingMunier Nazzal, Mohamed F. Osman, Heitham Albeshri, Darren B. Abbas, and Carol A. Angel 9chapterHISTORY OF WOUND HEALINGThe earliest accounts of wound healing date back to about 2000 b.c., when the Sumerians employed two modes of treatment: a spiritual method consisting of incantations, and a physical method of applying poultice-like materials to the wound. The Egyptians were the first to differentiate between infected and diseased wounds compared to noninfected wounds. The 1650 b.c. Edwin Smith Surgical Papyrus, a copy of a much older document, describes at least 48 different types of wounds. A later document (Ebers Papyrus, 1550 b.c.) relates the use of con-coctions containing honey (antibacterial properties), lint (absor-bent properties), and grease (barrier) for treating wounds. These same properties are still considered essential in contemporary daily wound management.The Greeks, equipped with the knowledge bequeathed by the Egyptians, went even further and classified wounds as acute or chronic in nature. Galen of Pergamum (120–201 a.d.), appointed as the doctor to the Roman gladiators, had an enormous number of wounds to deal with following gladiato-rial combats. He emphasized the importance of maintaining a moist environment to ensure adequate healing. It took almost 19 centuries for this important concept to be proven scientifi-cally, when it was shown that the epithelialization rate increases by 50% in a moist wound environment when compared to a dry wound environment.1The next major stride in the history of wound heal-ing was the discovery of antiseptics and their importance in reducing wound infections. Ignaz Philipp Semmelweis, a Hungarian obstetrician (1818–1865), noted that the inci-dence of puerperal fever was much lower if medical students, following cadaver-dissection class and prior to attending child-birth, washed their hands with soap and hypochlorite. Louis Pasteur (1822–1895) was instrumental in dispelling the theory of spontaneous generation of germs and proving that germs existed in and were always introduced from the environment. Joseph Lister probably made one of the most significant con-tributions to wound healing. On a visit to Glasgow, Scotland, Lister noted that some areas of the city’s sewer system were less murky than the rest. He discovered that the water from pipes that were dumping waste containing carbolic acid (phenol) was clear. In 1865, Lister began soaking his surgical instruments in phenol and spraying the operating rooms, reducing the post-operative mortality rates from 50% to 15%. After attending an impressive lecture by Lister in 1876, Robert Wood Johnson left the meeting and began 10 years of research that would ulti-mately result in the production of an antiseptic dressing in the form of cotton gauze impregnated with iodoform. Since then, several other materials have been used to impregnate cotton gauze to achieve antisepsis.The 1960s and 1970s led to the development of polymeric dressings. These polymeric dressings can be custom made to specific parameters, such as permeability to gases (occlusive vs. semi-occlusive), varying degrees of absorbency, and different physical forms. Due to the ability to customize, the available range of materials that aid in wound care has grown exponen-tially to include an ever-expanding variety. Currently, the prac-tice of wound healing encompasses manipulation and/or use of, among others, inflammatory cytokines, growth factors, and bio-engineered tissue. It is the combination of all these modali-ties that enables optimal wound healing. The role of organism in the perpetuation of nonhealing of chronic wounds 1History of Wound Healing 271Phases of Wound Healing 272Hemostasis and Inflammation / 272Proliferation / 273Matrix Synthesis / 274Maturation and Remodeling / 275Epithelialization / 275Role of Growth Factors in Normal Healing / 276Wound Contraction / 276Heritable Diseases of Connective Tissue 276Ehlers-Danlos Syndrome / 276Osteogenesis Imperfecta / 278Epidermolysis Bullosa / 279Acrodermatitis Enteropathica / 279Healing in Specific Tissues 279Gastrointestinal Tract / 279Bone / 280Cartilage / 281Tendon / 281Nerve / 281Fetal Wound Healing / 281Classification of Wounds 282Factors Affecting Wound Healing / 283Chronic Wounds / 289Excess Healing 291Treatment of Wounds 294Local Care / 294Antibiotics / 295Dressings / 295Skin Replacements / 296Cellular and Tissue-Based Products in Chronic Wound and Ulcer Management / 297Oxygen Therapy in Wound Healing / 299Biofilm and Chronic Wound Healing / 299Brunicardi_Ch09_p0271-p0304.indd 27101/03/19 4:49 PM 272has been better understood. Although wounds are classified under one entity, it is believed that they behave differently based on the host and organism involved. The future of wound healing is in “precision medicine” in which treatment strategies will be based on the host, the underlying mechanism, and the organisms in the wound bed and tissue.PHASES OF WOUND HEALINGWound healing is a complex process of overlapping phases that is initiated by an injury or wound. Normal wound healing is divided into phases defined by characteristic cellular popula-tions and biochemical activities: (a) hemostasis and inflammation, (b) proliferation, and (c) maturation and remodeling. An approximate timeline of these events is depicted in Fig. 9-1. This sequence of events in most circumstances spans the time from injury to resolution of acute wounds. All wounds need to progress through this series of cellular and biochemical events that characterize the phases of healing in order to suc-cessfully reestablish tissue integrity. However, multiple factors can interfere with this sequence and can lead to lengthy healing (chronic wounds) or nonhealing.Hemostasis and InflammationHemostasis precedes and initiates inflammation with the ensuing release of chemotactic factors from the wound site (Fig. 9-2A). Wounding by definition disrupts tissue integrity, leading to divi-sion of blood vessels and direct exposure of extracellular matrix to platelets. Exposure of subendothelial collagen to platelets results in platelet aggregation, degranulation, and activation of the coagulation cascade. Platelet α granules release a number of wound-active substances, such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), platelet-activating factor (PAF), fibronectin, and serotonin. In addition to achieving hemostasis, the fibrin clot serves as scaffolding for the migration into the wound of inflammatory cells such as poly-morphonuclear leukocytes (PMNs, neutrophils) and monocytes.Cellular infiltration after injury follows a character-istic, predetermined sequence (see Fig. 9-1). PMNs are the 2first infiltrating cells to enter the wound site, peaking at 24 to 48 hours. Increased vascular permeability, local prostaglan-din release, and the presence of chemotactic substances such as complement factors, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), TGF-β, platelet factor 4, or bacterial prod-ucts all stimulate neutrophil migration.The postulated primary role of neutrophils is phagocytosis of bacteria and tissue debris. PMNs are also a major source of cytokines early during inflammation, especially TNF-α3 which may have a significant influence on subsequent angiogenesis and collagen synthesis (see Fig. 9-2B). PMNs also release pro-teases such as collagenases, which participate in matrix and ground substance degradation in the early phase of wound heal-ing. Other than their role in limiting infections, these cells do not appear to play a role in collagen deposition or acquisition of mechanical wound strength. On the contrary, neutrophil fac-tors have been implicated in delaying the epithelial closure of wounds.4The second population of inflammatory cells that invades the wound consists of macrophages, which are recognized as being essential to successful healing.5 Derived from circulat-ing monocytes, macrophages achieve significant numbers in the wound by 48 to 96 hours post injury and remain present until wound healing is complete.Macrophages, like neutrophils, participate in wound debridement via phagocytosis and contribute to microbial stasis via oxygen radical and nitric oxide synthesis (see Fig. 9-2B,C). The macrophage’s central function is activation and recruitment of other cells via mediators such as cytokines and growth fac-tors, as well as directly by cell-cell interaction and intercellular adhesion molecules (ICAM). By releasing such mediators as TGF-β, vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), epithelial growth factor (EGF), and lac-tate, macrophages regulate cell proliferation, matrix synthesis, and angiogenesis.6,7 Macrophages also play a significant role in regulating angiogenesis and matrix deposition and remodeling (Table 9-1).T lymphocytes comprise another population of inflam-matory/immune cells that routinely invades the wound. Less Key Points1 Wound healing is a complex cellular and biochemical cascade that leads to restitution of integrity and function.2 All tissues heal by similar mechanisms, and the process undergoes phases of inflammation, cellular migration, pro-liferation, matrix deposition, and remodeling.3 Factors that impede normal healing include local, systemic, and technical conditions that the surgeon must take into account.4 Clinically, excess healing can be as significant a problem as impaired healing; genetic, technical, and local factors play a major role.5 Optimal outcome of acute wounds relies on complete eval-uation of the patient and of the wound and application of best practices and techniques.6 Antibiotics should be used only in the presence of infec-tion; colonization and contamination does not mean there is infection.7 Dressing should facilitate the major changes taking place during healing to produce an optimally healed wound and take into consideration the comorbid conditions associated with chronic wounds.8 Cellular and tissue-based products are additional mea-sures, and these products might accelerate the rate of heal-ing but will not replace basic wound care.9 Chronic wounds have a decrease in oxygen supply to the wound, which contributes to delayed healing; oxygen therapy might aid in the healing of certain types of wounds.10 Biofilm is the term used for the bacterial growth on a chronic wound that is encapsulated by a protective layer made up of the host and bacterial proteins; this layer makes it difficult to heal chronic wounds and control infection.Brunicardi_Ch09_p0271-p0304.indd 27201/03/19 4:49 PM 273WOUND HEALINGCHAPTER 9numerous than macrophages, T-lymphocyte numbers peak at about 1 week post injury and truly bridge the transition from the inflammatory to the proliferative phase of healing. Though known to be essential to wound healing, the role of lymphocytes in wound healing is not fully defined.8 A significant body of data supports the hypothesis that T lymphocytes play an active role in the modulation of the wound environment. Depletion of most wound T lymphocytes decreases wound strength and col-lagen content,9 while selective depletion of the CD8+ suppressor subset of T lymphocytes enhances wound healing. However, depletion of the CD4+ helper subset has no effect.10 Lympho-cytes also exert a downregulating effect on fibroblast collagen synthesis by cell-associated interferon IFN-γ, TNF-α, and IL-1. This effect is lost if the cells are physically separated, suggest-ing that extracellular matrix synthesis is regulated not only via soluble factors but also by direct cell-cell contact between lym-phocytes and fibroblasts.11ProliferationThe proliferative phase is the second phase of wound healing and roughly spans days 4 through 12 (see Fig. 9-2C). It is dur-ing this phase that tissue continuity is reestablished. Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound, and the strongest chemotactic factor for fibroblasts is PDGF.12,13 Upon entering the wound environment, recruited fibroblasts first need to proliferate, and then become activated, to carry out their primary function of matrix synthesis remodeling. This activation is mediated mainly by the cytokines and growth factors released from wound macrophages.Fibroblasts isolated from wounds synthesize more colla-gen than nonwound fibroblasts, they proliferate less, and they actively carry out matrix contraction. Although it is clear that the cytokine-rich wound environment plays a significant role in this phenotypic alteration and activation, the exact mediators are only partially characterized.14,15 Additionally, lactate, which accumulates in significant amounts in the wound environment over time (∼10 mmol), is a potent regulator of collagen syn-thesis through a mechanism involving adenosine diphosphate (ADP)-ribosylation.16,17Endothelial cells also proliferate extensively during this phase of healing. These cells participate in the formation of new capillaries (angiogenesis), a process essential to successful wound healing. Endothelial cells migrate from intact venules close to the wound. Their migration, replication, and new capil-lary tubule formation is under the influence of such cytokines and growth factors as TNF-α, TGF-β, and VEGF. Although Figure 9-1. The cellular, biochemical, and mechanical phases of wound healing.Phases of healing0246810121416MaturationProliferationInflammationmonths0246810121416Relative number of cellsNeutrophilsMacrophagesFibroblastsLymphocytes0246810121416Relative amount ofmatrix synthesisDays postwoundingCollagen ICollagen IIIWound-breakingstrengthFibronectinBrunicardi_Ch09_p0271-p0304.indd 27301/03/19 4:50 PM 274BASIC CONSIDERATIONSPART Imany cells produce VEGF, macrophages represent a major source in the healing wound, and VEGF receptors are located specifically on endothelial cells.18,19Matrix SynthesisBiochemistry of Collagen. Collagen, the most abundant pro-tein in the body, plays a critical role in the successful comple-tion of adult wound healing. Its deposition, maturation, and subsequent remodeling are essential to the functional integrity of the wound.Although there are at least 18 types of collagen described, the main ones of interest to wound repair are types I and III. Type I collagen is the major component of extracellular matrix in skin. Type III, which is also normally present in skin, becomes more prominent and important during the repair process.Biochemically, each chain of collagen is composed of a glycine residue in every third position. The second position in the triplet is made up of proline or lysine during the translation process. The polypeptide chain that is translated from mRNA contains approximately 1000 amino acid residues and is called protocollagen. Release of protocollagen into the endoplasmic reticulum results in the hydroxylation of proline and lysine by specific hydroxylases (Fig. 9-3). Prolyl hydroxylase requires oxygen and iron as cofactors, α-ketoglutarate as co-substrate, and ascorbic acid (vitamin C) as an electron donor. In the endo-plasmic reticulum, the protocollagen chain is also glycosylated by the linking of galactose and glucose at specific hydroxyly-sine residues. These steps of hydroxylation and glycosylation alter the hydrogen bonding forces within the chain, imposing steric changes that force the protocollagen chain to assume an α-helical configuration. Three α-helical chains entwine to form a right-handed superhelical structure called procollagen. At both ends, this structure contains nonhelical peptide domains called registration peptides. Although initially joined by weak, ionic bonds, the procollagen molecule becomes much stronger by the covalent cross-linking of lysine residues.Extracellularly, the nonhelical registration peptides are cleaved by a procollagen peptidase, and the procollagen strands undergo further polymerization and cross-linking. The resulting collagen monomer is further polymerized and cross-linked by the formation of intraand intermolecular covalent bonds.Collagen synthesis, as well as posttranslational modifica-tions, are highly dependent on systemic factors such as an adequate oxygen supply; the presence of sufficient nutrients (amino acids and carbohydrates) and cofactors (vitamins and trace metals); and the local wound environment (vascular supply and lack of infection). Addressing these factors and reversing nutritional defi-ciencies can optimize collagen synthesis and deposition.Proteoglycan Synthesis. Glycosaminoglycans comprise a large portion of the “ground substance” that makes up granula-tion tissue. Rarely found free, they couple with proteins to form proteoglycans. The polysaccharide chain is made up of repeat-ing disaccharide units composed of glucuronic or iduronic acid and a hexosamine, which is usually sulfated. The disaccharide EpidermisFibrinPlateletsClotNeutrophilsLymphocytesScabCollagenMacrophageEndothelialbudsDisruptedblood vesselRed bloodcellsDermisABCEpidermisDermisEpidermisDermisFibroblastFigure 9-2. The phases of wound healing viewed histologically. A. The hemostatic/inflammatory phase. B. Latter inflammatory phases reflecting infiltration by mononuclear cells and lympho-cytes. C. The proliferative phase, with associated angiogenesis and collagen synthesis.Table 9-1Macrophage activities during wound healingACTIVITYMEDIATORSPhagocytosisReactive oxygen speciesNitric oxideDebridementCollagenase, elastaseCell recruitment and activationGrowth factors: PDGF, TGF-β, EGF, IGFCytokines: TNF-α, IL-1, IL-6FibronectinMatrix synthesisGrowth factors: TGF-β, EGF, PDGFCytokines: TNF-α, IL-1, IFN-γEnzymes: arginase, collagenaseProstaglandinsNitric oxideAngiogenesisGrowth factors: FGF, VEGFCytokines: TNF-αNitric oxideEGF = epithelial growth factor; FGF = fibroblast growth factor; IGF = insulin-like growth factor; IFN-γ = interferon-γ; IL = interleukin; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.Brunicardi_Ch09_p0271-p0304.indd 27401/03/19 4:50 PM 275WOUND HEALINGCHAPTER 9composition of proteoglycans varies from about 10 units in the case of heparin sulfate to as much as 2000 units in the case of hyaluronic acid.The major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate. Fibroblasts synthesize these compounds, increasing their concentration greatly during the first 3 weeks of healing. The interaction between collagen and proteoglycans is being actively studied. It is thought that the assembly of collagen subunits into fibrils and fibers is depen-dent upon the lattice provided by the sulfated proteoglycans. Furthermore, it appears that the extent of sulfation is critical in determining the configuration of the collagen fibrils. As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding. However, with scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes.Maturation and RemodelingThe maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by a reorganization of previously synthesized collagen. Collagen is broken down by matrix metalloproteinases (MMPs), and the net wound collagen content is the result of a balance between collagenolysis and collagen synthesis. There is a net shift toward collagen synthesis and eventually the reestablishment of extracellular matrix com-posed of a relatively acellular collagen-rich scar.Wound strength and mechanical integrity in the fresh wound are determined by both the quantity and quality of the newly deposited collagen. The deposition of matrix at the wound site follows a characteristic pattern: fibronectin and collagen type III constitute the early matrix scaffolding; glycosamino-glycans and proteoglycans represent the next significant matrix components; and collagen type I is the final matrix. By several weeks post injury, the amount of collagen in the wound reaches a plateau, but the tensile strength continues to increase for sev-eral more months.20 Fibril formation and fibril cross-linking result in decreased collagen solubility, increased strength, and increased resistance to enzymatic degradation of the collagen matrix. Fibrillin, a glycoprotein secreted by fibroblasts, is essen-tial for the formation of elastic fibers found in connective tis-sue. Scar remodeling continues for many (6 to 12) months post injury, gradually resulting in a mature, avascular, and acellular scar. The mechanical strength of the scar never achieves that of the uninjured tissue.There is a constant turnover of collagen in the extracellular matrix, both in the healing wound as well as during normal tissue homeostasis. Collagenolysis is the result of collagenase activity, a class of MMPs that require activation. Both collagen synthesis and lysis are strictly controlled by cytokines and growth factors. Some factors affect both aspects of collagen remodeling. For example, TGF-β increases new collagen transcription and also decreases collagen breakdown by stimulating synthesis of tis-sue inhibitors of metalloproteinase.21 This balance of collagen deposition and degradation is the ultimate determinant of wound strength and integrity.EpithelializationEpithelialization is the final step in establishing tissue integrity. This process is characterized primarily by proliferation and migration of epithelial cells adjacent to the wound (Fig. 9-4). The process begins within 1 day of injury and is seen as thicken-ing of the epidermis at the wound edge. Marginal basal cells at the edge of the wound lose their firm attachment to the underly-ing dermis, enlarge, and begin to migrate across the surface of the provisional matrix. Fixed basal cells in a zone near the cut edge undergo a series of rapid mitotic divisions, and these cells appear to migrate by moving over one another in a leapfrog fashion until the defect is covered.22 Once the defect is bridged, the migrating epithelial cells lose their flattened appearance, become more columnar in shape, and increase their mitotic activity. Layering of the epithelium is reestablished, and the surface layer eventually keratinizes.23LysyloxidaseALDOL condensationCollagen genesPre-mRNAmRNA transcriptionmRNA processingmRNA translationOHOHTriple helix formationRibosomeon roughendoplasmicreticulumGolgiSecretory vesicleCell membraneProline and Lysine hydroxylationCollagen mRNASyndesineAldimineCH OCH OH OH OHOHOProcollagen peptidaseExtracellular space˜-1˜-1˜-2NonenzymaticNH2CCCCFigure 9-3. The steps of collagen synthesis. mRNA = messenger RNA.Brunicardi_Ch09_p0271-p0304.indd 27501/03/19 4:50 PM 276BASIC CONSIDERATIONSPART IReepithelialization is complete in less than 48 hours in the case of approximated incised wounds but may take sub-stantially longer in the case of larger wounds, where there is a significant epidermal/dermal defect. If only the epithelium and superficial dermis are damaged, such as occurs in split-thickness skin graft donor sites or in superficial second-degree burns, then repair consists primarily of reepithelialization with minimal or no fibroplasia and granulation tissue formation. The stimuli for reepithelialization remain incompletely defined; however, it appears that the process is mediated by a combination of a loss of contact inhibition; exposure to constituents of the extracel-lular matrix, particularly fibronectin; and cytokines produced by immune mononuclear cells.24,25 In particular EGF, TGF-β, basic fibroblast growth factor (bFGF), PDGF, and IGF-1 have been shown to promote epithelialization.Role of Growth Factors in Normal HealingGrowth factors and cytokines are polypeptides produced in nor-mal and wounded tissue that stimulate cellular migration, pro-liferation, and function. They often are named for the cells from which they were first derived (e.g., platelet-derived growth fac-tor, PDGF) or for their initially identified function (e.g., fibro-blast growth factor, FGF). These names are often misleading because growth factors have been demonstrated to have mul-tiple functions. Most growth factors are extremely potent and produce significant effects in nanomolar concentrations.They may act in an autocrine manner (where the growth factor acts on the cell producing it), a paracrine manner (by release into the extracellular environment, where it acts on the immediately neighboring cells), or in an endocrine manner (where the effect of the substance is distant to the site of release, and the substance is carried to the effector site through the blood stream). In addition to the concentration of the growth factor, the timing of release is as important to determine their effective-ness. As these growth factors exert their effects by cell-surface receptor binding, the appropriate receptor on the responding cells must be present at the time of release in order for the bio-logic effect to occur. Table 9-2 summarizes the principal growth factors found in healing wounds and their known effects on cells participating in the healing process. Growth factors have diver-gent actions on different cells; they can be chemoattractive to one cell type while stimulating replication of a different cell type. Little is known about the ratio of growth factor concentra-tions, which may be as important as the absolute concentration of individual growth factors.Growth factors act on cells via surface receptor binding. Various receptor types have been described, such as ion chan-nels, G-protein linked, or enzyme linked. The response elicited in the cell is usually one of phosphorylation or dephosphoryla-tion of second-messenger molecules through the action of phos-phatases or kinases, resulting in activation or deactivation of proteins in the cytosol or nucleus of the target cell. Phosphoryla-tion of nuclear proteins is followed by the initiation of transcrip-tion of target genes.26 The signal is stopped by internalization of the receptor-ligand complex.Wound ContractionAll wounds undergo some degree of contraction. For wounds that do not have surgically approximated edges, the area of the wound will be decreased by this action (healing by secondary intention). The myofibroblast has been postulated as the major cell responsible for contraction, and it differs from the normal fibroblast in that it possesses a cytoskeletal structure. Typically this cell contains α-smooth muscle actin in thick bundles called stress fibers, giving myofibroblasts contractile capability.27 The α-smooth muscle actin is undetectable until day 6, and then it is increasingly expressed for the next 15 days of wound healing.28 After 4 weeks, this expression fades, and the cells are believed to undergo apoptosis.29 A puzzling point is that the identification of myofibroblasts in the wound does not correspond directly to the initiation of wound contraction, which starts almost immedi-ately after injury. It is believed that fibroblasts might play a role in contraction. In vitro, fibroblasts placed in a collagen lattice actively move in the lattice and contract it without expressing stress fibers. It is postulated that the movement of cells with concomitant reorganization of the cytoskeleton is responsible for contraction.30HERITABLE DISEASES OF CONNECTIVE TISSUEHeritable diseases of connective tissue consist of a group of generalized, genetically determined, primary disorders of one of the elements of connective tissue: collagen, elastin, or muco-polysaccharide. Five major types, Ehlers-Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta, epidermolysis bullosa, and acrodermatitis enteropathica, will be discussed, as each provides unique challenges to the surgeon.Ehlers-Danlos SyndromeEhlers-Danlos syndrome (EDS) is a group of 10 disorders that present as a defect in collagen formation. Over half of the Hair follicleSweat glandBlood vesselsWoundEpidermisDermisRegeneratingepitheliumEpithelialislandEpidermisDermisHair follicleSweat glandBlood vesselsEpidermisDermisFigure 9-4. The healing by epithelialization of superficial cutane-ous wounds.Brunicardi_Ch09_p0271-p0304.indd 27601/03/19 4:50 PM 277WOUND HEALINGCHAPTER 9Table 9-2Growth factors participating in wound healingGROWTH FACTORWOUND CELL ORIGINCELLULAR AND BIOLOGIC EFFECTSPDGFPlatelets, macrophages, monocytes, smooth muscle cells, endothelial cellsChemotaxis: fibroblasts, smooth muscle, monocytes, neutrophilsMitogenesis: fibroblasts, smooth muscle cellsStimulation of angiogenesisStimulation of collagen synthesisEnhance reepithelizationModulate tissue remodelingFGFFibroblasts, endothelial cells, keratinocytes, smooth muscle cells, chondrocytesStimulation of angiogenesis (by stimulation of endothelial cell proliferation and migration)Mitogenesis: mesoderm and neuroectodermHGFFibroblastsStimulates fibroblasts, keratinocytes, chondrocytes, myoblastsSuppresses inflammation, granulation tissue formation, angiogenesis, reepithelializationKeratinocyte growth factorKeratinocytes, fibroblastsSignificant homology with FGF; stimulates keratinocytesEGFPlatelets, macrophages, monocytes (also identified in salivary glands, duodenal glands, kidney, and lacrimal glands)Stimulates proliferation and migration of all epithelial cell typesTGF-αKeratinocytes, platelets, macrophagesHomology with EGF; binds to EGF receptorMitogenic and chemotactic for epidermal and endothelial cellsTGF-β (three isoforms: β1, β2, β3)Platelets, T lymphocytes, macrophages, monocytes, neutrophils, fibroblasts, keratinocytesStimulates angiogenesisStimulates leukocyte chemotaxisTGF-β1 stimulates wound matrix production (fibronectin, collagen glycosaminoglycans); regulation of inflammationTGF-β3 inhibits scar formationInsulin-like growth factors (IGF-1, IGF-2)Platelets (IGF-1 in high concentrations in liver; IGF-2 in high concentrations in fetal growth); likely the effector of growth hormone actionPromote protein/extracellular matrix synthesisIncrease membrane glucose transportVascular endothelial growth factorMacrophages, fibroblasts, endothelial cells, keratinocytesMitogen for endothelial cells (not fibroblasts)Stimulates angiogenesisProinflammatoryIL-1IL-4IL-6ActivinAngiopoitein-1/-2CX3CL1Macrophages, leukocytes, keratinocytes, fibroblastsLeukocytesFibroblasts, endothelial cells, macrophages, keratinocytesKeratinocytes, fibroblastsEndothelial cellsMacrophages, endothelial cellsProinflammatoryStimulates angiogenesis, reepithelialization, tissue remodelingEnhances collagen synthesisStimulates inflammation, angiogenesis, reepithelialization, collagen deposition, tissue remodelingStimulates granulation tissue formation, keratinocyte differentiation, reepithelializationStimulates angiogenesisStimulates inflammation, angiogenesis, collagen depositionGranulocyte-macrophage colony-stimulating factorMacrophage/monocytes, endothelial cells, fibroblastsStimulates macrophage differentiation/proliferationCX3CL1 = chemokine (C-X3-C motif) ligand; EGF = epidermal growth factor; FGF = fibroblast growth factor; HGF = hepatocyte growth factor; IL = interleukin; PDGF = platelet-derived growth factor; TGF = transforming growth factor.Brunicardi_Ch09_p0271-p0304.indd 27701/03/19 4:50 PM 278BASIC CONSIDERATIONSPART Iaffected patients manifest genetic defects encoding α-chains of collagen type V, causing it to be either quantitatively or struc-turally defective. These changes lead to “classic” EDS with phenotypic findings that include thin, friable skin with promi-nent veins, easy bruising, poor wound healing, atrophic scar formation, recurrent hernias, and hyperextensible joints. Gas-trointestinal problems include bleeding, hiatal hernia, intesti-nal diverticulae, and rectal prolapse. Small blood vessels are fragile, making suturing difficult during surgery. Large vessels may develop aneurysms, varicosities, or arteriovenous fistulas or may spontaneously rupture.31-33 Table 9-3 presents a descrip-tion of EDS subtypes, including a recently recognized autoso-mal recessive form characterized by tenascin-X deficiency. The defect is a quantitative loss of protein, resulting in phenotypic changes similar to those observed in other types of EDS.EDS must be considered in every child with recurrent her-nias and coagulopathy, especially when accompanied by platelet abnormalities and low coagulation factor levels. Inguinal her-nias in these children resemble those seen in adults. Great care should be taken to avoid tearing the skin and fascia. The trans-versalis fascia is thin, and the internal ring is greatly dilated. Like adults, hernia repair in these patients with the use of mesh or felt may result in a lower incidence of recurrence.34Closing wounds in patients with EDS might represent a major challenge to the surgeon. Dermal wounds should be closed in two layers, approximated with the sutures under ten-sion, and the stitches should be left in place twice as long as usual. In addition, external fixation with adhesive tape can help reinforce the scar and prevent stretching.35Marfan’s Syndrome. Patients with Marfan’s syndrome have tall stature, arachnodactyly, lax ligaments, myopia, sco-liosis, pectus excavatum, and aneurysm of the ascending aorta. Patients who suffer from this syndrome also are prone to her-nias. Skin may be hyperextensible but shows no delay in wound healing.36,37The genetic defect associated with Marfan’s syndrome is a mutation in the FBN1 gene, which encodes for fibrillin. Pre-viously, it was thought that structural alteration of the micro-fibrillar system was responsible for the phenotypic changes seen with the disease. However, recent research indicates an intricate role that FBN1 gene products play in TGF-β signal-ing. These extracellular matrix molecules normally bind and regulate TGF-β signaling; abnormal FBN1 gene function may cause an increase in TGF-β signaling, particularly in the aortic wall.38Osteogenesis ImperfectaPatients with osteogenesis imperfecta (OI) have brittle bones, osteopenia, low muscle mass, hernias, and ligament and joint laxity. OI is a result of a mutation in type I collagen. Mutations in prolidase, an enzyme responsible for cleaving c-terminal pro-line and hydroxyproline, may have a role in the disease. There are four major OI subtypes with mild to lethal manifestations. Patients experience dermal thinning and increased bruisability. Scarring is normal, and the skin is not hyperextensible. Surgery can be successful but difficult in these patients, as the bones fracture easily under minimal stress.31,34 Table 9-4 lists the vari-ous features associated with the clinical subtypes of OI.Table 9-3Clinical, genetic, and biochemical aspects of Ehlers-Danlos subtypesTYPECLINICAL FEATURESINHERITANCEBIOCHEMICAL DEFECTISkin: soft, hyperextensible, easy bruising, fragile, atrophic scars; hypermobile joints; varicose veins; premature birthsADNot knownIISimilar to type I, except less severeADNot knownIIISkin: soft, not hyperextensible, normal scars; small and large joint hypermobilityADNot knownIVSkin: thin, translucent, visible veins, normal scarring, no hyperextensibility; no joint hypermobility; arterial, bowel, and uterine ruptureADType III collagen defectVSimilar to type IIXLRNot knownVISkin: hyperextensible, fragile, easy bruising; hypermobile joints; hypotonia; kyphoscoliosisARLysyl hydroxylase deficiencyVIISkin: soft, mild hyperextensibility, no increased fragility; extremely lax joints with dislocationsADType I collagen gene defectVIIISkin: soft, hyperextensible, easy bruising, abnormal scars with purple discoloration; hypermobile joints; generalized periodontitisADNot knownIXSkin: soft, lax; bladder diverticula and rupture; limited pronation and supination; broad clavicle; occipital hornsXLRLysyl oxidase defect with abnormal copper useXSimilar to type II with abnormal clotting studiesARFibronectin defectTNxHypermobile joints, skin fragilityARAbsence of tenascin X proteinAD = autosomal dominant; AR = autosomal recessive; XLR = X-linked recessive.Reproduced with permission from Cohen IK, Diegelmann RF, Lindblad WJ: Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA: WB Saunders/Elsevier; 1992.Brunicardi_Ch09_p0271-p0304.indd 27801/03/19 4:50 PM 279WOUND HEALINGCHAPTER 9Epidermolysis BullosaEpidermolysis bullosa (EB) is classified into four major sub-types: EB simplex, junctional EB, dystrophic EB, and Kindler’s syndrome. The first three are determined by location in various skin layers; the last can present as multiple blisters throughout different layers of skin. There are identified genetic defects for each subtype, but the overall phenotype is remarkably similar. The disease manifestations include impairment in tissue adhe-sion within the epidermis, basement membrane, or dermis, resulting in tissue separation and blistering with minimal trauma. Characteristic features of EB are blistering and ulceration. The recessively inherited dystrophic type is characterized by defects in the COL7A1 gene, encoding type 7 collagen, important for connecting the epidermis to the dermis, and therefore pheno-typically resulting in blistering.39 Management of nonhealing wounds in patients with EB is a challenge, as their nutritional status is compromised because of oral erosions and esophageal obstruction. Surgical interventions include esophageal dilata-tion and gastrostomy tube placement. Dermal incisions must be meticulously placed to avoid further trauma to skin.34,40 The skin requires nonadhesive pads covered by a “bulky” dressing to avoid blistering.Acrodermatitis EnteropathicaAcrodermatitis enteropathica (AE) is an autosomal recessive disease of children that causes an inability to absorb sufficient zinc from breast milk or food. The AE mutation affects zinc uptake in the intestine by preventing zinc from binding to the cell surface and its translocation into the cell. Recently, the genetic defect has been localized on chromosome 8q24.3 identi-fied as the SLC39A4 gene, expressed in the intestinal lumen and upregulated based on zinc stores.41 Zinc deficiency is associated with impaired granulation tissue formation, as zinc is a neces-sary cofactor for DNA polymerase and reverse transcriptase, and its deficiency may impair healing due to inhibition of cell proliferation.AE is characterized by impaired wound healing as well as erythematous pustular dermatitis involving the extremities and the areas around the bodily orifices. Diagnosis is confirmed by the presence of an abnormally low blood zinc level (<100 mg/dL). Oral supplementation with 100 to 400 mg zinc sulfate orally per day is curative for impaired healing.42,43HEALING IN SPECIFIC TISSUESGastrointestinal TractRepair and healing of the gastrointestinal tract is essential for the normal functions of the GI tract such as absorptive, bar-rier, and motor functions. Full-thickness GI injury healing remains an unresolved clinical issue. Healing of full-thickness GI wounds begins with a surgical or mechanical reapposition of the bowel ends, which is most often the initial step in the repair process. Sutures or staples are principally used, although various other means such as buttons, plastic tubes, and various wrappings have been attempted with variable success. Failure of healing results in dehiscence, leaks, and fistulas, which carry significant morbidity and mortality. Conversely, excessive heal-ing can be just as troublesome, resulting in stricture formation and stenosis of the lumen.The gross anatomic features of the GI tract are remarkably constant throughout most of its length. Within the lumen, the epithelium is supported by the lamina propria and underlying muscularis mucosa. The submucosa lies radially and circumfer-entially outside of these layers, is comprised of abundant col-lagenous and elastic fibers, and supports neural and vascular structures. Further toward the peritoneal surface of the bowel are the inner and outer muscle layers and ultimately a peritoneal extension, the serosa. The submucosa is the layer that imparts the greatest tensile strength and greatest suture-holding capac-ity, a characteristic that should be kept in mind during surgical repair of the GI tract. Additionally, serosal healing is essential for quickly achieving a watertight seal from the luminal side of the bowel. The importance of the serosa is underscored by the significantly higher rates of anastomotic failure observed clinically in segments of bowel that are extraperitoneal and lack serosa (i.e., the esophagus and rectum).Injuries to all parts of the GI tract undergo the same sequence of healing as cutaneous wounds. However, there are some significant differences (Table 9-5). Mesothelial (serosal) and mucosal healing can occur without scarring. The early integ-rity of the anastomosis is dependent on formation of a fibrin seal on the serosal side, which achieves water tightness, and on the suture-holding capacity of the intestinal wall, particularly the sub-mucosal layer. There is a significant decrease in marginal strength during the first week due to an early and marked collagenolysis. The lysis of collagen is carried out by collagenase derived from neutrophils, macrophages, and intraluminal bacteria. Recently, it has been shown that strains of Pseudomonas aeruginosa undergo phenotypic shifts characterized by higher collagenase secretion in an injured/anastomosed bowel environment.44 Collagenase activ-ity occurs early in the healing process, and during the first 3 to 5 days, collagen breakdown far exceeds collagen synthesis. The integrity of the anastomosis represents equilibrium between col-lagen lysis, which occurs early, and collagen synthesis, which takes a few days to initiate (Fig. 9-5). Collagenase is expressed following injury in all segments of the GI tract, but it is much more marked in the colon compared to the small bowel. Colla-gen synthesis in the GI tract is carried out by both fibroblasts and smooth muscle cells. Colon fibroblasts produce greater amounts of collagen than skin fibroblasts, reflecting different phenotypic features, as well as different responses to cytokines and growth factors among these different fibroblast populations. Ultimate anastomotic strength is not always related to the absolute amount of collagen, and the structure and arrangement of the collagen matrix may be more important.45Table 9-4Osteogenesis imperfecta: clinical and genetic featuresTYPECLINICAL FEATURESINHERITANCEIMild bone fragility, blue scleraDominantII“Prenatal lethal”; crumpled long bones, thin ribs, dark blue scleraDominantIIIProgressively deforming; multiple fractures; early loss of ambulationDominant/recessiveIVMild to moderate bone fragility; normal or gray sclera; mild short statureDominantReproduced with permission from Cohen IK, Diegelmann RF, Lindblad WJ: Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA: WB Saunders/Elsevier; 1992.Brunicardi_Ch09_p0271-p0304.indd 27901/03/19 4:50 PM 280BASIC CONSIDERATIONSPART ITechnical Considerations. Traditional teaching holds that in order for an anastomosis to heal without complications it must be tension free, have an adequate blood supply, receive adequate nutrition, and be free of sepsis. Although sound prin-ciples for all wound healing, there are several considerations unique to GI anastomotic healing. From a technical viewpoint, the ideal method of suturing two ends of bowel together has not yet been identified. Although debate exists concerning meth-ods of creating an anastomosis, clinically there has been no convincing evidence that any given technique has any advan-tage over another (i.e., hand-sutured vs. stapled, continuous vs. interrupted sutures, absorbable vs. nonabsorbable sutures, or singlevs. two-layer closure). A recent meta-analysis revealed that stapled ileocolic anastomoses have fewer leak rates than hand-constructed ones, but this might not apply to colo-colic or small bowel anastomoses.46Fluid third spacing, tissue edema, and increased intraab-dominal pressure secondary to overzealous fluid administration can result in blood flow compromise in small vessels at the edge of anastomosis and thus interfere with GI healing.47,48BoneFollowing any type of injury to bone, several changes take place at the site of injury to restore structural and functional integrity. Most of the phases of healing resemble those observed in der-mal healing, but some notable individual characteristics apply to Table 9-5Comparison of wound healing in the gastrointestinal tract and skin  GI TRACTSKINWound environmentpHVaries throughout GI tract in accordance with local exocrine secretionsUsually constant except during sepsis or local infection MicroorganismsAerobic and anaerobic, especially in the colon and rectum; problematic if they contaminate the peritoneal cavitySkin commensals rarely cause problems; infection usually results from exogenous contamination or hematogenous spread Shear stressIntraluminal bulk transit and peristalsis exert distracting forces on the anastomosisSkeletal movements may stress the suture line but pain usually acts as a protective mechanism preventing excess movement Tissue oxygenationDependent on intact vascular supply and neocapillary formationCirculatory transport of oxygen as well as diffusionCollagen synthesisCell typeFibroblasts and smooth muscle cellsFibroblasts Lathyrogensd-Penicillamine has no effect on collagen cross-linkingSignificant inhibition of cross-linking with decreased wound strength SteroidsContradictory evidence exists concerning their negative effect on GI healing; increased abscess in the anastomotic line may play a significant roleSignificant decrease in collagen accumulationCollagenase activity—Increased presence throughout GI tract after transection and reanastomosis; during sepsis, excess enzyme may promote dehiscence by decreasing suture-holding capacity of tissueNot as significant a role in cutaneous woundsWound strength—Rapid recovery to preoperative level.Less rapid than GI tissueScar formationAgeDefinite scarring seen in fetal wound sitesUsually heals without scar formation in the fetusDaysTensile strengthResultant curveStrength of newcollagen increaseswith synthesisStrength of collagendecreases due tolysisFigure 9-5. Diagrammatic representation of the concept of GI wound healing as a fine balance between collagen synthesis and collagenolysis. The “weak” period when collagenolysis exceeds col-lagen synthesis can be prolonged or exacerbated by any factors that upset the equilibrium. (Reproduced with permission from Dunphy JE: Fundamentals of Wound Management in Surgery. New York, NY: Chirurgecom, Inc.; 1976.)Brunicardi_Ch09_p0271-p0304.indd 28001/03/19 4:50 PM 281WOUND HEALINGCHAPTER 9bone injuries. The initial stage of hematoma formation consists of an accumulation of blood at the fracture site, which also con-tains devitalized soft tissue, dead bone, and necrotic marrow. The next stage accomplishes the liquefaction and degradation of nonviable products at the fracture site. The normal bone adja-cent to the injury site can then undergo revascularization, with new blood vessels growing into the fracture site. This is similar to the formation of granulation in soft tissue. The symptoms associated with this stage are characteristic of inflammation, with clinical evidence of swelling and erythema.Three to 4 days following injury, soft tissue forms a bridge between the fractured bone segments in the next stage (soft callus stage). The soft tissue is deposited where neovasculariza-tion has taken place and serves as an internal splint, preventing damage to the newly laid blood vessels and achieving a fibrocar-tilaginous union. The soft callus is formed externally along the bone shaft and internally within the marrow cavity. Clinically, this phase of healing is characterized by the cessation of pain and inflammatory signs.The next phase consists of mineralization of the soft callus and conversion to bone (hard callus stage). This may take up to 2 to 3 months and leads to complete bony union. The bone is now considered strong enough to allow weight bearing and will appear healed on radiographs. Then remodeling phase follows, in which the excessive callus is reabsorbed and the marrow cav-ity is recanalized. Remodeling allows for the correct transmis-sion of forces and restores the contours of the bone.As in dermal healing, the process of osseous union is mediated by soluble growth factors and cytokines. The most extensively studied group is the bone morphogenic proteins (BMPs), which belong to the TGF-β superfamily. By stimulat-ing the differentiation of mesenchymal cells into chondroblasts and osteoblasts, BMPs directly affect bone and cartilage repair. Other growth factors such as PDGF, TGF-β, TNF-α, and bFGF also participate in bony repair by mediating the inflammatory and proliferative phases of healing.CartilageCartilage consists of cells (chondrocytes) surrounded by an extracellular matrix made up of several proteoglycans, colla-gen fibers, and water. Unlike bone, cartilage is very avascular and depends on diffusion for transmittal of nutrients across the matrix. Additionally, the hypervascular perichondrium contrib-utes substantially to the nutrition of the cartilage. Therefore, injuries to cartilage may be associated with permanent defects due to tenuous blood supply.The healing response of cartilage depends on the depth of injury. In a superficial injury, there is disruption of the pro-teoglycan matrix and injury to the chondrocytes. There is no inflammatory response, but an increase in synthesis of proteo-glycan and collagen dependent entirely on the chondrocyte. The healing power of cartilage is often inadequate, and over-all regeneration is incomplete. Therefore, superficial cartilage injuries are slow to heal and often result in persistent structural defects.In contrast to superficial injuries, deep injuries involve the underlying bone and soft tissue. This leads to the exposure of vascular channels of the surrounding damaged tissue that may help in the formation of granulation tissue. Hemorrhage allows for the initiation of the inflammatory response and the subse-quent mediator activation of cellular function for repair. As the granulation tissue is laid down, fibroblasts migrate toward the wound and synthesize fibrous tissue that undergoes chondrifica-tion. Gradually, hyaline cartilage is formed, which restores the structural and functional integrity of the injured site.TendonTendons and ligaments are specialized structures that link mus-cle and bone, and bone and bone, respectively. They consist of parallel bundles of collagen interspersed with spindle cells. Tendons and ligaments can be subjected to a variety of injuries, such as laceration, rupture, and contusion. Due to the mobility of the underlying bone or muscles, the damaged ends usually separate. Tendon and ligament healing progresses in a similar fashion as in other areas of the body (i.e., through hematoma formation, organization, laying down of reparative tissue, and scar formation). Matrix is characterized by accumulation of types I and III collagen along with increased water, DNA, and glycosaminoglycan content. As the collagen fibers are orga-nized, transmission of forces across the damaged portion can occur. Restoration of the mechanical integrity may never be equal to that of the undamaged tendon.Tendon vasculature has a clear effect on healing. Hypovas-cular tendons tend to heal with less motion and more scar for-mation than tendons with better blood supply. The specialized cells, tenocytes, are metabolically very active and retain a large regenerative potential, even in the absence of vascularity. Cells on the tendon surface are identical to those within the sheath and play a role in tendon healing as well.NerveNerve injuries are very common, with an estimated 200,000 repairs performed every year in the United States. Peripheral nerves are a complex arrangement of axons, nonneuronal cells, and extracellular elements. There are three types of nerve inju-ries: neurapraxia (focal demyelination), axonotmesis (interrup-tion of axonal continuity but preservation of Schwann cell basal lamina), and neurotmesis (complete transection). Following all types of injury, the nerve ends progress through a predictable pattern of changes involving three crucial steps: (a) survival of axonal cell bodies; (b) regeneration of axons that grow across the transected nerve to reach the distal stump; and (c) migration and connection of the regenerating nerve ends to the appropriate nerve ends or organ targets.Phagocytes remove the degenerating axons and myelin sheath from the distal stump (Wallerian degeneration). Regen-erating axonal sprouts extend from the proximal stump and probe the distal stump and the surrounding tissues. Schwann cells envelope and help in remyelinating the regenerating axons. Functional units are formed when the regenerating axons con-nect with the appropriate end targets. Several factors play a role in nerve healing, such as growth factors, cell adhesion mol-ecules, and nonneuronal cells and receptors. Growth factors include nerve growth factor, brain-derived neurotrophic factor, basic and acidic fibroblastic growth factors, and neuroleukin. Cell adhesion molecules involved in nerve healing include nerve adhesion molecule, neuron-glia adhesion molecule, myelin adhesion glycoprotein, and N-cadherin. This complex interplay of growth factors and adhesion molecules helps in nerve regeneration.Fetal Wound HealingThe main characteristic that distinguishes the healing of fetal wounds from that of adult wounds is the lack of scar forma-tion. Understanding how fetal wounds achieve integrity without Brunicardi_Ch09_p0271-p0304.indd 28101/03/19 4:50 PM 282BASIC CONSIDERATIONSPART Ievidence of scarring holds promise for the possible manipula-tion of unwanted fibrosis or excessive scar formation in adults.Although early fetal healing is characterized by the absence of scarring and resembles tissue regeneration, there is a phase of transition during gestational life when a more adult-like healing pattern emerges. This so-called “transition wound” occurs at the beginning of the third trimester, and during this period, there is scarless healing; however, there is a loss of the ability to regenerate skin appendages.49 Eventually a classic, adult-patterned healing with scar formation occurs exclusively, although overall healing continues to be faster than in adults.There are a number of characteristics that may influence the differences between fetal and adult wounds. These include wound environment, inflammatory responses, differential growth factor profiles, and wound matrix.Wound Environment. The fetus is bathed in a sterile, tem-perature-stable fluid environment, although this alone does not explain the observed differences. Experiments have demon-strated that scarless healing may occur outside of the amniotic fluid environment, and conversely, scars can form in utero.50,51Inflammation. The extent and robustness of the inflammatory response correlates directly with the amount of scar formation in all healing wounds. Reduced fetal inflammation due to the immaturity of the fetal immune system may partially explain the lack of scarring observed. Not only is the fetus neutrope-nic, but fetal wounds also contain lower numbers of PMNs and macrophages.52Growth Factors. Fetal wounds are notable for the absence of TGF-β, which may have a significant role in scarring. Blocking TGF-β1 or TGF-β2 using neutralizing antibodies considerably reduces scar formation in adult wounds. Exogenous application of TGF-β3 downregulates TGF-β1 and TGF-β2 levels at the wound site with a resultant reduction in scarring.53 Thus, the balance between the concentration and/or activity of TGF-β iso-forms may be important for regulating scar production.Wound Matrix. The fetal wound is characterized by excessive and extended hyaluronic acid production, a high-molecular-weight glycosaminoglycan that is produced primarily by fibro-blasts. Although adult wounds also produce hyaluronic acid, its synthesis is sustained only in the fetal wound. Components of amniotic fluid, most specifically fetal urine, have a unique abil-ity to stimulate hyaluronic acid production.54 Fetal fibroblasts produce more collagen than adult fibroblasts, and the increased level of hyaluronic acid may aid in the orderly organization of collagen. As a result of these findings, hyaluronic acid is used topically to enhance healing and to inhibit postoperative adhesion formation.55 The collagen pattern of fetal wounds is reticular in nature and resembles surrounding tissue, while adult patterns express large bundles of parallel collagen fibrils ori-ented perpendicular to the surface.56CLASSIFICATION OF WOUNDSWounds are classified as either acute or chronic. By definition, an acute wound becomes chronic if healing is not achieved after 4 weeks of treatment. Acute wounds heal in a predictable man-ner and time frame as previously mentioned. The process occurs with few, if any, complications, and the end result is a well-healed wound. Surgical wounds can heal in several ways. An incised wound that is clean and closed by sutures is said to heal by primary intention. Often, because of bacterial contamination or tissue loss, a wound will be left open to heal by granula-tion tissue formation and contraction; this constitutes healing by secondary intention. Delayed primary closure, or healing by tertiary intention, represents a combination of the first two, con-sisting of the placement of sutures, allowing the wound to stay open for a few days, and the subsequent closure of the sutures (Fig. 9-6).The healing spectrum of acute wounds is broad (Fig. 9-7). In examining the acquisition of mechanical integrity and strength during healing, the normal process is characterized by a con-stant and continual increase that reaches a plateau at some point after injury. In regular wounds, the maximal wound strength is reached after about 6 weeks of healing. A fully healed wound achieves only 75% to 80% of a normal tissue. Wounds with delayed healing are characterized by decreased wound-breaking strength in comparison to wounds that heal at a normal rate; however, they eventually achieve the same integrity and strength as wounds that heal normally. Conditions such as nutritional deficiencies, infections, or severe trauma cause delayed heal-ing, which reverts to normal with correction of the underlying pathophysiology. Impaired healing is characterized by a failure to achieve mechanical strength equivalent to normally healed wounds. Patients with compromised immune systems such as those with diabetes, chronic steroid usage, or tissues damaged by radiotherapy are prone to this type of impaired healing. The surgeon must be aware of these situations and exercise great care in the placement of incision and suture selection, postop-erative care, and adjunctive therapy to maximize the chances of healing without supervening complications.In general, wounds heal by a combination of mecha-nisms, including connective tissue deposition, contraction, and Primary IntentionSecondary IntentionTertiary IntentionContractionContractionConnective TissueRepairConnective TissueRepairEpithelializationEpithelializationFigure 9-6. Different clinical approaches to the closure and heal-ing of acute wounds.Brunicardi_Ch09_p0271-p0304.indd 28201/03/19 4:50 PM 283WOUND HEALINGCHAPTER 9epithelialization, depending on wound type. Surgically closed wounds need mostly epithelialization for healing, while open wounds require a combination of tissue contraction, connective tissue deposition, and epithelialization to a lesser extent. Chronic ulcers heal by secondary intention similar to open wounds.Normal healing is affected by both systemic and local fac-tors (Table 9-6). The clinician must be familiar with these fac-tors and should attempt to counteract their deleterious effects. Complications occurring in wounds with higher risk can lead to failure of healing or the development of chronic, nonhealing wounds.Factors Affecting Wound HealingAdvanced Age. Most surgeons believe that aging produces intrinsic physiologic changes that result in delayed or impaired wound healing. Clinical experience with elderly patients tends to support this belief. Studies of hospitalized surgical patients show a direct correlation between older age and poor wound healing outcomes such as dehiscence and incisional hernia.57,58 However, these statistics fail to take into account underlying illnesses or diseases as a possible source of impaired wound healing in the elderly. The increased incidence of cardiovascu-lar disease, metabolic diseases (diabetes mellitus, malnutrition, and vitamin deficiencies), and cancer, and the widespread use of drugs that impair wound healing may all contribute to the higher incidence of wound problems in the elderly. However, more recent clinical experience suggests that major operative interventions can be accomplished safely in the elderly.The results of animal studies regarding the effects of aging on wound healing have yielded contradictory results. In healthy human volunteers, there was a significant delay of 1.9 days in the epithelialization of superficial skin defects in those older than 70 years of age when compared to younger volunteers.59 In the same volunteers, using a micro-model of fibroplasia, no dif-ference in DNA or hydroxyproline wound accumulation could be demonstrated between the young and elderly groups; how-ever, the young volunteers had a significantly higher amount of total α-amino nitrogen in their wounds, a reflection of total protein content of the wound. Thus, although wound collagen synthesis does not seem to be impaired with advanced age, non-collagenous protein accumulation at wounded sites is decreased with aging, which may impair the mechanical properties of scar-ring in elderly patients. Generally, in a relatively healthy person age will cause a delay in healing rather than nonhealing.Hypoxia, Anemia, and Hypoperfusion. Low oxygen tension has a profoundly deleterious effect on all aspects of wound heal-ing. Fibroplasia, although stimulated initially by the hypoxic wound environment, is significantly impaired by local hypoxia. Optimal collagen synthesis requires oxygen as a cofactor, partic-ularly for the hydroxylation steps. Increasing subcutaneous oxy-gen tension levels by increasing the fraction of inspired oxygen (Fio2) of inspired air for brief periods during and immediately following surgery results in enhanced collagen deposition and in decreased rates of wound infection after elective surgery.60-62Major factors affecting local oxygen delivery include hypoperfusion either for systemic reasons (low volume or car-diac failure) or due to local causes (arterial insufficiency, local vasoconstriction, or excessive tension on tissues). The level of vasoconstriction of the subcutaneous capillary bed is exquisitely responsive to fluid status, temperature, and hyperactive sympa-thetic tone as is often induced by postoperative pain. Correction of these factors can have a remarkable influence on wound out-come, particularly on decreasing wound infection rates.61-63 Mild to moderate normovolemic anemia does not appear to adversely affect wound oxygen tension and collagen synthesis. However, profound anemia with 15% less hematocrit can interfere with wound healing.63Steroids and Chemotherapeutic Drugs. Large doses or chronic usage of glucocorticoids reduce collagen synthesis and wound strength.64 The major effect of steroids is to inhibit the inflammatory phase of wound healing (angiogenesis, neutro-phil and macrophage migration, and fibroblast proliferation) and the release of lysosomal enzymes. The stronger the anti-inflammatory effect of the steroid compound used, the greater the inhibitory effect on wound healing. Steroids used after the first 3 to 4 days after injury do not affect wound healing as severely as when they are used in the immediate postoperative 3Normal healingDelayed healingImpaired healing chronicTimeWound mechanical strengthFigure 9-7. The acquisition of wound mechanical strength over time in normal, delayed, and impaired healing.Table 9-6Factors affecting wound healingSystemic Age Nutrition Trauma Metabolic diseases Immunosuppression Connective tissue disorders SmokingLocal Mechanical injury Infection Edema Ischemia/necrotic tissue Topical agents Ionizing radiation Low oxygen tension Foreign bodiesBrunicardi_Ch09_p0271-p0304.indd 28301/03/19 4:50 PM 284BASIC CONSIDERATIONSPART Iperiod. Therefore, if possible, their use should be delayed, or alternatively, forms with lesser anti-inflammatory effects should be administered.In addition to their effect on collagen synthesis, steroids also inhibit epithelialization and contraction and contribute to increased rates of wound infection, regardless of the time of administration.64 Steroid-delayed healing of cutaneous wounds can be stimulated to epithelialize by topical application of vitamin A.64,65 Collagen synthesis of steroid-treated wounds also can be stimulated by vitamin A.All chemotherapeutic antimetabolite drugs adversely affect wound healing by inhibiting early cell proliferation, wound DNA and protein synthesis, attenuation of the inflamma-tory phase, decrease fibrin deposition, and delay wound contrac-tion, all of which are critical to successful healing. The effect is worse if these agents are given preoperatively; so a delay in the use of such drugs for about 2 weeks after injury appears to lessen wound healing impairment.66 Extravasation of most che-motherapeutic agents is associated with tissue necrosis, marked ulceration, and protracted healing at the affected site.67Metabolic Disorders. Diabetes mellitus is the best known of the metabolic disorders contributing to increased rates of wound infection and failure.68 Uncontrolled diabetes results in reduced inflammation, angiogenesis, and collagen synthe-sis. Additionally, the largeand small-vessel disease that is the hallmark of advanced diabetes contributes to hypoperfusion and local hypoxemia. Defects in granulocyte function, capillary ingrowth, and fibroblast proliferation all have been described in diabetes. Obesity, insulin resistance, hyperglycemia, and dia-betic renal failure contribute significantly and independently to the impaired wound healing observed in diabetics.69 In wound studies on experimental diabetic animals, insulin restores colla-gen synthesis and granulation tissue formation to normal levels if given during the early phases of healing.70 In clean, nonin-fected, and well-perfused experimental wounds in human dia-betic volunteers, type 1 diabetes mellitus was noted to decrease wound collagen accumulation in the wound, independent of the degree of glycemic control. Type 2 diabetic patients showed no effect on collagen accumulation when compared to healthy, age-matched controls.71 Furthermore, the diabetic wound appears to be lacking in sufficient growth factor levels, which signal normal healing. It remains unclear whether decreased collagen synthesis or an increased breakdown due to an abnormally high proteolytic wound environment is responsible.Careful preoperative correction of blood sugar levels improves the outcome of wounds in diabetic patients. Increas-ing the inspired oxygen tension, judicious use of antibiotics, and correction of other coexisting metabolic abnormalities all can result in improved wound healing. Additionally, revasculariza-tion to local areas with chronic ulcers will aid in the healing process.Uremia also has been associated with disordered wound healing and impairs defenses for infection. Experimentally, uremic animals demonstrate decreased wound collagen synthe-sis and breaking strength, causing delayed healing of intestinal anastomosis and abdominal wounds. The contribution of uremia alone to this impairment, rather than that of associated malnutri-tion, is difficult to assess.69 The clinical use of dialysis to correct the metabolic abnormalities and nutritional restoration should impact greatly on the wound outcome of such patients. In some uremic patients, wounds might be associated with abnormal deposition of calcium and phosphate in the tissue leading to uremic gangrene syndrome (calciphylaxis). In such patients, the wounds are extremely painful and difficult to heal.Obesity is the largest growing public health problem in the United States and the world. Over 60% of Americans are overweight or obese. Uncomplicated obesity (i.e., in the absence of comorbid conditions such as cardiovascular disease, diabetes, or respiratory insufficiency) has by itself significant deleterious effects on wound healing. Visceral adiposity is active metaboli-cally and immunologically and, through generation of proin-flammatory cytokines and adipokines, leads to the development of the metabolic syndrome. Many of these molecules have effects on cells participating in the healing response. In nondia-betic obese rodents, wounds are mechanically weaker, and there is less dermal and reparative scar collagen. Preadipocytes infil-trate the dermis, and although they can evolve into fibroblasts, their regulatory mechanisms appear different from those of dermal or wound fibroblasts. Many studies indicate that obese patients have high rates of perioperative complications, with estimates as high as 30% for wound dehiscence, 17% for surgi-cal site infections, 30% for incisional hernias, 19% for seromas, 13% for hematomas, and 10% for fat necrosis.72-74 Increased subcutaneous fat was associated with a tenfold increased risk of surgery-related complications including anastomotic leaks, abdominal collection, and wound infections.75 In many studies, obesity is a constant and major risk factor for hernia formation and recurrence after repair. The mechanism by which obesity impairs wound healing awaits complete delineation.Nutrition. The importance of nutrition in the recovery from traumatic or surgical injury has been recognized by clinicians since the time of Hippocrates. Poor nutritional intake or lack of individual nutrients significantly alters many aspects of wound healing. The clinician must pay close attention to the nutritional status of patients with wounds, since wound failure or wound infections may be no more than a reflection of poor nutrition. Although the full interaction of nutrition and wound healing is still not fully understood, efforts are being made to develop wound-specific nutritional interventions and institute the phar-macologic use of individual nutrients as modulators of wound outcomes.Experimental rodents fed either a 0% or 4% protein diet have impaired collagen deposition with a secondary decrease in skin and fascial wound-breaking strength and increased wound infection rates. Induction of energy-deficient states by providing only 50% of the normal caloric requirement leads to decreased granulation tissue formation and matrix protein deposition in rats. Acute fasting in rats markedly impairs collagen synthesis while decreasing procollagen mRNA.76Clinically, it is extremely rare to encounter pure energy or protein malnutrition, and the vast majority of patients exhibit combined protein-energy malnutrition. Such patients have diminished hydroxyproline accumulation (an index of collagen deposition) into subcutaneously implanted polytetrafluoroeth-ylene tubes when compared to normally nourished patients (Fig. 9-8). Furthermore, malnutrition correlates clinically with enhanced rates of wound complications and increased wound failure following diverse surgical procedures. This reflects impaired healing response as well as reduced cell-mediated immunity, phagocytosis, and intracellular killing of bacte-ria by macrophages and neutrophils during protein-calorie malnutrition.76Two additional nutrition-related factors warrant discus-sion. First, the degree of nutritional impairment need not be Brunicardi_Ch09_p0271-p0304.indd 28401/03/19 4:50 PM 285WOUND HEALINGCHAPTER 9long-standing in humans, as opposed to the experimental situa-tion. Thus, patients with brief preoperative illnesses or reduced nutrient intake in the period immediately preceding the injury or operative intervention will demonstrate impaired fibroplasias.77,78 Second, brief and not necessarily intensive nutritional interven-tion, either via the parenteral or enteral route, can reverse or prevent the decreased collagen deposition noted with malnutri-tion or with postoperative starvation.79The possible role of single amino acids in enhanced wound healing has been studied for the last several decades. Arginine appears most active in terms of enhancing wound fibroplasia. Arginine deficiency results in decreased wound-breaking strength and wound-collagen accumulation in chow-fed rats. Rats that are given 1% arginine HCl supplementation, and there-fore are not arginine-deficient, have enhanced wound-breaking strength and collagen synthesis when compared to chow-fed controls.80 Studies have been carried out in healthy human vol-unteers to examine the effect of arginine supplementation on collagen accumulation. Young, healthy, human volunteers (age 25–35 years) were found to have significantly increased wound-collagen deposition following oral supplementation with either 30 g of arginine aspartate (17 g of free arginine) or 30 g of argi-nine Hall (24.8 g of free arginine) daily for 14 days.81 In a study of healthy older humans (age 67–82 years), daily supplements of 30 g of arginine aspartate for 14 days resulted in significantly enhanced collagen and total protein deposition at the wound site when compared to controls given placebos. There was no enhanced DNA synthesis present in the wounds of the arginine-supplemented subjects, suggesting that the effect of arginine is not mediated by an inflammatory mode of action.82 In this and later studies, arginine supplementation, whether administered orally or parenterally, had no effect on the rate of epithelializa-tion of a superficial skin defect. This further suggests that the main effect of arginine on wound healing is to enhance wound collagen deposition. Recently, a dietary supplemental regimen of arginine, β-hydroxy-β-methyl butyrate, and glutamine was found to significantly and specifically enhance collagen depo-sition in elderly, healthy human volunteers when compared to an isocaloric, isonitrogenous supplement (Fig. 9-9).83 As increases in breaking strength during the first weeks of healing are directly related to new collagen synthesis, arginine supple-mentation may result in an improvement in wound strength as a consequence of enhanced collagen deposition.The vitamins most closely involved with wound healing are vitamin C and vitamin A. Scurvy or vitamin C deficiency leads to a defect in wound healing, particularly via a failure in collagen synthesis and cross-linking. Biochemically, vitamin C is required for the conversion of proline and lysine to hydroxy-proline and hydroxylysine, respectively. Vitamin C deficiency has also been associated with an increased incidence of wound infection, and if wound infection does occur, it tends to be more severe. These effects are believed to be due to an associated impairment in neutrophil function, decreased complement activ-ity, and decreased walling-off of bacteria secondary to insuffi-cient collagen deposition. The recommended dietary allowance is 60 mg daily. This provides a considerable safety margin for most healthy nonsmokers. In severely injured or extensively burned patients, this requirement may increase to as high as 2 g daily. There is no evidence that excess vitamin C is toxic; however, there is no evidence that supratherapeutic doses of vitamin C are of any benefit.84Vitamin A deficiency impairs wound healing, while sup-plemental vitamin A benefits wound healing in nondeficient humans and animals. Vitamin A increases the inflammatory OHP (nmol/mg)1.52.01.00.50.0Adequatefood intakeInadequatefood intake1.51.00.5OHP (µg/cm)0.0WellnourishedMalnourishedFigure 9-8. Effect of malnutrition on collagen deposition in exper-imental human wounds. OHP = hydroxyproline.54321ASPLYSOHPExperimentalControl˜ANFigure 9-9. Ratios of 14-day to 7-day values for aspartate (ASP), lysine (LYS), hydroxyproline (OHP), and α-amino nitrogen (αAN) in volunteers given dietary supplements of arginine, β-hydroxy-β-methylbutyrate, and glutamine. P <.05. (Reproduced with per-mission from Williams JZ, Abumrad NN, Barbul A. Effect of a specialized amino acid mixture on human collagen deposition, Ann Surg. 2002 Sep;236(3):369-374.)Brunicardi_Ch09_p0271-p0304.indd 28501/03/19 4:50 PM 286BASIC CONSIDERATIONSPART Iresponse in wound healing, probably by increasing the labil-ity of lysosomal membranes. There is an increased influx of macrophages, with an increase in their activation and increased collagen synthesis. Vitamin A directly increases collagen pro-duction and epidermal growth factor receptors when it is added in vitro to cultured fibroblasts. As mentioned before, supple-mental vitamin A can reverse the inhibitory effects of cortico-steroids on wound healing. Vitamin A also can restore wound healing that has been impaired by diabetes, tumor formation, cyclophosphamide, and radiation. Serious injury or stress leads to increased vitamin A requirements. In the severely injured patient, supplemental doses of vitamin A have been recom-mended. Doses ranging from 25,000 to 100,000 IU per day have been advocated.The connections between specific minerals and trace ele-ments and deficits in wound healing are complex. Frequently, deficiencies are multiple and include macronutrient deficien-cies. As with some of the vitamins described earlier, the specific trace element may function as a cofactor or part of an enzyme that is essential for homeostasis and wound healing. Clinically, preventing deficiencies is often easier to accomplish than diag-nosing them.Zinc is the most well-known element in wound heal-ing and has been used empirically in dermatologic conditions for centuries. It is essential for wound healing in animals and humans. There are over 150 known enzymes for which zinc is either an integral part or an essential cofactor, and many of these enzymes are critical to wound healing.85 With zinc deficiency, there is decreased fibroblast proliferation, decreased collagen synthesis, impaired overall wound strength, and delayed epithe-lialization. These defects are reversed by zinc supplementation. To date, no study has shown improved wound healing with zinc supplementation in patients who are not zinc deficient.86Infections. Wound infections continue to represent a major medical problem, both in terms of how they affect the outcome of surgical procedures (surgical site infections), and for their impact on the length of hospital stay and medical costs.87 Many otherwise successful surgical operations fail because of the development of wound infections. The occurrence of infections is of major concern when implants are used, and their occur-rence may lead to the removal of the prosthetic material, thus subjecting the patient to further operations and severe risk of morbidity and mortality. Infections can weaken an abdominal closure or hernia repair and result in wound dehiscence or recur-rence of the hernia. Cosmetically, infections can lead to disfig-uring, unsightly, or delayed closures.Exhaustive studies have been undertaken that examine the appropriate prophylactic treatment of operative wounds. Bacte-rial contaminants normally present on skin are prevented from entry into deep tissues by intact epithelium. Surgery breaches the intact epithelium, allowing bacteria access to these tissues and the bloodstream. Antibiotic prophylaxis is most effective when adequate concentrations of antibiotic are present in the tissues at the time of incision, and assurance of adequate pre-operative antibiotic dosing and timing has become a significant hospital performance measure.88 The addition of antibiotics after operative contamination has occurred clearly is ineffective in preventing postoperative wound infections.Studies that compare operations performed with and without antibiotic prophylaxis demonstrate that classes II, III, and IV procedures (see below) treated with appropriate prophylactic antibiotics have only one third the wound infection rate of previously reported untreated series.89 More recently, repeat dosing of antibiotics has been shown to be essential in decreasing postoperative wound infections in operations with durations exceeding the biochemical half-life (t1/2) of the anti-biotic or in which there is large-volume blood loss and fluid replacement.90,91 In lengthy cases, those in which prosthetic implants are used, or when unexpected contamination is encoun-tered, additional doses of antibiotic may be administered for 24 hours postoperatively.Selection of antibiotics for use in prophylaxis should be tailored to the type of surgery to be performed, operative con-taminants that might be encountered during the procedure, and the profile of resistant organisms present at the institution where the surgery is performed. The continuing widespread appear-ance of methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE) has significantly restricted the selection of these agents for routine use. Surgery-specific treatment guidelines are provided in Table 9-7.90Patients with prosthetic heart valves or any implanted vascular or orthopedic prostheses should receive antibiotic prophylaxis prior to any procedure in which significant bac-teremia is anticipated. Dental procedures require prophylaxis with broad-spectrum penicillins or amoxicillin, while urologic instrumentation should be pretreated with a second-generation cephalosporin. Patients with prostheses who undergo gastroin-testinal surgery should receive anaerobic coverage combined with a cephalosporin. Nasal screening and decolonization for S aureus carriers are recommended for selected procedures (i.e., cardiac, orthopedic, neurosurgical procedures with implants).The incidence of wound infection is about 5% to 10% nationwide and has not changed during the last few decades. Quantitatively, it has been shown that if the wound is contami-nated with >105 microorganisms per gram of tissue, the risk of wound infection is markedly increased, but this threshold may be much lower in the presence of foreign materials. The source of pathogens for the infection is usually the endogenous flora of the patient’s skin, mucous membranes, or from hollow organs. The most common organisms responsible for wound infections in order of frequency are Staphylococcus species, coagulase-negative Streptococcus, enterococci, and Escherichia coli. The incidence of wound infection bears a direct relationship to the degree of contamination that occurs during the operation from the disease process itself (clean—class I, clean contaminated—class II, contaminated—class III, and dirty—class IV). Many factors contribute to the development of postoperative wound infections. Most surgical wound infections become apparent within 7 to 10 days postoperatively, although a small number manifest years after the original operative intervention. With the hospital stay becoming shorter and shorter, many infections are detected in the outpatient setting, leading to underreporting of the true incidence of wound infections absent intensive sur-veillance. There has been much debate about the actual defini-tion of wound infection. The narrowest definition would include wounds that drain purulent material with bacteria identified on culture. The broader definition would include all wounds drain-ing pus, whether or not the bacteriologic studies are positive; wounds that are opened by the surgeon; and wounds that the surgeon considers infected.92Anatomically, wound infections can be classified as superficial incisional, deep incisional, and organ/space wound infections, involving fascia, muscle, or the abdominal cavity. Brunicardi_Ch09_p0271-p0304.indd 28601/03/19 4:50 PM 287WOUND HEALINGCHAPTER 9Table 9-7Antimicrobial prophylaxis for surgeryNATURE OF OPERATIONCOMMON PATHOGENSRECOMMENDED ANTIMICROBIALSADULT DOSAGE BEFORE SURGERY1CardiacStaphylococcus aureus, S. epidermidisCefazolin orCefuroxime orVancomycin41–2 g IV2,31.5 g IV31 g IVGastrointestinalEsophageal/gastroduodenalEnteric gram-negative bacilli, gram-positive cocciHigh risk5 only: cefazolin61–2 g IV2Biliary tractEnteric gram-negative bacilli, enterococci, clostridiaHigh risk7 only: cefazolin6,81–2 g IV2ColorectalEnteric gram-negative bacilli, anaerobes, enterococciOral: neomycin + erythromycin base9 or metronidazole9Parenteral: cefoxitin6 orCefotetan6 orCefazolin +Metronidazole6 orAmpicillin/sulbactamsee note 91–2 g IV1–2 g IV1–2 g IV20.5 g IV3 g IVAppendectomy, nonperforated11Same as for colorectalCefoxitin6 or cefotetan6 orCefazolin6 +Metronidazole1–2 g IV1–2 g IV20.5 g IVGenitourinaryCystoscopy aloneEnteric gram-negative bacilli, enterococciHigh risk only12: ciprofloxacin10 orTrimethoprim-sulfamethoxazole500 mg PO or 400 mg IV1 DS tabletCystoscopy with manipulation or upper tract instrumentation13Enteric gram-negative bacilli, enterococciCiprofloxacin10 orTrimethoprim-sulfamethoxazole500 mg PO or 400 mg IV1 DS tabletOpen or laparoscopic surgery14Enteric gram-negative bacilli, enterococciCefazolin61–2 g IV2Gynecologic and obstetricVaginal, abdominal, or laparoscopic hysterectomyEnteric gram-negative bacilli, anaerobes, group B streptococci, enterococciCefazolin6 or cefoxitin6 or cefotetan6 or Ampicillin/sulbactam6,101–2 g IV23 g IVCesarean sectionSame as for hysterectomyCefazolin61–2 g IV2Abortion, surgicalSame as for hysterectomyDoxycycline300 mg PO15Head and neck surgeryIncisions through oral or pharyngeal mucosaAnaerobes, enteric gram-negative bacilli, S. aureusClindamycin orCefazolin +Metronidazole orAmpicillin/sulbactam10600–900 mg IV1–2 g IV20.5 g IV3 g IVNeurosurgeryS. aureus, S. epidermidisCefazolin1–2 g IV2OphthalmicS. epidermidis, S. aureus, streptococci, enteric gram-negative bacilli, Pseudomonas spp.Gentamicin, tobramycin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin or neomycin-gramicidin-polymyxin BOR cefazolinMultiple drops topically over 2 to 24 hours100 mg subconjuctivallyOrthopedicS. aureus, S. epidermidisCefazolin16 or Vancomycin2,161–2 g IV2, 1 g IVThoracic (noncardiac)S. aureus, S. epidermidis, streptococci, enteric gram-negative bacilliCefazolin orAmpicillin/sulbactam10 or Vancomycin41–2 g IV23 g IV1 g IV(Continued)Brunicardi_Ch09_p0271-p0304.indd 28701/03/19 4:50 PM 288BASIC CONSIDERATIONSPART IAbout three-fourths of all wound infections are superficial, involving skin and subcutaneous tissue only. Clinical diagnosis is easy when a postoperative wound looks edematous and ery-thematous and is tender. Often the presentation is more subtle, and the development of postoperative fever, usually low-grade; the development of a mild and unexplained leukocytosis; or the presence of undue incisional pain should direct attention to the wound. Inspection of the wound is most useful in detecting sub-tle edema around the suture or staple line, manifested as a waxy appearance of the skin, which characterizes the early phase of infection. If a wound infection is suspected, several stitches or staples around the most suspicious area should be removed with insertion of a cotton-tipped applicator into the subcutane-ous area to open a small segment of the incision. This causes minimal if any discomfort to the patient. Presence of pus man-dates further opening of the subcutaneous and skin layers to the full extent of the infected pocket. Samples should be taken for aerobic and anaerobic cultures, with very few patients requir-ing antibiotic therapy. Patients who are immunosuppressed (diabetics and those on steroids or chemotherapeutic agents), who have evidence of tissue penetration or systemic toxicity, or who have had prosthetic devices inserted (vascular grafts, heart valves, artificial joints, or mesh) should be treated with systemic antibiotics.92Deep wound infections arise immediately adjacent to the fascia, either above or below it, and often have an intra-abdominal component. Most intra-abdominal infections do not, however, communicate with the wound. Deep infections present with fever and leukocytosis. The incision may drain pus spon-taneously, or the intra-abdominal extension may be recognized following the drainage of what was thought to be a superficial wound infection, but pus draining between the fascial sutures will be noted. Sometimes wound dehiscence will occur.The most dangerous of the deep infections is necrotizing fasciitis. It results in high mortality, particularly in the elderly. This is an invasive process that involves the fascia and leads to secondary skin necrosis. Pathophysiologically, it is a septic thrombosis of the vessels between the skin and the deep layers. Table 9-7Antimicrobial prophylaxis for surgeryNATURE OF OPERATIONCOMMON PATHOGENSRECOMMENDED ANTIMICROBIALSADULT DOSAGE BEFORE SURGERY1VascularArterial surgery involving a prosthesis, the abdominal aorta, or a groin incisionS. aureus, S. epidermidis, enteric gram-negative bacilliCefazolin orVancomycin41–2 g IV21 g IVLower extremity amputation for ischemiaS. aureus, S. epidermidis, enteric gram-negative bacilli, clostridiaCefazolin or Vancomycin41–2 g IV21 g IV1Parenteral prophylactic antimicrobials can be given as a single IV dose begun within 60 min before the operation. For prolonged operations (>3 h) or those with major blood loss, or in patients with extensive burns, additional intraoperative doses should be given at intervals 1–2 times the half-life of the drug (ampicillin/sulbactam q2 h, cefazolin q4 h, cefuroxime q4 h, cefoxitin q2 h, clindamycin q6 h, vancomycin q12 h) for the duration of the procedure in a patient with normal renal function. If vancomycin or a fluoroquinolone is used, the infusion should be started 60–120 min before the initial incision to minimize the possibility of an infusion reaction close to the time of induction of anesthesia and to have adequate tissue levels at the time of incision.2The recommended dose of cefazolin is 1 g for patients who weigh 80 kg and 2 g for those >80 kg. Morbidly obese patients may need higher doses.3Some experts recommend an additional dose when patients are removed from bypass during open heart surgery.4Vancomycin can be used in hospitals in which methicillin-resistant Staphylococcus aureus (MRSA) and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillin or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 min, hypotension may occur; treatment with diphenhydramine (Benadryl and others) and further slowing of the infusion rate may be helpful. Some experts would give 15 mg/kg of vancomycin to patients weighing more than 75 kg up to a maximum of 1.5 g with a slower infusion rate (90 min for 1.5 g). For procedures in which gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (gentamicin, tobramycin, or amikacin), aztreonam, or a fluoroquinolone.5Morbid obesity, GI obstruction, decreased gastric acidity or gastrointestinal motility, gastric bleeding, malignancy or perforation, or immunosuppression.6For patients allergic to penicillin and cephalosporins, clindamycin or vancomycin with either gentamicin, ciprofloxacin, levofloxacin, or aztreonam is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section.7Age >70 y, acute cholecystitis, nonfunctioning gallbladder, obstructive jaundice, or common duct stones.8Cefotetan, cefoxitin, and ampicillin/sulbactam are reasonable alternatives.9In addition to mechanical bowel preparation, 1 g of neomycin plus 1 g of erythromycin at 1 p.m., 2 p.m., and 11 p.m. or 2 g of neomycin plus 2 g of metronidazole at 7 p.m. and 11 p.m. the day before an 8 a.m. operation.10Due to increasing resistance of E. coli to fluoroquinolones and ampicillin/sulbactam, local sensitivity profiles should be reviewed prior to use.11For a ruptured viscous, therapy is often continued for about 5 d.12Urine culture positive or unavailable, preoperative catheter, transrectal prostate biopsy, or placement of prosthetic material.13Shock wave lithotripsy, ureteroscopy.14Including percutaneous renal surgery, procedures with entry into the urinary tract, and those involving implantation of a prosthesis. If manipulation of bowel is involved, prophylaxis is given according to colorectal guidelines.15Divided into 100 mg before procedure and 200 mg after.16If a tourniquet is to be used in the procedure, the entire dose of antibiotic must be infused prior to its inflation.Reprinted with special permission from Treatment Guidelines from The Medical Letter, October 2012; Vol. 10(122):73. www.medicalletter.org.(Continued)Brunicardi_Ch09_p0271-p0304.indd 28801/03/19 4:50 PM 289WOUND HEALINGCHAPTER 9The skin demonstrates hemorrhagic bullae and subsequent frank necrosis, with surrounding areas of inflammation and edema. The fascial necrosis is usually wider than the skin involvement or than the surgeon estimates on clinical grounds. The patient is toxic and has high fever, tachycardia, and marked hypovo-lemia, which if uncorrected, progresses to cardiovascular col-lapse. Bacteriologically, this is a mixed infection, and samples should be obtained for Gram stain smears and cultures to aid in diagnosis and treatment. As soon as bacteriologic studies have been obtained, high-dose penicillin treatment needs to be started (20–40 million U/d intravenously) due to concern over the presence of Clostridia perfringens and other related species; broad-spectrum antibiotics should be added and the regimen modified based on culture results. Cardiovascular resuscitation with electrolyte solutions, blood, and/or plasma is carried out as expeditiously as possible prior to induction of anesthesia. The aim of surgical treatment is thorough removal of all necrosed skin and fascia. If viable skin overlies necrotic fascia, multiple longitudinal skin incisions can be made to allow for excision of the devitalized fascia. Although removal of all necrotic tissue is the goal of the first surgical intervention, the distinction between necrotic and simply edematous tissue often is difficult. Careful inspection every 12 to 24 hours will reveal any new necrotic areas, and these need further debridement and excision. When all necrotic tissue has been removed and the infection has been controlled, the wounds may be covered with homoor xeno-grafts until definitive reconstruction and autografting can take place.The mere presence of bacteria in an open wound, either acute or chronic, does not constitute an infection, because large numbers of bacteria can be present in the normal situation. In addition, the bacteria identified by cultures may not be repre-sentative of the bacteria causing the actual wound infection. There seems to be confusion as to what exactly constitutes wound infection. For purposes of clarity, we have to differ-entiate between contamination, colonization, and infection. Contamination is the presence of bacteria without multiplica-tion, colonization is multiplication without host response, and infection is the presence of host response in reaction to depo-sition and multiplication of bacteria. The presence of a host response helps to differentiate between infection and coloniza-tion as seen in chronic wounds. The host response that helps in diagnosing wound infection comprises cellulitis, abnormal discharge, delayed healing, change in pain, abnormal granula-tion tissue, bridging, and abnormal color and odor.As discussed previously, neutrophils play a major role in preventing wound infections. Chronic granulomatous disease (CGD) comprises a genetically heterogeneous group of dis-eases in which the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxide enzyme is deficient. This defect impairs the intracellular killing of microorganisms, leav-ing the patient liable to infection by bacteria and fungi. Afflicted patients have recurrent infections and form granulomas, which can lead to obstruction of the gastric antrum and genitourinary tracts and poor wound healing. Surgeons become involved when the patient develops infectious or obstructive complications.The nitro blue tetrazolium (NBT) reduction test is used to diagnose CGD. Normal neutrophils can reduce this com-pound, while neutrophils from affected patients do not, facili-tating the diagnosis via a colorimetric test. Clinically, patients develop recurrent infections such as pneumonia, lymphadenitis, hepatic abscess, and osteomyelitis. Organisms most commonly responsible are S. aureus, Aspergillus, Klebsiella, Serratia, or Candida. When CGD patients require surgery, a preoperative pulmonary function test should be considered since they are predisposed to obstructive and restrictive lung disease. Wound complications, mainly infection, are common. Sutures should be removed as late as possible since the wounds heal slowly. Abscess drains should be left in place for a prolonged period until the infection is completely resolved.93Hyperglycemia has been shown to be a significant risk factor of postoperative infections.94 Tight blood glucose con-trol, beginning preoperatively and continued into the operating room and beyond, has been associated with significant reduc-tion in infectious complications, in particular following cardiac surgery.95,96 Too tight of a glycemic control (80–100 mg/dL) appears to be associated with more complications and is as effec-tive, if not less than, moderate control (120–180 mg/dL).97,98Another host factor that has been implicated in the devel-opment of superficial surgical site infection relates to the state of the subcutaneous capillary bed. Thomas K. Hunt had shown through several decades of work that this capillary bed is exqui-sitely sensitive to hypovolemia,99 hypothermia,100 and stress, leading to rapid vasoconstriction with secondary impaired oxy-gen delivery and increased rates of infection.61 Maintenance of euvolemia, core temperature above 36°C to 36.5°C, and pain control have all been shown singly and additively to reduce rates of wound infections.63 Another suggestion has been to increase inspired Fio2 to 0.8 for the duration of the operation and in the immediate postoperative period, as a means of increasing sub-cutaneous tissue oxygen delivery. Although successful in most studies,62,101 there have also been negative results from such a single approach102; this suggests that addressing volume, tem-perature, pain control, and oxygen delivery in concert may be the more fruitful approach to reduce surgical wound infections.Chronic WoundsChronic wounds are defined as wounds that have failed to pro-ceed through the orderly process that produces satisfactory ana-tomic and functional integrity or that have proceeded through the repair process without producing an adequate anatomic and functional result. The majority of wounds that have not healed in 3 months are considered chronic, although a duration as low as 4 weeks has been used to indicate chronicity. Skin ulcers, which usually occur in traumatized or vascular compromised soft tis-sue, are also considered chronic in nature, and proportionately are the major component of chronic wounds. In addition to the factors discussed earlier that can delay wound healing, other causative mechanisms may also play a role in the etiology of chronic wounds. Repeated trauma, poor perfusion or oxygen-ation, and/or excessive inflammation contribute to the causation and the perpetuation of the chronicity of wounds.Unresponsiveness to normal regulatory signals also has been implicated as a predictive factor of chronic wounds. This may come about as a failure of normal growth factor synthesis,103 and thus an increased breakdown of growth factors within a wound environment that is markedly proteolytic because of overexpression of protease activity or a failure of the normal antiprotease inhibitor mechanisms.104 Fibroblasts from chronic wounds also have been found to have decreased proliferative potential, perhaps because of senescence105 or decreased expres-sion of growth factor receptors.106 Chronic wounds occur due to various etiologic factors, and several of the most common are discussed later.Brunicardi_Ch09_p0271-p0304.indd 28901/03/19 4:50 PM 290BASIC CONSIDERATIONSPART IMalignant transformation of chronic ulcers can occur in any long-standing wound (Marjolin’s ulcer). Any wound that does not heal for a prolonged period of time is prone to malig-nant transformation. Malignant wounds are differentiated clini-cally from nonmalignant wounds by the presence of overturned wound edges (Fig. 9-10). In patients with suspected malignant transformations, biopsy of the wound edges must be performed to rule out malignancy. Cancers arising de novo in chronic wounds include both squamous and basal cell carcinomas.Ischemic Arterial Ulcers. These wounds occur due to a lack of blood supply and are typically extremely painful in patients with pure ischemic ulcers. They usually are associated with other symptoms of peripheral vascular disease, such as history of intermittent claudication, rest pain, and color or trophic changes. These wounds commonly are present at the most distal portions of the extremities such as the interdigital clefts, although more proxi-mal locations are also encountered. On examination, there may be diminished or absent pulses with decreased ankle-brachial index and poor formation of granulation tissue. Other signs of peripheral ischemia, such as dryness of skin, hair loss, scaling, and pallor can be present. The wound itself usually is shallow with smooth mar-gins, and a pale base and surrounding skin may be present. The management of these wounds is two-pronged and includes revas-cularization and wound care.107 Nonhealing of these wounds is the norm unless successful revascularization is performed. In patients with ischemia and bed confinement, prevention of ulcer devel-opment is extremely important. Removal of restrictive stockings (in patients with critical ischemia), frequent repositioning, and surveillance are vital to preventing these ulcers.108Venous Stasis Ulcers. Although there is unanimous agree-ment that venous ulcers are due to venous stasis and increased venous pressure, there is less consensus as to what are the exact pathophysiologic pathways that lead to ulceration and impaired healing. On the microvascular level, there is alteration and distention of the dermal capillaries with leakage of fibrinogen into the tissues; polymerization of fibrinogen into fibrin cuffs leads to perivascular cuffing that can impede oxygen exchange, thus contributing to ulceration. These same fibrin cuffs and the leakage of macromolecules such as fibrinogen and α2-macroglobulin trap growth factors and impede wound healing.103 Another hypothesis suggests that neutrophils adhere to the cap-illary endothelium and cause plugging with diminished dermal blood flow. Venous hypertension and capillary damage lead to extravasation of hemoglobin. The products of this breakdown are irritating and cause pruritus and skin damage. The result-ing brownish pigmentation of skin combined with the loss of subcutaneous fat produces characteristic changes called lipoder-matosclerosis. Regardless of the pathophysiologic mechanisms, the clinically characteristic picture is that of an ulcer that fails to reepithelialize despite the presence of adequate granulation tis-sue in a patient with skin color changes in the area of ulceration and signs of venous hypertension.Venous stasis occurs due to increased venous hyperten-sion caused by either venous insufficiency or venous outflow obstruction. Venous insufficiency can be due to any combina-tion of deep, superficial, and perforator vein valvular reflux. The higher the ambulatory venous hypertension, the higher the chance of ulceration. Chronic venous ulcers are commonly painless. Stasis ulcers tend to occur at the sites of incompetent Figure 9-10. Typical appearance of the malignant transformation of a long-standing chronic wound. (Used with permission by Dr. Robert S. Kirsner, University of Miami.)Brunicardi_Ch09_p0271-p0304.indd 29001/03/19 4:50 PM 291WOUND HEALINGCHAPTER 9perforators, the most common being above the medial malleo-lus, over Cockett’s perforator. Upon examination, the typical location combined with a history of venous incompetence and other skin changes is diagnostic. The wound usually is shallow with irregular margins and pigmented surrounding skin.The cornerstone of treatment of venous ulcers is compres-sion therapy, although the best method to achieve it remains controversial. Compression can be accomplished via rigid or flexible means. The most commonly used method is the rigid, zinc oxide–impregnated, nonelastic bandage. Others have proposed a four-layered bandage approach as a more optimal method of obtaining graduated compression.109 Wound care in these patients focuses on maintaining a moist wound environ-ment, which can be achieved with hydrocolloids. Other, more modern approaches include use of vasoactive substances and growth factor application, as well as the use of skin substitutes. Recently, sprayed allogeneic keratinocytes and fibroblasts plus four-layer bandages have been shown to hasten healing when compared to compression alone.110 Addressing the causes of venous hypertension aids in the healing of venous ulcers.109 Unfortunately, recurrences are frequent despite preventative measures, largely because of patients’ lack of compliance.111Diabetic Wounds. Ten percent to 25% of diabetic patients run the risk of developing ulcers. There are approximately 50,000 to 60,000 amputations performed in diabetic patients each year in the United States. The major contributors to the formation of diabetic ulcers include neuropathy, foot deformity, and isch-emia. It is estimated that 60% to 70% of diabetic ulcers are due to neuropathy, 15% to 20% are due to ischemia, and another 15% to 20% are due to a combination of both. The neuropathy is both sensory and motor and is secondary to persistently elevated glucose levels. The loss of sensory function allows unrecognized injury to occur from ill-fitting shoes, foreign bodies, or other trauma. The motor neuropathy or Charcot’s foot leads to col-lapse or dislocation of the interphalangeal or metatarsophalan-geal joints, causing pressure on areas with little protection. There is also severe microand macrovascular circulatory impairment.Once ulceration occurs, the chances of healing are poor and the chances of recurrent ulceration are high. The treatment of diabetic wounds involves local and systemic measures.112 Achievement of adequate blood sugar levels is very impor-tant. Most diabetic wounds are infected, and eradication of the infectious source is paramount to the success of healing. Treatment should address the possible presence of osteomyeli-tis and should employ antibiotics that achieve adequate levels both in soft tissue and bone. Wide debridement of all necrotic or infected tissue is another cornerstone of treatment. Offloading of the ulcerated area by using specialized orthotic shoes or casts allows for ambulation while protecting the fragile wound environment. Topical application of PDGF and granulocyte-macrophage colony-stimulating factor has met with limited but significant success in achieving closure.113 The application of engineered skin allograft substitutes, although expensive, also has shown some significant success.114 Preven-tion and specifically foot care play an important role in the man-agement of diabetics.115Decubitus or Pressure Ulcers. The incidence of pressure ulcers ranges from 2.7% to 9% in the acute care setting, in com-parison to 2.4% to 23% in long-term care facilities. A pressure ulcer is a localized area of tissue necrosis that develops when soft tissue is compressed between a bony prominence and an external surface. Excessive pressure causes capillary collapse and impedes the delivery of nutrients to body tissues. Pressure ulcer formation is accelerated in the presence of friction, shear forces, and moisture. Other contributory factors in the patho-genesis of pressure ulcers include immobility, altered activity levels, altered mental status, chronic conditions, and altered nutritional status. The four stages of pressure ulcer formation are as follows: stage I, no blanching erythema of intact skin; stage II, partial-thickness skin loss involving epidermis or der-mis or both; stage III, full-thickness skin loss, but not through the fascia; and stage IV, full-thickness skin loss with extensive involvement of muscle and bone.The treatment of established pressure ulcers is most suc-cessful when carried out in a multidisciplinary manner by involving wound care teams consisting of physicians, nurses, dietitians, physical therapists, and nutritionists. Care of the ulcer itself comprises debridement of all necrotic tissue, maintenance of a favorable moist wound environment that will facilitate healing, relief of pressure, and addressing host issues such as nutritional, metabolic, and circulatory status. Debridement is most efficiently carried out surgically, but enzymatic proteo-lytic preparations and hydrotherapy also are used. The wound bed should be kept moist by employing dressings that absorb secretions but do not desiccate the wound.116 Operative repair, usually involving flap rotation, has been found to be useful in obtaining closure. Unfortunately, recurrence rates are extremely high, owing to the population at risk and the inability to fully address the causative mechanisms.117EXCESS HEALING Clinically, excess healing can be as significant as delayed or nonhealing. It is likely that more operative interventions are required for correction of the morbidity associated with excessive healing than are required for wound failure. The clinical manifestations of exuberant healing are protean and dif-fer in the skin (mutilating or debilitating scars, burn contrac-tions), tendons (frozen repairs), the GI tract (strictures or stenoses), solid organs (cirrhosis, pulmonary fibrosis), or the peritoneal cavity (adhesive disease).Hypertrophic scars (HTSs) and keloids represent an over-abundance of fibroplasia in the dermal healing process. HTSs rise above the skin level but stay within the confines of the origi-nal wound and often regress over time. Keloids rise above the skin level as well, but they extend beyond the border of the original wound and rarely regress spontaneously (Fig. 9-11). Both HTSs and keloids occur after trauma to the skin and may be tender, pruritic, and cause a burning sensation. Keloids are 15 times more common in darker-pigmented ethnicities, with individuals of African, Spanish, and Asian ethnicities being especially susceptible. Men and women are equally affected. Genetically, the predilection to keloid formation appears to be autosomal dominant with incomplete penetration and variable expression.117,118HTSs usually develop within 4 weeks after trauma. The risk of HTS increases if epithelialization takes longer than 21 days, independent of site, age, and race. Rarely elevated more than 4 mm above the skin level, HTSs stay within the boundaries of the wound. They usually occur across areas of tension and flexor surfaces, which tend to be at right angles to joints or skin creases. The lesions are initially erythematous and raised and over time may evolve into pale, flatter scars.4Brunicardi_Ch09_p0271-p0304.indd 29101/03/19 4:50 PM 292BASIC CONSIDERATIONSPART IKeloids can result from surgery, burns, skin inflamma-tion, acne, chickenpox, zoster, folliculitis, lacerations, abrasions, tattoos, vaccinations, injections, insect bites, or ear piercing, or may arise spontaneously. Keloids tend to occur 3 months to years after the initial insult, and even minor injuries can result in large lesions. They vary in size from a few millimeters to large, pedun-culated lesions with a soft to rubbery or hard consistency. While they project above surrounding skin, they rarely extend into underlying subcutaneous tissues. Certain body sites have a higher incidence of keloid formation, including the skin of the earlobe as well as the deltoid, presternal, and upper back regions. They rarely occur on eyelids, genitalia, palms, soles, or across joints. Keloids rarely involute spontaneously, and surgical intervention can lead to recurrence, often with a worse result (Table 9-8).Histologically, both HTSs and keloids demonstrate increased thickness of the epidermis with an absence of rete ridges. There is an abundance of collagen and glycoprotein deposition. Normal skin has distinct collagen bundles, mostly parallel to the epithelial surface, with random connections between bundles by fine fibrillar strands of collagen. In HTS, the collagen bundles are flatter and more random, and the fibers are in a wavy pattern. In keloids, the collagen bundles are virtu-ally nonexistent, and the fibers are connected haphazardly in loose sheets with a random orientation to the epithelium. The collagen fibers are larger and thicker, and myofibroblasts are generally absent.119Keloidal fibroblasts have normal proliferation param-eters but synthesize collagen at a rate 20 times greater than that observed in normal dermal fibroblasts, and 3 times higher than fibroblasts derived from HTS. Abnormal amounts of extracel-lular matrix such as fibronectin, elastin, and proteoglycans also are produced. The synthesis of fibronectin, which promotes clot generation, granulation tissue formation, and reepithelializa-tion, decreases during the normal healing process; however, production continues at high levels for months to years in HTSs and keloids. This perturbed synthetic activity is mediated by altered growth factor expression. TGF-β expression is higher in HTS, and both HTSand keloid-derived fibroblasts respond to lower concentrations of TGF-β than do normal dermal fibro-blasts. HTSs also express increased levels of insulin-like growth factor-1, which reduces collagenase mRNA activity and increases mRNA for types I and II procollagen.120 Keloid fibroblasts have enhanced expression of TGF-β1 and TGF-β2, VEGF, and plasminogen activator inhibitor-1 and an increased number of PDGF receptors; they also have upregulated anti-apoptotic gene expression, which can be differentially expressed within different areas of the same scar.The underlying mechanisms that cause HTSs and keloids are not known. The immune system appears to be involved in the formation of both HTSs and keloids, although the exact relationship is unknown. Much is inferred from the presence of various immune cells in HTSs and keloids. For example, in both HTSs and keloids, keratinocytes express human leuko-cyte antigen (HLA)-2 and ICAM-1 receptors, which are absent Figure 9-11. Recurrent keloid on the neck of a 17-year-old patient that had been revised several times. (Reproduced with permission from Cohen IK, Diegelmann RF, Lindblad WJ: Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA: WB Saunders/ Elsevier; 1992.)Table 9-8Characteristics of keloids and hypertrophic scars KELOIDHYPERTROPHIC SCARIncidenceRareFrequentEthnic groupsAfrican American, Asian, HispanicNo predilectionPrior injuryYesYesSite predilectionNeck, chest, ear lobes, shoulders, upper backAnywhereGeneticsAutosomal dominant with incomplete penetrationNoTimingSymptom-free interval; may appear years after injury4–6 weeks post injurySymptomsPain, pruritus, hyperesthesia, growth beyond wound marginsRaised, some pruritus, respects wound confinesRegressionNoFrequent spontaneousContractureRareFrequentHistologyHypocellular, thick, wavy collagen fibers in random orientationParallel orientation of collagen fibersBrunicardi_Ch09_p0271-p0304.indd 29201/03/19 4:50 PM 293WOUND HEALINGCHAPTER 9in normal scar keratinocytes. Keloids also have increased deposition of immunoglobulins IgG, IgA, and IgM, and their formation correlates with serum levels of IgE. Antinuclear antibodies against fibroblasts, epithelial cells, and endothelial cells are found in keloids, but not HTSs. HTSs have higher T lymphocyte and Langerhans cell contents. There is also a larger number of mast cells present in both HTSs and keloids compared to normal scars. Another recently described cell pop-ulation is the fibrocyte, a leukocyte subpopulation derived from peripheral mononuclear cells. Present in large numbers at the site of excess scarring, fibrocytes can stimulate fibroblast num-bers and collagen synthesis. They also generate large numbers of cytokines, growth factors, and extracellular matrix proteins, which are characteristically upregulated in keloid tissue. Other mechanisms that may cause abnormal scarring include mechani-cal tension (although keloids often occur in areas of minimal tension) and prolonged irritation and/or inflammation that may lead to the generation of abnormal concentrations of profibrotic cytokines.Treatment goals for keloid and HTS include restoration of function to the area, relief of symptoms, and prevention of recurrence. Many patients seek intervention due to cosmetic concerns. Because the underlying mechanisms causing keloids and HTSs remain unknown, many different modalities of treat-ment have been used without consistent success.121Excision alone of keloids is subject to a high recurrence rate, ranging from 45% to 100%. Inclusion of the dermal advancing edge that characterizes keloids, use of incisions in skin tension lines, and tension-free closure all have been pro-posed to decrease recurrence rates. There are fewer recurrences when surgical excision is combined with other modalities such as intralesional corticosteroid injection, topical application of silicone sheets, or the use of radiation or pressure. Surgery is recommended for debulking large lesions or as second-line therapy when other modalities have failed. Silicone application is relatively painless and should be maintained for 24 hours a day for about 3 months to prevent rebound hypertrophy. It may be secured with tape or worn beneath a pressure garment. The mechanism of action is not understood, but increased hydration of the skin, which decreases capillary activity, inflammation, hyperemia, and collagen deposition, may be involved. Silicone is more effective than other occlusive dressings and is an espe-cially good treatment for children and others who cannot toler-ate the pain involved in other modalities.102Intralesional corticosteroid injections decrease fibroblast proliferation, collagen and glycosaminoglycan synthesis, the inflammatory process, and TGF-β levels. When used alone, however, there is a variable rate of response and recurrence; therefore, steroids are recommended as first-line treatment for keloids and second-line treatment for HTSs if topical thera-pies have failed. Intralesional injections are more effective on younger scars. They may soften, flatten, and give symptomatic relief to keloids, but they cannot make the lesions disappear, and they cannot narrow wide HTSs. Success is enhanced when used in combination with surgical excision. Serial injections every 2 to 3 weeks are required. Complications include skin atrophy, hypopigmentation, telangiectasias, necrosis, and ulceration.Although radiation destroys fibroblasts, it has variable, unreliable results and produces poor results, with 10% to 100% recurrence when used alone. It is more effective when combined with surgical excision. The timing, duration, and dosage for radiation therapy are still controversial, but doses ranging from 1500 to 2000 rads appear effective. Given the risks of hyperpig-mentation, pruritus, erythema, paresthesias, pain, and possible secondary malignancies, radiation should be reserved for adults with scars resistant to other modalities.Pressure aids collagen maturation, flattens scars, and improves thinning and pliability. It reduces the number of cells in a given area, possibly by creating ischemia, which decreases tissue metabolism and increases collagenase activity. External compression is used to treat HTSs, especially after burns. Ther-apy must begin early, and a pressure between 24 and 30 mmHg must be achieved in order to exceed capillary pressure, yet pre-serve peripheral blood circulation. Garments should be worn for 23 to 24 hours a day for up to 1 or more years to avoid rebound hypertrophy. Scars older than 6 to 12 months respond poorly.Topical retinoids also have been used as treatment for both HTSs and keloids, with reported responses of 50% to 100%. Intralesional injections of IFN-γ, a cytokine released by T lymphocytes, reduce collagen types I, II, and III by decreasing mRNA and possibly by reducing levels of TGF-β. As mono-therapy, IFN-γ has failed because of high recurrence rates due to resistance to repeated injections. More recently, imiquimod, an immunomodulator that induces IFN-γ and other cytokines at the site of application, has been recommended following exci-sion. Intralesional injections of chemotherapeutic agents such as 5-fluorouracil have been used both alone and in combina-tion with steroids. The use of bleomycin or mitomycin C has been reported to achieve some success in older scars resistant to steroids.Peritoneal Scarring. Peritoneal adhesions are fibrous bands of tissues formed between organs that are normally separated and/or between organs and the internal body wall. Most intra-abdominal adhesions are a result of peritoneal injury, either by a prior surgical procedure or due to intra-abdominal infection. Postmortem examinations demonstrate adhesions in 67% of patients with prior surgical procedures and in 28% with a history of intra-abdominal infection. Intra-abdominal adhesions are the most common cause (65%–75%) of small bowel obstruction, especially in the ileum. Operations in the lower abdomen have a higher chance of producing small bowel obstruction. Follow-ing rectal surgery, left colectomy, or total colectomy, there is an 11% chance of developing small bowel obstruction within 1 year, and this rate increases to 30% by 10 years. Adhesions also are a leading cause of secondary infertility in women and can cause substantial abdominal and pelvic pain. Adhesions account for 2% of all surgical admissions and 3% of all lapa-rotomies in general surgery.122Adhesions form when the peritoneal surface is damaged due to surgery, thermal or ischemic injury, inflammation, or foreign body reaction. The injury disrupts the protective meso-thelial cell layer lining the peritoneal cavity and the underlying connective tissue. The injury elicits an inflammatory response consisting of hyperemia, fluid exudation, release, and activation of white blood cells and platelets in the peritoneal cavity, activa-tion of inflammatory cytokines, and the onset of the coagulation and complement cascades. Fibrin deposition occurs between the damaged but opposed serosal surfaces. These filmy adhesions often are transient and degraded by proteases of the fibrinolytic system, with restoration of the normal peritoneal surface. If insufficient fibrinolytic activity is present, permanent fibrous adhesions will form by collagen deposition within 1 week of the injury (Fig. 9-12).Brunicardi_Ch09_p0271-p0304.indd 29301/03/19 4:50 PM 294BASIC CONSIDERATIONSPART IExtensive research has been done on the effect of surgery and peritonitis on the fibrinolytic and inflammatory cascades within the peritoneal cavity. During normal repair, fibrin is prin-cipally degraded by the fibrinolytic protease plasmin, which is derived from inactive plasminogen through the action of two plasminogen activators (PA): tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Fibrino-lytic activity in peritoneal fluid is reduced after abdominal sur-gery due to initial decreases in tPA levels and later to increases in plasminogen activator inhibitor-1 (PAI-1), which are induced by various cytokines, including TNF-α, IL-1, and interleukin-6 (IL-6).123There are two major strategies for adhesion prevention or reduction. Surgical trauma is minimized within the peritoneum by careful tissue handling, avoiding desiccation and ischemia, and spare use of cautery, laser, and retractors. Fewer adhesions form with laparoscopic surgical techniques due to reduced tis-sue trauma. The second major advance in adhesion prevention has been the introduction of barrier membranes and gels, which separate and create barriers between damaged mesothelial sur-faces, allowing for adhesion-free healing. Currently, only three products are Food and Drug Administration (FDA) approved for reducing adhesion formation: Interceed (oxidized regen-erated cellulose, indicated only in pelvic surgery), Seprafilm (a film composed of hyaluronic acid and carboxymethylcel-lulose) that is usually applied below the incision, and Adept (4% icodextrin, a corn starch derivative in electrolyte solution, also for use mainly in pelvic surgery). However, use of these substances directly over bowel anastomoses is contraindicated due to an elevated risk of leak.124 There have been innumerable studies investigating different molecules in hopes of preventing adhesion formation, but most of the success is limited to animal models, and clinically significant results in humans have yet to be achieved.TREATMENT OF WOUNDSLocal Care (Fig. 9-13)Management of acute wounds begins with obtaining a careful history of the events surrounding the injury. The history is fol-lowed by a meticulous examination of the wound. Examination should assess the depth and configuration of the wound, the extent of nonviable tissue, and the presence of foreign bodies and other contaminants. The wound/ulcer should be described based on location, dimensions, presence of infection, drainage and type of drainage, base characteristics, presence or absence of necrosis, presence of pain, and description of edges. Possible etiology should be mentioned, and the presence of sys-temic factors and circulation should be evaluated.After completion of the history, examination, and admin-istration of tetanus prophylaxis, the wound should be meticu-lously anesthetized. Lidocaine (0.5%–1%) or bupivacaine (0.25%–0.5%) combined with a 1:100,000 to 1:200,000 dilution of epinephrine provides satisfactory anesthesia and hemostasis. 5ThrombinCoagulationFibrinogenPeritoneal fluidInflammationFibrin++PAI-1, PAI-2tPA, uPAFibrin residuesFibrinolysisFibrinolysisdegradationRestitutionFibroblasts and capillariesFibrous adhesionPeritoneal injuryBleedingMacrophagesmesotheliumPlateletsTFFigure 9-12. Fibrin formation and degradation in peritoneal tis-sue repair and adhesion formation. PAI-1, PAI-2 = types 1 and 2 plasminogen activator inhibitor; TF = tissue factor; tPA = tissue plasminogen activator; uPA = urokinase plasminogen activator.Figure 9-13. Algorithm for management of acute wounds.Management of Acute Wounds1. Examinationa) Depth? Underlying structures injuredb) Configuration?c) Nonviable tissue?4. Follow-upa) Cellulitis/drainage?b) Suture removal -4–5 days for face -7–10 days other skin3. Approximationa) Deep layers -Fascial layers only -Absorbable sutureb) Superficial layers -Meticulous alignment -Nonabsorbable sutures in skin -Staples -Monofilament -Dermal glues2. Preparationa) Anesthetic -Lidocaine w or w/o epinephrineb) Exploration -Underlying structures injuredc) Cleansing -Pulsed irrigation, saline onlyd) Hemostasise) Debride nonviable tissuef) Betadine on surrounding sking) Antibiotics (rare)h) TetanusBrunicardi_Ch09_p0271-p0304.indd 29401/03/19 4:50 PM 295WOUND HEALINGCHAPTER 9Epinephrine should not be used in wounds of the fingers, toes, ears, nose, or penis, due to the risk of tissue necrosis secondary to terminal arteriole vasospasm in these structures.Irrigation to visualize all areas of the wound and remove foreign material is best accomplished with normal saline (with-out additives). High-pressure wound irrigation is more effective in achieving complete debridement of foreign material and non-viable tissues. Iodine, povidone-iodine, hydrogen peroxide, and organically based antibacterial preparations have all been shown to impair wound healing due to injury to wound neutrophils and macrophages, and thus should not be used. All hematomas present within wounds should be carefully evacuated and any remaining bleeding sources controlled with ligature or cautery. If the injury has resulted in the formation of a marginally viable flap of skin or tissue, this should be resected or revascularized prior to further wound repair and closure.After the wound has been anesthetized, explored, irri-gated, and debrided, the area surrounding the wound should be cleaned, inspected, and the surrounding hair clipped. The area surrounding the wound should be prepared with povi-done iodine, chlorhexidine, or similar bacteriostatic solutions and draped with sterile towels. Having ensured hemostasis and adequate debridement of nonviable tissues and removal of any remaining foreign bodies, irregular, macerated, or beveled wound edges should be debrided in order to provide a fresh edge for reapproximation. Although plastic surgical techniques such as Wor Z-plasty are seldom recommended for acute wounds, great care must be taken to realign wound edges properly. This is particularly important for wounds that cross the vermilion border, eyebrow, or hairline. Initial sutures that realign the edges of these different tissue types will speed and greatly enhance the aesthetic outcome of the wound repair.In general, the smallest suture required to hold the vari-ous layers of the wound in approximation should be selected in order to minimize suture-related inflammation. Nonabsorbable or slowly absorbing monofilament sutures are most suitable for approximating deep fascial layers, particularly in the abdomi-nal wall. Subcutaneous tissues should be closed with braided absorbable sutures, with care to avoid placement of sutures in fat. Multiple layer closure of the abdominal wall is preferable. However, additional layers with sutures might increase the risk of wound infection.In areas of significant tissue loss, rotation of adjacent mus-culocutaneous flaps or free flaps may be required to provide sufficient tissue mass for closure. In cases of significant superfi-cial tissue loss, split-thickness skin grafting (placed in a delayed manner to assure an adequate tissue bed) may be required and will speed formation of an intact epithelial barrier to fluid loss and infection. In acute, contaminated wounds with skin loss, use of porcine skin xenografts or skin cadaveric allografts might be needed to avoid infection.After closing deep tissues and replacing significant tissue deficits, skin edges should be reapproximated for cosmesis and to aid in rapid wound healing. Skin edges may be quickly reap-proximated with stainless steel staples or nonabsorbable mono-filament sutures. Care must be taken to remove these from the wound prior to epithelialization of the skin tracts where sutures or staples penetrate the dermal layer. Failure to remove the sutures or staples prior to 7 to 10 days after repair will result in a cosmetically inferior wound. Where wound cosmesis is impor-tant, the aforementioned problems may be avoided by place-ment of buried dermal sutures using absorbable braided sutures. This method of wound closure allows for a precise reapproxi-mation of wound edges and may be enhanced by application of wound closure tapes to the surface of the wound. Intradermal absorbable sutures do not require removal.The development of octyl-cyanoacrylate tissue glues has shown good results for the management of simple, linear wounds with viable skin edges. These new glues are less prone to brittleness and have superior burst-strength characteristics. Studies have shown them to be suitable for use in contaminated situations without significant risk of infection. When used in the previously mentioned types of wounds, these glues appear to provide superb cosmetic results and result in significantly less trauma than sutured repair, particularly when used in pediatric patients.AntibioticsAntibiotics should be used only when there is an obvious wound infection. Most wounds are contaminated or colonized with bacteria. The presence of a host response constitutes an infection and justifies the use of antibiotics. Signs of infec-tion to look for include erythema, cellulitis, swelling, and puru-lent discharge. Indiscriminate use of antibiotics should be avoided to prevent emergence of multidrug-resistant bacteria.Antibiotic treatment of acute wounds must be based on organisms suspected to be found within the infected wound and the patient’s overall immune status. When a single specific organism is suspected, treatment may be commenced using a single antibiotic. Conversely, when multiple organisms are suspected, as with enteric contamination or when a patient’s immune function is impaired by diabetes, chronic disease, or medication, treatment should commence with a broad-spectrum antibiotic or several agents in combination. Antibiotics also can be delivered topically as part of irrigations or dressings, although their efficacy is questionable.DressingsThe main purpose of wound dressings is to provide the ideal envi-ronment for wound healing. The dressing should facilitate the major changes taking place during healing to produce an opti-mally healed wound. Although the ideal dressing still is not a clinical reality, technological advances are promising (Table 9-9).Dressings should take into account the type of wound and the comorbid conditions and associated factors such as edema and circulation. In patients with edema, dressing should compress the edematous area to aid in healing. In patients with significant circulation compromise, a compressing dress-ing should be avoided. The dressing should maintain 67Table 9-9Desired characteristics of wound dressingsPromote wound healing (maintain moist environment)ConformabilityPain controlOdor controlNonallergenic and nonirritatingPermeability to gasSafetyNontraumatic removalCost-effectivenessConvenienceBrunicardi_Ch09_p0271-p0304.indd 29501/03/19 4:50 PM 296BASIC CONSIDERATIONSPART Ian adequate moist environment but should help absorption excessive drainage. Occlusion of a wound with dressing mate-rial helps healing by controlling the level of hydration and oxy-gen tension within the wound. It also allows transfer of gases and water vapor from the wound surface to the atmosphere. Occlusion affects both the dermis and epidermis, and it has been shown that exposed wounds are more inflamed and develop more necrosis than covered wounds. Occlusion also helps in dermal collagen synthesis and epithelial cell migration and lim-its tissue desiccation. Since it may enhance bacterial growth, occlusion is contraindicated in infected and/or highly exudative wounds.Dressings can be classified as primary or secondary. A pri-mary dressing is placed directly on the wound and may provide absorption of fluids and prevent desiccation, infection, and adhe-sion of a secondary dressing. A secondary dressing is one that is placed on the primary dressing for further protection, absorption, compression, and occlusion. Although the ideal dressing does not exist, many types of dressings help achieve certain goals, so knowledge of the wound and the dressing function is essential to make it possible to choose the appropriate dressing.Absorbent Dressings. This type of dressing helps con-trol exudate without soaking through the dressing, which can increase infection potential.Nonadherent Dressings. Nonadherent dressings are impreg-nated with paraffin, petroleum jelly, or water-soluble jelly for use as nonadherent coverage. A secondary dressing must be placed on top to seal the edges and prevent desiccation and infection.Occlusive and Semiocclusive Dressings. Occlusive and semiocclusive dressings provide a good environment for clean, minimally exudative wounds. These film dressings are water-proof and impervious to microbes but permeable to water vapor and oxygen.Hydrophilic and Hydrophobic Dressings. These dressings are components of a composite dressing. Hydrophilic dressing aids in absorption, whereas a hydrophobic dressing is water-proof and prevents absorption.Hydrocolloid and Hydrogel Dressings. Hydrocolloid and hydrogel dressings attempt to combine the benefits of occlusion and absorbency. Hydrocolloids and hydrogels form complex structures with water, and fluid absorption occurs with particle swelling, which aids in atraumatic removal of the dressing. Absorption of exudates by the hydrocolloid dressing leaves a yellowish-brown gelatinous mass after dressing removal that can be washed off. Hydrogel is a cross-linked polymer that has high water content. Hydrogels allow a high rate of evaporation without compromising wound hydration, which makes them useful in burn wound treatment.Alginates. Alginates are derived from brown algae and con-tain long chains of polysaccharides containing mannuronic and glucuronic acid. The ratios of these sugars vary with the species of algae used, as well as the season of harvest. Processed as the calcium forms, alginates turn into soluble sodium alginate through ion exchange in the presence of wound exudates. The polymers gel, swell, and absorb a great deal of fluid. Alginates are being used when there is skin loss, in open surgical wounds with medium exudation, and on full-thickness chronic wounds. Alginate widely used as primary dressing and can be reinforced with other forms of dressing such as compression dressing.Absorbable Materials. Absorbable materials are mainly used within wounds as hemostats and include collagen, gelatin, oxi-dized cellulose, and oxidized regenerated cellulose.Medicated Dressings. Medicated dressings have long been used as a drug-delivery system. Agents delivered in the dress-ings include benzoyl peroxide, zinc oxide, neomycin, and bacitracin-zinc. These agents have been shown to increase epi-thelialization by 28%.The type of dressing to be used depends on the amount of wound drainage. A nondraining wound can be covered with semiocclusive dressing. Drainage of less than 1 to 2 mL/d may require a semiocclusive or absorbent nonadherent dressing. Moderately draining wounds (3–5 mL/d) can be dressed with a nonadherent primary layer plus an absorbent secondary layer plus an occlusive dressing to protect normal tissue. Heavily draining wounds (>5 mL/d) require a similar dressing as mod-erately draining wounds, but with the addition of a highly absor-bent secondary layer.Mechanical Devices. Mechanical therapy augments and improves on certain functions of dressings, in particular the absorption of exudates and control of odor. The negative pres-sure dressing systems assists in wound closure by applying localized negative pressure to the surface and margins of the wound. The negative-pressure therapy is applied to a special foam dressing cut to the dimensions of the wound and posi-tioned in the wound cavity or over a flap or graft. The continu-ous negative pressure is very effective in removing exudates from the wound. This form of therapy has been found to be effective for chronic open wounds (diabetic ulcers and stages III and IV pressure ulcers), acute and traumatic wounds,125 flaps and grafts, and subacute wounds (i.e., dehisced incisions), although more randomized trials need to be carried out to con-firm efficacy. Different types of sponges are available to use on wounds with negative pressure systems.Skin ReplacementsAll wounds require coverage in order to prevent evaporative losses and infection and to provide an environment that pro-motes healing. Both acute and chronic wounds may demand use of skin replacement, and several options are available.Conventional Skin Grafts. Skin grafts have long been used to treat both acute and chronic wounds. Split(partial-) thickness grafts consist of the epidermis plus part of the dermis, whereas full-thickness grafts retain the entire epidermis and dermis. Autologous grafts (autografts) are transplants from one site on the body to another; allogeneic grafts (allografts, homografts) are transplants from a living nonidentical donor or cadaver to the host; and xenogeneic grafts (heterografts) are taken from another species (e.g., porcine). Split-thickness grafts require less blood supply to restore skin function. The dermal component of full-thickness grafts lends mechanical strength and resists wound contraction better, resulting in improved cosmesis. Allo-geneic and xenogeneic grafts require the availability of tissue, are subject to rejection, and may contain pathogens.The use of skin grafts or bioengineered skin substitutes and other innovative treatments (e.g., topically applied growth factors, systemic agents, and gene therapy) cannot be effec-tive unless the wound bed is adequately prepared. This may include debridement to remove necrotic or fibrinous tissue, control of edema, revascularization of the wound bed, reduc-tion in the bacterial burden, with minimal exudate. Temporary Brunicardi_Ch09_p0271-p0304.indd 29601/03/19 4:50 PM 297WOUND HEALINGCHAPTER 9placement of allografts or xenografts may be used to prepare the wound bed.Cellular and Tissue-Based Products in Chronic Wound and Ulcer ManagementWound management and ulcer healing are among the most chal-lenging problems in medical practices. The lack of large clini-cal trials, the heterogeneity of wound causes, and mechanisms of chronicity add to the complexity of wound management. In most cases, management is based on the experi-ence of the providers and the availability of the treatment modalities within the health facilities. In spite of advances in wound care, the basic principles of wound management remain to be essential to healing. Additional measures and products might accelerate the rate of healing but will not replace basic wound care. The basic principles include achieving optimal blood flow, control of infection, removal of debris, proper dress-ing, offloading the injured area, and compression therapy in certain cases. Once these basic principles have been achieved, advanced treatment modalities such as cellular and tissue-based products (CTP) can be considered for enhanced healing. CTPs presumably act by altering the biology of wounds and ulcers or by preparing the wound/ulcer bed for healing and other potential procedures. CTPs are divided into two categories: dermoindu-cive and democonductive.126 As the name indicates, dermoindu-cive products help provide cells and factors that will activate healing within the wound by inducing tissue growth or inducing granulation within the wound. Such products include Apligraph (Organogenesis, Canton, MA), Theraskin (Soluble systems, LLC, Newport News, VA), and Dermagraft (Organogenesis Canton, MA). None of these products have achieved healing in all wounds, but generally they have improved the percentage of healing, or achieved healing over a shorter period of time. In a pivotal Apligraf study, for example, it was found that patients who received Apligraf achieved 56% healing over 65 days com-pared to 38% healing over 90 days in those who received saline dressing.127 On the other hand, the dermoconductive products provide scaffolding to a wound ending in a neodermis by allow-ing migration of surrounding tissues across the wound, and this helps healing. An example of such products is Integra, which is composed of type 1 bovine collagen, shark chrondroitin 6-sulfate, and a silicone layer and helps to prepare the wound bed for subsequent skin grafting.128 In our experience, we use Integra for wound bed preparation in superficial wounds but also, in some cases, in deeper wounds. In addition, we also use it to cover exposed bone, especially smaller areas and tendons; how-ever, it might require more than one application in some cases to achieve optimal wound bed preparation. In a systematic review of the literature, the authors reviewed 15 randomized trials, one prospective comparative study, and five systematic reviews. The authors concluded that living cell-based skin sub-stitutes have a convincing supportive body of evidence in wound healing with some promise for acellular skin substitutes.129 In their review, the authors indicated that the evidence they based their review on was of low quality. Stem cell–based therapy is gaining more traction in the management of difficult wounds. Although it was initially used as an attempt to achieve scarless healing, stem cell therapy has gained more popularity in recent years as a means for enhanced healing and skin regeneration, in addition to reduction of scar formation. Similar to other fields, stem cells in wound healing produce growth factors and che-mokines that can differentiate into different cells and tissues. Stem cells in wound healing are mostly derived from human amniotic membrane of placental tissue. Examples of such prod-ucts include Epiphex (MiMedx Group Inc, Marietta CA) and Grafix (Osirix Therapeutics Inc, Columbia, MD), among others. It is believed that the growth factors in the amniotic membranes are preserved through different processes, thus assisting with wound healing. Multiple growth factors derived from the amni-otic membrane are thought to contribute to wound healing, including vascular endothelia growth factor, platelet-derived growth factor, epidermal growth factor, transforming growth factor, and others.130,131 A significant drawback of such products is that they are extremely expensive. Furthermore, it is recom-mended that these products should be used weekly to achieve optimal healing, which adds to the cost of using such products.Originally, these products were devised to provide cover-age of extensive wounds because of the limited availability of autografts, which remains the ideal tissue coverage. However, CTPs have now gained acceptance as natural dressings. Manu-factured by tissue engineering, they combine novel materials with living cells to provide functional skin substitutes, providing a bridge between dressings and skin grafts.Skin substitutes have the theoretical advantages of being readily available and not requiring painful harvests like in skin grafts, and they may be applied freely or with surgical sutur-ing. In addition, they promote healing, either by stimulating host cytokine generation or by providing cells that may also produce growth factors locally. Their disadvantages include limited sur-vival, high cost, and the need for multiple applications (Table 9-10). Allografting, albeit with a very thin graft, may at times be required to accomplish complete coverage.A variety of skin substitutes are available, each with its own set of advantages and disadvantages; however, the ideal skin substitute has yet to be developed (Table 9-11). The devel-opment of the newer composite substitutes, which provide both the dermal and epidermal components essential for permanent skin replacement, may represent an advance toward that goal.Cultured epithelial autografts (CEAs) represent expanded autologous or homologous keratinocytes. CEAs are expanded from a biopsy of the patient’s own skin, will not be rejected, and can stimulate reepithelialization as well as the growth of underlying connective tissue. Keratinocytes harvested from a biopsy roughly the size of a postage stamp are cultured with fibroblasts and growth factors and grown into sheets that can cover large areas and give the appearance of normal skin. Until the epithelial sheets are sufficiently expanded, the wound must be covered with an occlusive dressing or a temporary allograft or xenograft. The dermis regenerates very slowly, if at all, for full-thickness wounds because the sheets are very fragile, are difficult to work with, are susceptible to infection, and do not resist contracture well, leading to poor cosmetic results.8Table 9-10Desired features of tissue-engineered skinRapid reestablishment of functional skin (epidermis/dermis)Receptive to body’s own cells (e.g., rapid “take” and integration)Graftable by a single, simple procedureGraftable on chronic or acute woundsEngraftment without use of extraordinary clinical intervention (i.e., immunosuppression)Brunicardi_Ch09_p0271-p0304.indd 29701/03/19 4:50 PM 298BASIC CONSIDERATIONSPART ICEAs are available from cadavers, unrelated adult donors, or neonatal foreskins. Fresh or cryopreserved cultured alloge-neic keratinocytes can be left in place long enough to be super-seded by multiplying endogenous skin cells because, unlike allografts containing epidermal Langerhans cells, they do not express major histocompatibility antigens. Cryopreserved CEAs are readily available “off the shelf,” and provide growth factors that may aid healing. However, like autologous keratinocyte sheets, the grafts lack the strength provided by a dermal compo-nent and pose a risk of disease transmission.Viable fibroblasts can be grown on bioabsorbable or non-bioabsorbable meshes to yield living dermal tissue that can act as a scaffold for epidermal growth. Fibroblasts stimulated by growth factors can produce type I collagen and glycosamino-glycans (e.g., chondroitin sulfates), which adhere to the wound surface to permit epithelial cell migration, as well as adhesive ligands (e.g., the matrix protein fibronectin), which promote cell adhesion. This approach has the virtue of being less timeconsuming and expensive than culturing keratinocyte sheets. There are a number of commercially available, bioengineered dermal replacements approved for use in burn wound treatment as well as other indications.Bioengineered skin substitutes have evolved from kera-tinocyte monolayers to dermal equivalents to split-thickness products with a pseudo-epidermis, and most recently, to prod-ucts containing both epidermal and dermal components that resemble the three-dimensional structure and function of nor-mal skin (see Table 9-11). Indicated for use with standard com-pression therapy in the treatment of venous insufficiency ulcers and for the treatment of neuropathic diabetic foot ulcers, these bilayered skin equivalents also are being used in a variety of wound care settings.Growth Factor Therapy. As discussed previously, it is believed that nonhealing wounds result from insufficient or inadequate growth factors in the wound environment. A simplistic solu-tion would be to flood the wound with single or multiple growth factors in order to “jump-start” healing and reepithelialization. Although there is a large body of work demonstrating the effects of growth factors in animals, translation of these data into clinical practice has met with limited success. Growth factors for clinical use may be either recombinant or homologous/autologous. Autol-ogous growth factors are harvested from the patient’s own plate-lets, yielding an unpredictable combination and concentration of factors, which are then applied to the wound. This approach allows treatment with patient-specific factors at an apparently physiologic ratio of growth factor concentrations. Disappoint-ingly, a recent meta-analysis failed to demonstrate any value for autologous platelet-rich plasma in the treatment of chronic wounds.132 Recombinant molecular biologic means permit the purification of high concentrations of individual growth factors. Current FDA-approved formulations, as well as those used exper-imentally, deliver concentrations approximately 103 times higher than those observed physiologically.At present, only platelet-derived growth factor BB (PDGF-BB) is currently approved by the FDA for treatment of diabetic foot ulcers. Application of recombinant human PDGF-BB in a gel suspension to these wounds increases the incidence of total healing and decreases healing time. Several other growth factors have been tested clinically and show some promise, but currently none are approved for use. A great deal more needs to be discovered about the concentration, temporal release, and receptor cell population before growth factor therapy is to make a consistent impact on wound healing.Gene or Cell Therapy. Given the disappointing results from the application of purified growth factors onto wounds, the pos-sible therapeutic potential of gene therapy has been recognized and studied. Direct access to the open wound bed, which char-acterizes almost all chronic wounds, has facilitated this therapy. Gene delivery to wounds includes traditional approaches such as viral vectors and plasmid delivery or, more recently, electro-poration and microseeding.Although a variety of genes expressing interleukin-8, PDGF, IGF-1, keratinocyte growth factor, and laminin-5 have been successfully delivered to wounds in both animal and human models, the effects have been modest and specific to unique wound situations. Delivering extra genes into the wound bed presents the challenge of expression of the necessary signals to turn the genes on and off at appropriate times so that dys-regulated, hypertrophic, and abnormal healing does not occur. Elaborate systems have been created for topical use as on/off switches for genes. The more important question is which genes to express, in what temporal sequence, and in what regions of the wound bed, as it is unlikely that a single gene coding for one protein can significantly affect overall healing. There is growing consensus that delivery of genes is not going to represent the universal solution. Although gene therapy replaces missing or Table 9-11Advantages and disadvantages of various bioengineered skin substitutesSKIN SUBSTITUTEADVANTAGESDISADVANTAGESCultured allogeneic keratinocyte graftNo biopsy needed“Off the shelf” availabilityProvides wound coveragePromotes healingUnstableDoes not prevent wound contractureInadequate cosmesisPossibility of disease transmissionFragileBioengineered dermal replacementPrevents contractureGood prep for graft applicationLimited ability to drive reepithelializationLargely serves as temporary dressingCultured bilayer skin equivalentMore closely mimics normal anatomyDoes not need secondary procedureEasily handledCan be sutured, meshed, etc.CostShort shelf lifeTrue engraftment questionableBrunicardi_Ch09_p0271-p0304.indd 29801/03/19 4:50 PM 299WOUND HEALINGCHAPTER 9defective genes, most acute wounds already have and express the necessary genes for successful healing and the wound envi-ronment produces signals adequate to the activation of these genes. What, if any, are the deficiencies in gene expression or activity in failed wounds is unknown.Another approach is to deliver multiple genes coding for proteins that can act synergistically and even in a timed sequence, as would occur during normal healing. This would involve the use of activated cells that participate in the heal-ing sequence that could be delivered in an activated state to the wound environment. Use of mesenchymal stem cells as a delivery vector for many genes simultaneously is the latest such approach. The feasibility of applying bone marrow-derived, umbilical cord-derived, adipose-derived, and epidermal stem cells that can differentiate into various cells that participate in the wound healing response also has been documented. These cells, as part of their differentiation and activation in the wound, have been shown to produce a variety of growth factors includ-ing VEGF, PDGF, bFGF, and MMP-9. The challenges remain how to maintain the viability and activity of the transplanted cells, how to document that the observed effects are due to the delivered cells, and what are the mechanisms necessary for reg-ulating or ending their activity.Oxygen Therapy in Wound HealingOxygen is required for almost all steps of wound healing and is also an important factor in the body’s defense against bacterial infection.133 In addition to its role in healing, oxygen plays an essential role in the production of reactive oxygen species such as superoxide that are angiogenesis stimulators and are bacterio-static. Chronic wounds have a decreased oxygen supply, and for a long time lack of oxygen was recognized as a potential cause of delayed healing. To counteract this delay, supple-mental oxygen therapy was used to improve healing, and both local oxygen therapy and systemic therapy were used for that purpose. Local therapy included oxygen dressings and topical oxygen therapy, while systemic therapy included supplemental inspired oxygen therapy and pressurized oxygen treatment.134 Of the different methods of oxygen therapy, pressurized oxy-gen, also termed hyperbaric oxygen therapy (HBOT) is the most used modality and the most investigated. In HBOT, oxygen is delivered under pressure, more than atmospheric pressure, lead-ing to a higher concentration of oxygen in tissues. The Undersea and Hyperbaric Medical Society (UHMS) defined HBOT as an intervention that involves breathing near 100% oxygen intermit-tently under high pressure achieved by a pressurized chamber to more than sea level pressure (sea level pressure = 1 atmosphere absolute [ATA]). The therapeutic pressure should be at least 1.4 ATA. Chambers can be single occupancy or multiple occu-pancy.135 Although there are numerous indications and potential indications for HBOT, there are 14 accepted indications by Undersea and Hyperbaric Medical Society, and the FDA. Indi-cations related to wounds and ulcers include clostridial myone-crosis, crush injury, radiation-induced soft tissue and bone necrosis, necrotizing soft tissue infections, diabetic ulcers Wag-ner III or higher, refractory osteomyelitis, and thermal burns.135 Two systemic reviews were published on the effect of HBOT on wound healing. The first one was published in 2003 on all stud-ies done up to 2001.136 Generally, the review showed beneficial effects of HBOT on different disease processes. HBOT was found to improve graft survival, complete healing of grafts, and lessen infection in patients with a graft. Patients with osteoradionecrosis showed improved bone changes. The effect on tissue radionecrosis was described as positive, but not all studies showed statistical significance. HBOT was found to have improved amputation rates in patients with gas gangrene with better healing. In addition, HBOT was found to reduce mortality rates from necrotizing fasciitis, and significantly decreased wound size in nonhealing diabetic wounds. In the sec-ond systemic review, a total of 29 studies published between 2001 and 2016 were included. A total of 14 studies were related to chronic wounds: 12 studies in acute wounds, 1 study on both acute and chronic wounds, and 2 experimental studies. Out of those 29 studies, 18 (62%) showed at least one positive out-come.134 One of the drawbacks of such studies in general is the lack of heterogeneity and the lack of accurate randomization. Perhaps, HBOT in diabetic foot ulcers attracted more attention than other forms of skin ulcers. In patients with diabetic foot ulcers, studies showed that HBOT led to significantly more healing wounds at 1 year,137 greater reduction in the wound bed,138 greater healing with less proximal amputation,139 and more complete wound healing at 1 month after HBOT.140Biofilm and Chronic Wound HealingTraditionally, nonhealing of chronic wounds has been associ-ated with numerous risk factors, including longer duration of ulcers, advanced age, increased body mass index, venous reflux, arterial and venous disease, nutritional deficiencies, diabetes mellitus, and smoking. Chronic bacterial infection is another factor that has been associated with nonhealing wounds.Chronic wounds, in general, behave differently in relation to bacterial growth when compared to acute wounds. Chronic wounds develop bacterial growth that is resistant to invasion by antibiotics and is protected from the host immune defenses. Biofilm is the term used for the bacterial growth on a chronic wound that is encapsulated by a protective layer made up of the host and bacterial proteins. Bjarnsholt et al have suggested a simplified definition of the biofilm as “an aggregate of bacteria tolerant to treatment and the host defense.” It has been found that more than 60% of chronic wounds have a biofilm.141 Biofilms lead to a chronic inflammatory process that will interfere with healing.142 Biofilms are formed in three stages. The first stage—the reversible bacterial adhesion stage—is formed by adhesion of bacteria to the surface of the wound. The second stage is the permanent adhesion or maturation stage in which the organisms permanently attach, proliferate, and maturate in the wound surface. This stage depends on a micro-bial-to-microbial cell communication system, called quorum sensing, in which small signaling molecules are released and gradually increase in concentration. The signaling molecules regulate gene expression and help form the biofilm. Lastly, in the third stage, organisms secrete a surrounding protective matrix called the extracellular polymeric substance (EPS). Once a biofilm colony forms, it will continuously shed bacteria to uncolonized areas, causing more biofilm colonies to form.143,144The presence of biofilms protects bacteria from the host defenses. Bacteria will then begin to exhibit phenotypic and genotypic plurality: the former allows bacteria to adapt to dif-ferent growth conditions such as nutrient availability, pH, and oxidizing potential within the biofilm, while the latter allows for virulence and bacterial resistance to drugs. The genetic plurality is passed horizontally among bacteria in the wound, adding to the resistance to treatment and allowing the bacteria to avoid the defense mechanisms of the host such as bacterial phagocytosis, 910Brunicardi_Ch09_p0271-p0304.indd 29901/03/19 4:50 PM 300BASIC CONSIDERATIONSPART Ineutrophil degranulation, and formation of reactive oxygen spe-cies.145-147 In some cases, the biofilm allows bacteria to become quiescent and thus become less sensitive to antimicrobials that typically affect dividing bacterial cells.144,148Biofilms can form and recover from debridement rap-idly. Fully mature biofilm colonies can form within 2 to 4 days depending on the species and growth conditions. Common bacterial species such as Staphylococcus, Streptococcus, and Pseudomonas can attach to the surface of the wound in min-utes, forming adherent microcolonies in 2 to 4 hours. Bacterial species develops the extracellular polymeric substances (EPS) and resistance to disinfectants, antiseptics, and antibiotics in 6 to 12 hours. The biofilm then develops into mature colonies in 2 to 4 days. Furthermore, it rapidly recovers form mechanical disruption, such as debridement, within 24 hours.144The presence of biofilms leads to delayed wound healing by stimulating chronic inflammation in the wound. The host responds to the biofilms by mobilizing macrophages and neutro-phils to the biofilm area, resulting in secretions of high levels of reactive oxygen species and proteases that can cause damage to the normal and healing tissue. The resulting increase in exudate production provides a source of nutrients to the biofilms, lead-ing to more resistance to healing.149The best method of treating wounds with biofilms is not well defined. It is believed that frequent debridement to mechanically remove the biofilm remains to be the best method of treatment. The frequency of debridement is not well defined, although a weekly debridement has been suggested to improve healing. More than one method of debridement might be needed in wounds resistant to healing. A few products have been sug-gested to control and remove biofilms, such as surfactant and some wound cleansing formulas. In addition, topical broad-spectrum antimicrobials such as silver, iodine, honey, and others have been suggested to aid in the treatment of biofilms. Using a various combination of debridement methods, cleansing agents, and antimicrobials may be needed in resistant chronic wounds. An effective therapy to combat biofilm should include effective removal of the biofilm, antimicrobial eradication of bacteria/organisms, and prevention of biofilm recurrence, and these treat-ment options may need to be repeated multiple times to achieve effective therapy. 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Surg Gynecol Obstet. 1982;154(3):421-429. 67. Larson DL. Alterations in wound healing secondary to infu-sion injury. Clin Plast Surg. 1990;17(3):509-517. 68. Cruse PJE, Foord RA. A prospective study of 23,649 surgical wounds. Arch Surg. 1973;107(2):206-210. 69. Yue DK, McLennan S, Marsh M, et al. Effects of experimental diabetes, uremia, and malnutrition on wound healing. Diabetes. 1987;36(3):295-299. 70. Goodson WH III, Hunt TK. Studies of wound healing in exper-imental diabetes mellitus. J Surg Res. 1977;22(3):221-227. 71. Black E, Vibe-Petersen J, Jorgensen LN, et al. Decrease in collagen deposition in wound repair in type I diabetes independent of glycemic control. Arch Surg. 2003;138(1): 34-40.Brunicardi_Ch09_p0271-p0304.indd 30101/03/19 4:50 PM 302BASIC CONSIDERATIONSPART I 72. Spiliotis J, Tsiveriotis K, Datsis AD, et al. Wound dehiscence is still a problem in the 21st century: a retrospective study. World J Emerg Surg. 2009;4:12. 73. Coon D, Gusenoff JA, Kannan N, et al. Body mass and surgi-cal complications in the postbariatric reconstructive patient: analysis of 511 cases. Ann Surg. 2009;249:397-401. 74. Arthurs ZM, Cuadrado D, Sohn V, et al. Post-bariatric pan-niculectomy: pre-panniculectomy body mass index impacts the complication profile. Am J Surg. 2007;193:567-570. 75. Tsukada K, Miyazaki T, Kato H, et al. Body fat accumulation and postoperative complications after abdominal surgery. Am Surg. 2004;70:347-351. 76. Williams JZ, Barbul A. Nutrition and wound healing. Surg Clin North Am. 2003;83(3):571-596. 77. Goodson WH, Jensen JA, Gramja-Mena L, West J, Granja-Mena L, Chavez-Estrella J. The influence of a brief pre-operative illness on postoperative healing. Ann Surg. 1987;205(3):250-255. 78. Winsor JA, Knight GS, Hill GL. Wound healing in surgical patients: recent food intake is more important than nutritional status. Br J Surg. 1988;75(2):135-137. 79. Haydock DA, Hill GL. Improved wound healing response in surgical patients receiving intravenous nutrition. Br J Surg. 1987;74(4):320-323. 80. Seifter E, Rettura G, Barbul A, Levenson SM. Argi-nine: an essential amino acid for injured rats. Surgery. 1978;84(2):224-230. 81. Barbul A, Lazarou S, Efron DT, Wasserkrug HL, Efron G. Arginine enhances wound healing in humans. Surgery. 1990;108(2):331-336. 82. Kirk SJ, Regan MC, Holt D, Holt DR, Wasserkrug HL, Barbul A. Arginine stimulates wound healing and immune function in aged humans. Surgery. 1993;114(2):155-159. 83. Williams JZ, Abumrad NN, Barbul A. Effect of a specialized amino acid mixture on human collagen deposition. Ann Surg. 2002;236(3):369-374. 84. Levenson SM, Seifter E, VanWinkle W. Nutrition. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management in Surgery. New York: Appleton-Century-Crofts; 1979:286. 85. Jeejeebhoy KN, Cheong WK. Essential trace metals: defi-ciencies and requirements. In: Fischer JE, ed. Nutrition and Metabolism in the Surgical Patient. Boston: Little, Brown and Company; 1996:295. 86. Wilkinson EAJ, Hawke CI. Oral zinc for arterial and venous ulcers (Cochrane Review), in The Cochrane Library, 1:2002. Oxford: Update Software. 87. Robson MC. Wound infection: a failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am. 1997;77(3):637-650. 88. Birkmeyer NJO, Birkmeyer JD. Strategies for improving surgical quality—should payers reward excellence or effort? N Engl J Med. 2006;354(8):864-870. 89. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibi-otics and the risk of surgical-wound infection. N Engl J Med. 1992;326(5):281-286. 90. Anonymous. Antimicrobial prophylaxis for surgery. Med Letter. 2012;10(122):73-78. 91. Gupta N, Kaul-Gupta R, Carstens MM, et al. Analyzing pro-phylactic antibiotic administration in procedures lasting more than four hours: are published guidelines being followed? Am Surg. 2003;69(8):669-673. 92. Arnold MA, Barbul A. Surgical site infections. In: Cameron JL, ed. Current Surgical Therapy. 9th ed. St. Louis: Mosby-Elsevier; 2008:1152-1160. 93. Liese JG, Jendrossek V, Jannson A, et al. Chronic granuloma-tous disease in adults. Lancet. 1996;347(8996):220-223. 94. Ramos M, Khalpey Z, Lipsitz S, et al. Relationship of peri-operative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery. Ann Surg. 2008;248:585-591. 95. Van den Berghe G, Wouters P, Weekers P, et al. Inten-sive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367. 96. Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glyce-mic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent isch-emic events. Circulation. 2004;109:1497-1502. 97. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraop-erative insulin therapy versus conventional glucose manage-ment during cardiac surgery: a randomized trial. Ann Int Med. 2007;146:233-243. 98. Lazar HL, McDonnell MM, Chipkin S, et al. Effects of aggressive versus moderate glycemic control on clinical out-comes in diabetic coronary artery bypass patients. Ann Surg. 2011;254:458-463. 99. Gottrup F, Firmin R, Rabkin J, et al. Directly measured tissue oxygen tension and arterial oxygen tension assess tissue perfu-sion. Crit Care Med. 1987;15:1030-1036. 100. Sheffield CW, Sessler DI, Hopf HW, et al. Centrally and locally mediated thermoregulatory responses alter subcutane-ous oxygen tension. Wound Repair Regen. 1996;4:339-345. 101. Maragakis LL, Cosgrove SE, Martinez EA, et al. Intraopera-tive fraction of inspired oxygen is a modifiable risk factor for surgical site infection after spinal surgery. Anesthesiology. 2009;110:556-562. 102. Meyhoff C, Weyyerslev J, Jorgensen LN, et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI Randomized Clinical Trial. JAMA. 2009;302:1543-1550. 103. Falanga V, Eaglstein WH. The “trap” hypothesis of venous ulceration. Lancet. 1993;341(8851):1006-1008. 104. Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia. 2002;45(7):1011-1116. 105. Stanley A, Osler T. Senescence and the healing rates of venous ulcers. J Vasc Surg. 2001;33(6):1206-1211. 106. Kim BC, Kim HT, Park SH, et al. Fibroblasts from chronic wounds show altered TGF-β-signaling and decreased TGF-β type II receptor expression. J Cell Physiol. 2003;195(3):331-336. 107. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the treat-ment of arterial insufficiency ulcers. Wound Repair Regen. 2006;14(6):693-710. 108. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the pre-vention of lower extremity arterial ulcers. Wound Repair Regen. 2008;16(2):175-188. 109. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the treatment of venous ulcers. Wound Repair Regen. 2006;14(6):649-662. 110. Kirsner RS, Marston WA, Snyder RJ, et al. Sprayed-applied cell therapy with human allogeneic fibroblasts and keratino-cytes for treatment of chronic venous leg ulcers: a phase 2, multicenter, double-blind, randomized, place-controlled trial. Lancet. 2012;380:977-985. 111. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the prevention of venous ulcers. Wound Repair Regen. 2008;16(2):147-150. 112. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680-692. 113. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet. 2003;361(9368):1545-1551.Brunicardi_Ch09_p0271-p0304.indd 30201/03/19 4:50 PM 303WOUND HEALINGCHAPTER 9 114. Steed DL, Attinger C, Brem H, et al. Guidelines for the prevention of diabetic ulcers. Wound Repair Regen. 2008;16(2):169-174. 115. Whitney J, Phillips L, Aslam R, et al. Guidelines for the treatment of pressure ulcers. Wound Repair Regen. 2006;14(6):663-679. 116. Stechmiller JK, Cowan L, Whitney J, et al. Guidelines for the prevention of pressure ulcers. Wound Repair Regen. 2008;16(2):151-168. 117. Niessen FB, Spauwen PH, Schalkwijk J, et al. On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg. 1999;104(5):1435-1458. 118. Marneros AG, Norris JE, Olsen BR, Reichenberger E. Clinical genetics of familial keloids. Arch Dermatol. 2001; 137(11):1429-1434. 119. Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scar-ring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17:113-125. 120. Butler PD, Longaker MT, Yang GP. Current progress in keloid research and treatment. J Am Coll Surg. 2008;206(4):731-741. 121. Mustoe TA. Evolution of silicone therapy and mecha-nism of action in scar management. Aesthetic Plast Surg. 2008;32(1):82-92. 122. Dijkstra FR, Nieuwenhuijzen M, Reijnen MM, van Goor H. Recent clinical developments in pathophysiology, epidemiol-ogy, diagnosis and treatment of intra-abdominal adhesions. Scand J Gastroenterol Suppl. 2000;232:52-59. 123. Cheong YC, Laird SM, Shellton JB, Ledger WL, Li TC, Cooke ID. The correlation of adhesions and peritoneal fluid cytokine concentrations: a pilot study. Hum Reprod. 2002;17:1039-1045. 124. Zeng Q, Yu Z, You J, Zhang Q. Efficacy and safety of Seprafilm for preventing postoperative abdominal adhe-sion: systematic review and meta-analysis. World J Surg. 2007;31(11):2125-2131. 125. Armstrong DG, Lavery L; Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet. 2005;366:1704-1710. 126. Kim PJ, Heilala M, Stenverg JS, Weinraub GM. Bioen-gineered alternative tissues and hyperbaric oxygen in lower extremity wound healing. Clin Podiatr Med Surg. 2007;24(3):529-546. 127. Veves A, Falanga V, Armostrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic dia-betic foot ulcers: a prospective randomized multicenter clini-cal trial. Diabetes Care. 2001;24(2):290-295. 128. Kim PJ, Attinger CE, Steinberg JS, Evans KK. Integra bilayer wound matrix application for complex lower extremity soft tissue reconstruction. Surg Technol Inter. 2014;24:65-73. 129. Felder JM, Goyal SS, Attinger CE. A systematic review of skin substitutes for foot ulcers. Plast Recontr Surg. 2012;130(1):145-164. 130. Gu C, Huang S, Gao D, et al. Angiogenic effect of mesenchy-mal stem cells as a therapeutic target for enhancing diabetic wound healing. Int J Low Extrem Wounds. 2014;13(2):88-93. 131. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chroion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32:135-146. 132. Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, et al. Autol-ogous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012;10:CD006899. 133. Rodriguez PG, Felix FN, Woodley DT, Shim EK. The role of oxygen in wound healing: a review of the literature. Dermatol Surg. 2008:34:1159-1169. 134. De Smet GH, Kroese LF, Menon AG, et al. Oxygen thera-pies and their effects on wound healing. Wound Rep Reg. 2017;25(4):591-608. 135. Weaver LK, ed. The Undersea and Hyperbaric Medical Soci-ety Manual on Hyperbaric Oxygen Therapy Indications. 13th ed. North Palm Beach, FL: Best Publishing Company; 2014, ix-xi. 136. Wang C, Schwaitzberg S, Berliner E, Zarin DA, Lau J. Hyper-baric oxygen for treating wounds: a systemic review of the literature. Arch Surg. 2003;138:272-280. 137. Londahl M, Katzman P, Nilson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic wound ulcers in patients with diabetes. Diabetes Care. 2010;33(5):998-1003. 138. Ma L, Li P, Shi Z, Hou T, Chen X, Du J. A prospective, random-ized, controlled study of hyperbaric oxygen therapy: effects on healing and oxidative stress of ulcer tissue in patients with diabetic foot ulcers. Ostomy Wound Manag. 2103;59(3):18-24. 139. Duzgun AP, Satir HZ, Ozozan O, Saylam B, Kulah B, Coskun F. Effect of hyperbaric oxygen therapy on diabetic foot ulcers. J Foot Ankle Surg. 2008;47(6):515-519. 140. Kaur S, Pawar M, Banerjee N, Garg R. Evaluation of the efficacy of hyperbaric oxygen therapy in the management of chronic nonhealing ulcer and role of periwound transcu-taneous oximetry as predictor of wound healing response: a randomized prospective controlled trial. J Anaesthesiol Clin Pharmacol. 2012:28(1):70-75. 141. Bjarnsholt T, Cooper R, Fletcher J, et al. Management of biofilm. WoundsInternational.com. Available at: http://www .woundsinternational.com/wuwhs/view/position-document-management-of-biofilm. Accessed June 26, 2018. 142. Wolcott R, Rhoads D, Dowd S. Biofilms and chronic wound inflammation. J Wound Care. 2008;17(8):333-341. 143. Scali C, Kunimoto B. An update on chronic wounds and the role of biofilms. J Cutan Med Surg. 2013;17(6):371-376. 144. Philips PL, Wolcott RD, Fletcher J, Schultz GS. Biofilms made easy. WoundsInternational.com. Available at: http://www .woundsinternational.com/made-easys/view/biofilms-made-easy. Accessed June 26, 2018. 145. Thomson CH. Biofilms: do they affect wound healing? Int Wound J. 2011;8(1):63-67. 146. Bjarnshot T, Bjarnsholt T, Kirketerp-Moller K, Jensen P, et al. Why chronic wounds won’t heal: a novel hypothesis. Wound Repair Regen. 2008;16(1):2-10. 147. Leid J, Wilson C, Shirtliff M, Hassett DJ, Parsek MR, Jeffers AK. The exopolysaccharide alginate protects Pseudomonas aeruginosa biofilm bacteria from INF-gamma-mediated mac-rophage killing. J Immunol. 2005;175(1):7512-7518. 148. Hall-Stoodley L, Stoodley P. Evolving concepts in biofilm infections. Cell Microbiol. 2009;11(7):1034-1043. 149. Lawrence JR, Swerhone GD, Kuhlicke U, Neu TR. In situ evidence of microdomains in the polymer matrix of bacterial microcolonies. Can J Microbiol. 2007;53(3):450-458.Brunicardi_Ch09_p0271-p0304.indd 30301/03/19 4:50 PM

Brunicardi_Ch09_p0271-p0304.indd 30401/03/19 4:50 PMThis page intentionally left blankONCOLOGY AND SURGICAL PRACTICEAs the population ages, oncology is becoming a larger portion of surgical practice. The surgeon often is responsible for the initial diagnosis and management of solid tumors. Knowledge of cancer epidemiology, etiology, staging, and natural history is required for initial patient assessment, as well as to determina-tion of the optimal surgical therapy.Modern cancer therapy is multidisciplinary, involving the coordinated care of patients by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radi-ologists, and primary care physicians. Primary (or defini-tive) surgical therapy refers to en bloc resection of tumor with adequate margins of normal tissues and regional lymph nodes as necessary. Adjuvant therapy refers to radiation therapy and systemic therapies, including chemotherapy, immunotherapy, hormonal therapy, and, increasingly, biologic therapy. The pri-mary goal of surgical and radiation therapy is local and regional control. On the other hand, the primary goal of adjuvant therapy is systemic control by treatment of distant foci of subclinical dis-ease to prevent distant recurrence. Surgeons must be familiar with adjuvant therapies to coordinate multidisciplinary care and to determine the best sequence of therapy. They must also be aware of the potential for patients to receive effective systemic therapies prior to surgery as a means of reducing tumor volume.Recent advances in molecular biology are revolutionizing medicine. New information is being translated rapidly into clinical use, with the development of new prognostic and predictive markers and new biologic therapies. Increasingly cancer therapy is becoming personalized, incorporating information about each patient’s tumor characteristics, patient’s own genome, as well as host immune responses and tumor microenvironment, into clinical decisionmaking. It is therefore essential that surgeons understand the prin-ciples of molecular oncology to appropriately interpret these new contributions and incorporate them into practice.12OncologyWilliam E. Carson III, Funda Meric-Bernstam, and Raphael E. Pollock 10chapterOncology and Surgical Practice 305Epidemiology 306Basic Principles of Cancer Epidemiology / 306Cancer Incidence and Mortality in the United States / 306Global Statistics on Cancer Incidence and Mortality / 307Cancer Biology 310Hallmarks of Cancer / 310Cell Proliferation and Transformation / 310Cancer Initiation / 310Cell-Cycle Dysregulation in Cancer / 311Oncogenes / 313Alterations in Apoptosis in Cancer Cells / 314Autophagy in Cancer Cells / 315Cancer Invasion / 315Angiogenesis / 316Metastasis / 316Epithelial-Mesenchymal Transition / 317Cancer Stem Cells / 318Cancer Etiology 318Cancer Genomics / 318Tumor Heterogeneity and Molecular Evolution / 319Genes Associated With Hereditary Cancer Risk / 320APC Gene and Familial Adenomatous Polyposis / 324PTEN and Cowden Disease / 325RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2 / 325Chemical Carcinogens / 326Physical Carcinogens / 326Viral Carcinogens / 326Cancer Risk Assessment 328Cancer Screening 330Cancer Diagnosis 332Cancer Staging 333Tumor Markers 334Prognostic and Predictive Tissue Markers / 334Serum Markers / 335Circulating Tumor Cells / 336Bone Marrow Micrometastases / 337Surgical Approaches to Cancer Therapy 337Multidisciplinary Approach to Cancer / 337Surgical Management of Primary Tumors / 337Surgical Management of the Regional Lymph Node Basin / 338Surgical Management of Distant Metastases / 339Chemotherapy 340Clinical Use of Chemotherapy / 340Principles of Chemotherapy / 340Anticancer Agents / 340Combination Chemotherapy / 341Drug Toxicity / 341Administration of Chemotherapy / 341Hormonal Therapy 342Targeted Therapy 342Immunotherapy 342Gene Therapy 345Mechanisms of Intrinsic and Acquired Drug Resistance 345Radiation Therapy 346Physical Basis of Radiation Therapy / 346Biologic Basis of Radiation Therapy / 346Radiation Therapy Planning / 347Side Effects / 348Cancer Prevention 348Trends in Oncology 349Cancer Screening and Diagnosis / 349Surgical Therapy / 349Systemic Therapy / 349Brunicardi_Ch10_p0305-p0354.indd 30522/02/19 2:14 PM 306Key Points1 Modern cancer therapy is multidisciplinary, involving coor-dinated care by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiolo-gists, and primary care physicians.2 Understanding cancer biology is essential to successfully implement personalized cancer therapy.3 The following alterations are critical for malignant cancer growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, potential for limitless replication, angiogenesis, invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.EPIDEMIOLOGYBasic Principles of Cancer EpidemiologyThe term incidence refers to the number of new cases occur-ring. Incidence is usually expressed as the number of new cases per 100,000 persons per year. Mortality refers to the number of deaths occurring and is expressed as the number of deaths per 100,000 persons per year. Incidence and mortality data are usually available through cancer registries. Mortality data are also available as public records in many countries where deaths are registered as vital statistics, often with the cause of death. In areas where cancer registries do not exist, mortality data are used to extrapolate incidence rates. These numbers are likely to be less accurate than registry data, as the relationship between incidence and cause-specific death is likely to vary significantly among countries owing to the variation in health care delivery.The incidence of cancer varies by geography. This is due in part to genetic differences and in part to differences in environ-mental and dietary exposures. Epidemiologic studies that moni-tor trends in cancer incidence and mortality have tremendously enhanced our understanding of the etiology of cancer. Further-more, analysis of trends in cancer incidence and mortality allows us to monitor the effects of different preventive and screening measures, as well as the evolution of therapies for specific cancers.The two types of epidemiologic studies that are conducted most often to investigate the etiology of cancer and the effect of prevention modalities are cohort studies and case-control stud-ies. Cohort studies follow a group of people who initially do not have a disease over time and measure the rate of development of a disease. In cohort studies, a group that is exposed to a certain environmental factor or intervention usually is compared to a group that has not been exposed (e.g., smokers vs. nonsmokers). A case-control study compares a group of patients affected with a disease to a group of individuals without the disease and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the rela-tionship between the risk factor and the disease. The results are expressed in terms of an odds ratio, or relative risk. A relative risk <1 indicates a protective effect of the exposure, whereas a relative risk >1 indicates an increased risk of developing the disease with exposure.Cancer Incidence and Mortality in the United StatesIn the year 2017, it is estimated that 1.7 million new cancer cases will be diagnosed in the United States, excluding carci-noma in situ of any site except bladder, and excluding basal cell and squamous cell carcinomas of the skin.1 In addition, 63,410 cases of carcinoma in situ of the breast, and 74,680 of melanoma in situ are expected.1It is estimated that in 2017 an estimated 600,920 people will die of cancer in the United States, corresponding to about 1650 deaths per day.1 The estimated new cancer cases and deaths by cancer type are shown in Table 10-1.1 The most com-mon causes of cancer death in men are cancers of the lung and bronchus, colon and rectum, and prostate; in women, the most common cancers are of the lung and bronchus, breast, and colon and rectum.1 These four cancers account for almost half of total cancer deaths among men and women.The annual age-adjusted cancer incidence rates among males and females for selected cancer types are shown in Fig. 10-1.1 Incidence rates are declining for most cancer sites (Fig. 10-2).1 Incidence rates for thyroid cancer have begun to stabilize recently, possibly due to changes in clinical practice guidelines that were initiated in 2009 and included more conservative indications for biopsy. The age-adjusted incidence rate of breast cancer started to decrease from 2001 to 2004.2 This decrease in breast cancer inci-dence has at least temporally been associated with the first report of the Women’s Health Initiative, which documented an increased risk of coronary artery disease and breast cancer with the use of hormone replacement therapy; this was followed by a drop in the use of hormone replacement therapy by postmenopausal women in the United States.2 Unfortunately, there was a slight increase in breast cancer incidence from 2004 to 2013. This was driven wholly by nonwhite women; rates increased by about 2% per year among women other than white or black and by 0.5% per year among black women. Thus, rates have risen slightly in women as a whole from 2013 to 2017, although rates remained stable in white women.Declines in colorectal cancer incidence have been mainly attributed to increased screening that allows for removal of pre-cancerous polyps. Prostate cancer rates rapidly increased and decreased between 1995 and 1998. These trends are thought to be attributable to increased use of prostate-specific antigen (PSA) screening.3 Due to growing concerns about overdiagno-sis and overtreatment, a U.S. Preventive Services Task Force recommended against routine use of PSA testing to screen for prostate cancer. As a result, there was more than 10% annual reduction in prostate cancer incidence from 2010 to 2013. Dif-ferences in lung cancer incidence patterns between women and men are thought to reflect historical differences in tobacco use. Differences in smoking prevalence is also thought to contribute to regional differences in lung cancer incidence. Lung cancer incidence is fourfold higher in Kentucky, which has the highest smoking prevalence, compared with Utah, which has the lowest smoking prevalence.1The 5-year survival rates for selected cancers are listed in Table 10-2. From 2010 to 2014, cancer death rates decreased by 1.8% per year in men and by 1.4% per year in women.1 These declines in mortality have been consistent in the past decade and larger than what was observed in the previous decade.3 Over the Brunicardi_Ch10_p0305-p0354.indd 30622/02/19 2:14 PM 307ONCOLOGYCHAPTER 10Table 10-1Estimated new cancer cases and deaths, United States, 2017a ESTIMATED NEW CASESESTIMATED DEATHS ESTIMATED NEW CASESESTIMATED DEATHSAll cancers1,688,780600,920Genital system279,80059,100Oral cavity and pharynx49,6709700 Uterine cervix12,8204210Digestive system310,440157,700 Uterine corpus61,38010,920 Esophagus16,94015,690 Ovary22,44014,080 Stomach28,00010,960 Vulva60201150 Small intestine10,1901390 Vagina and other genital, female48101240 Colon and rectum95,520 / 39,91050,260b Prostate161,36026,730 Anus, anal canal,  and anorectum82001100 Testis8850410 Liver and  intrahepatic bile duct40,71028,920 Penis and other genital, male2120360 Gallbladder and other biliary11,7403830Urinary system146,65032,190 Pancreas53,67043,090 Urinary bladder79,03016,870 Other digestive organs55602460 Kidney and renal pelvis63,99014,400Respiratory system243,170160,420 Ureter and other urinary organs3630920 Larynx13,3603660Eye and orbit3130330 Lung and bronchus220,500155,870Brain and other nervous system23,80016,700 Other respiratory organs7310890Endocrine system59,2503010Bones and joints32601550 Thyroid56,8702010Soft tissue (including heart)12,3904990 Other endocrine23801000Skin (excluding basal and squamous)95,36013,590Lymphoma80,50021,210 Melanoma87,1109730Multiple myeloma30,28012,590 Other nonepithelial82503860Leukemia62,13024,500Breast255,18041,070Other and unspecified primary sitesc33,77042,270aRounded to the nearest 10, cases exclude basal cell and squamous cell skin cancers and in situ carcinoma except bladder. About 63,410 cases of carcinoma in situ of the female breast and 74,680 cases of melanoma in situ were diagnosed in 2017.bDeaths for colon and rectum cancers are combined because a large number of deaths from rectal cancer are misclassified as colon.cMore deaths than cases may reflect lack of specificity in recording underlying cause of death on death certificate and/or an undercount in the case estimate.Modified with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.past 3 decades, the 5-year relative survival rate for all cancers combined has increased by 20% among whites and 24% among blacks. Improvements in survival for the most common cancers have been similar across both sexes but are more pronounced among patients age 50 to 64 years than among those older than 65 years. This difference may reflect reduced efficacy of new therapies in the elderly or perhaps lower utilization.1 Progress has been rapid for hematopoietic and lymphoid malignancies due to improved treatment protocols and the discovery of tar-geted therapies. The decrease in lung cancer death rates in men is thought to be due to a decrease in tobacco use, whereas the decreases in death rates from breast, colorectal cancer, and prostate cancer likely reflect advances in early detection and treatment. For instance, there is potential for lung cancer to be diagnosed at an earlier stage through the use of screening with low-dose computed tomography.Global Statistics on Cancer Incidence and MortalityThe five most common cancers for men worldwide are lung, prostate, colorectal cancer, stomach, and liver and for women are breast, colorectal, cervix, lung, and stomach.4 Notably, for several cancer types there is wide geographical variability in cancer incidence (Fig. 10-3). The mortality rates for different cancers also vary significantly among countries. This is attribut-able not only to variations in incidence but also to variations in survival after a cancer diagnosis. The survival rates are influ-enced by treatment patterns as well as by variations in cancer screening practices, which affect the stage of cancer at diagno-sis. For example, the 5-year survival rate for stomach cancer is much higher in Japan, where the cancer incidence is high enough to warrant mass screening, which is presumed to lead to earlier diagnosis. In the case of prostate cancer, on the other Brunicardi_Ch10_p0305-p0354.indd 30722/02/19 2:14 PM 308BASIC CONSIDERATIONSPART Ihand, the mortality rates diverge much less than the incidence rates among countries. Survival rates for prostate cancer are much higher in North America than in developing countries.5 It is possible that the extensive screening practices in the United States allow discovery of cancers at an earlier, more curable stage; however, it is also possible that this screening leads to discovery of more latent, less biologically aggressive cancers, which may not have caused death even if they had not been identified.In 2008 (the last date for which complete data are available), about 1 million new cases of stomach cancer were estimated to have occurred (988,000 cases, 7.8% of the total), making it the fourth most common malignancy in the world, behind cancers of the lung, breast, and colorectal cancer. The incidence of stomach cancer varies significantly among different regions of the world. The difference in risk by country is presumed to be primarily due to differences in dietary factors. The risk is increased by high consumption of preserved salted foods, such as meats and pick-les, and decreased by high intake of fruits and vegetables.5 There also is some international variation in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development.5 Fortunately, a steady decline is being observed in the incidence and mortality rates of gastric cancer. This may be related to improvements in preservation and storage of foods as well as due to changes in the prevalence of H pylori.5 More than 70% of cases (713,000 cases) occur in developing countries, and half the cases in the world occur in Eastern Asia (mainly in China).4 Age-standardized incidence rates are about twice as high for men as for women, ranging from 3.9 in Northern Africa to 42.4 in Eastern Asia for men, and from 2.2 in Southern Africa to 18.3 in Eastern Asia for women. Stomach cancer is the second leading cause of cancer death in both sexes worldwide.Overall, the incidence of breast cancer is rising in most countries. Incidence varies from 19.3 per 100,000 women in Eastern Africa to 89.7 per 100,000 women in Western Europe, and are high in developed regions of the world (except Japan) and low in most of the developing regions.4 Although breast cancer has been linked to cancer susceptibility genes, mutations in these genes account for only 5% to 10% of breast tumors, which suggests that the wide geographic variations in breast cancer incidence are not due to geographic variations in the prevalence of these genes. Most of the differences, therefore, are attributed to differences in reproductive factors, diet, alcohol, obesity, physical activity, and other environmental differences. Indeed, breast cancer risk increases significantly in females MalesFemalesBreastLung & bronchusColon & rectumUterine corpusNon-Hodgkin lymphomaThyroidMelanoma of the skinPancreasLeukemiaKidney & renal pelvisAll Sites252,710105,51064,01061,38042,47034,94032,16025,84025,70023,380852,63030%12%8%7%5%4%4%3%3%3%100%MalesFemalesLung & bronchusProstateColon & rectumPancreasLiver & intrahepatic bile ductLeukemiaEsophagusUrinary bladderNon-Hodgkin lymphomaBrain & other nervous systemAll SitesLung & bronchusBreastColon & rectumPancreasOvaryLeukemiaNon-Hodgkin lymphomaUterine corpusLiver & intrahepatic bile ductBrain & other nervous systemAll Sites71,28040,61023,11020,79014,08010,92010,2009,3108,6907,080282,50025%14%8%7%5%4%4%3%3%3%100%84,59027,15026,73022,30019,61014,30012,72012,24011,4509,620318,42027%9%8%7%6%4%4%4%4%3%100%ProstateLung & bronchusColon & rectumUrinary bladderMelanoma of the skinNon-Hodgkin lymphomaKidney & renal pelvisOral cavity & pharynxLeukemiaLiver & intrahepatic bile ductAll Sites161,360116,99071,42060,49052,17040,61040,08036,29035,72029,200836,15019%14%9%7%6%5%5%4%4%3%100%Estimated new casesEstimated deathsFigure 10-1. Ten leading cancer types with the estimated new cancer cases and deaths by sex in the United States, 2013. *Excludes basal and squamous cell skin cancers and in situ carcinomas except those of the urinary bladder. Estimates are rounded to the nearest 10 (Modified with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)Brunicardi_Ch10_p0305-p0354.indd 30822/02/19 2:14 PM 309ONCOLOGYCHAPTER 10who have migrated from Asia to America.5 The range of breast cancer mortality rates is much less (approximately 6 to 19 per 100,000) because of the more favorable survival of breast cancer in developed regions. As a result, breast cancer ranks as the fifth cause of death from cancer overall (458,000 deaths), but it is still the most frequent cause of cancer death in women in both developing (269,000 deaths, 12.7% of total) and developed regions (estimated 189,000 deaths).4There is a 25-fold variation in colon cancer incidence world-wide.5 The incidence of colon and rectal cancer is higher in devel-oped countries than in developing countries. The incidence rates are highest in North America, Australia and New Zealand, and Western Europe, and especially in Japanese men.5 In contrast, the incidence is relatively low in North Africa, South America, and Eastern, Southeastern, and Western Asia. These geographic differences are thought to reflect environmental exposures and are presumed to be related mainly to dietary differences in con-sumption of animal fat, meat, and fiber.5Worldwide liver cancer is the fifth most common cancer in men (523,000 cases, 7.9% of the total) and the seventh in women (226,000 cases, 6.5% of the total). Almost 85% of liver cancer cases occur in developing countries, and particularly in men.4 The overall sex ratio of male to female is 2:4. The regions of high incidence are Eastern and Southeastern Asia, Middle and Western Africa, as well as Melanesia and Micronesia/Polynesia (particularly in men). Low rates are estimated in developed regions, with the exception of Southern Europe. There were an estimated 694,000 deaths from liver cancer in 2008 (477,000 in men, 217,000 in women), and because of its high fatality (overall ratio of mortality to incidence of 0.93), liver cancer is the third most common cause of death from cancer worldwide. The geographical distribution of the mortality rates is similar to that observed for incidence. Worldwide, the major risk factors for liver cancer are infection with hepatitis B and C viruses and consumption of foods contaminated with aflatoxin. Hepatitis B immunization in children has recently been shown to reduce the incidence of liver cancer.5In summary, the incidence rates of many common cancers vary widely by geography. This is due in part to genetic dif-ferences, including racial and ethnic differences. It is due also in part to differences in environmental and dietary exposures, factors that can potentially be altered. Therefore, establishment of regional and international databases is critical to improving our understanding of the etiology of cancer and will ultimately assist in the initiation of targeted strategies for global cancer prevention. Furthermore, the monitoring of cancer mortality rates and 5-year cancer-specific survival rates will identify regions where there are inequities of health care, so that access to health care can be facilitated and guidelines for treatment can be established.Liver*ThyroidUterine corpusMelanoma of the skinColorectumLung & bronchusBreastFemale197519801985199019952000200520102013025Year of diagnosis5075100125150175200225250025Year of diagnosisLiver*ThyroidMelanoma of the skinUrinary bladderColorectumLung & bronchusProstateMaleRate per 100,000 population5075100125150175200225250197519801985199019952000200520102013Figure 10-2. Trends in cancer incidence rates for selected cancer by sex among males and females for selected cancer types, United States, 1975 to 2009. Rates are age adjusted to the 2000 U.S. standard population. +Liver includes intrahepatic bile duct. (Modified with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)Brunicardi_Ch10_p0305-p0354.indd 30922/02/19 2:14 PM 310BASIC CONSIDERATIONSPART ITable 10-2Five-year relative survival rates adjusted to normal life expectancy by year of diagnosis, United States, 1975–2008 RELATIVE 5-YEAR SURVIVAL RATES (%)CANCER TYPE1975–19771987–19892005-2011All cancers495669Brain222935Breast (female)758491Uterine cervix697069Colon516169Uterine corpus878383Esophagus51020Hodgkin’s disease727988Kidney505774Larynx666663Leukemia344362Liver3518Lung and bronchus121318Melanoma of the skin828893Multiple myeloma252849Non-Hodgkin’s lymphoma475172Oral cavity535466Ovary363846Pancreas248Prostate688399Rectum485868Stomach152030Testis839597Thyroid929598Urinary bladder737979Data from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.CANCER BIOLOGYHallmarks of CancerAlthough there are >100 types of cancer, it has been proposed that there are six essential alterations in cell physiology that dic-tate malignant growth: self-sufficiency of growth signals, insen-sitivity to growth-inhibitory signals, evasion of apoptosis (programmed cell death), potential for limitless replication, angiogenesis, and invasion and metastasis.6 Recently two additional hallmarks have emerged—reprogramming of energy metabolism and evading immune destruction.7 These hallmarks of cancer are being pursued as targets for cancer ther-apy (Fig. 10-4).Cell Proliferation and TransformationIn normal cells, cell growth and proliferation are under strict control. In cancer cells, cells become unresponsive to normal growth controls, which leads to uncontrolled cell division. Human cells require several genetic changes for neoplastic transformation. Cell type–specific differences also exist in the process by which a normal cell is transformed into a cancer-ous one. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics.8 These include loss of contact inhibition (i.e., cells continue to proliferate after a con-fluent monolayer is formed); an altered appearance and poor adherence to other cells or to the substratum; loss of anchorage dependence for growth; immortalization; and gain of tumorige-nicity (i.e., the ability to give rise to tumors when injected into an appropriate host).Cancer InitiationTumorigenesis is proposed to have three steps: initiation, promo-tion, and progression. Initiating events such as gain of function of genes known as oncogenes or loss of function of genes known as tumor-suppressor genes may lead a single cell to acquire a dis-tinct growth advantage. Although tumors usually arise from a sin-gle cell or clone, it is thought that sometimes not a single cell but 3Brunicardi_Ch10_p0305-p0354.indd 31022/02/19 2:14 PM 311ONCOLOGYCHAPTER 10rather a large number of cells in a target organ may have under-gone the initiating genetic event. Thus, many normal-appearing cells may have an increased malignant potential. This is referred to as a field effect. The initiating events are usually genetic and occur as deletions of tumor-suppressor genes or amplification or mutation of oncogenes. Subsequent events can lead to accumula-tions of additional deleterious mutations in the clone.Cancer is thought to be a disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers (e.g., atypical ductal hyperplasia to ductal carcinoma in situ to invasive ductal carcinoma of the breast). Fearon and Vogelstein proposed the model for colorec-tal tumorigenesis presented in Fig. 10-5.9 Colorectal tumors arise from the mutational activation of oncogenes coupled with muta-tional inactivation of tumor-suppressor genes, the latter being the predominant change.9 Mutations in at least four or five genes are required for formation of a malignant tumor, while fewer changes suffice for a benign tumor. Although genetic mutations often occur in a preferred sequence, a tumor’s biologic properties are determined by the total accumulation of its genetic changes.Gene expression is a multistep process that starts from transcription of a gene into messenger ribonucleic acid (mRNA) and then translation of this sequence into the functional protein. There are several controls at each level. In addition to alterations at the genome level (e.g., amplifications of a gene), alterations at the transcription level (e.g., methylation of the DNA leading to transcriptional silencing) or at the level of mRNA process-ing, mRNA stability, mRNA translation, or protein stability, all can alter the levels of critical proteins and thus contribute to tumorigenesis. Alternatively, changes in the genomic sequence can lead to a mutated product with altered function.Cell-Cycle Dysregulation in CancerThe proliferative advantage of tumor cells is a result of their ability to bypass a quiescent state. Cancer cells often show alterations in signal transduction pathways that lead to prolif-eration in response to external signals. Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allow-ing unregulated cell growth and proliferation.The cell cycle is divided into four phases (Fig. 10-6).10 During the synthetic or S phase, the cell generates a single copy of its genetic material, whereas in the mitotic or M phase, the cellular components (including copies of DNA) are partitioned between two daughter cells. The G1 and G2 phases represent gap phases, during which the cells prepare themselves for All cancers< 11.2< 0.3< 0.5< 0.7< 1.0< 11.2< 0.4< 0.7< 1.0< 1.6< 4.9Liver cancerStomach cancer< 13.4< 16.6< 22.5< 31.9< 2.2< 3.1< 4.1< 6.0< 11.4BreastFigure 10-3. Estimated cancer incidence worldwide in 2008. Age-standardized incidence rates per 100,000 for all cancers (upper left), breast cancer (upper right), liver cancer (lower left), and stomach cancer (lower right). (Modified with permission from Ferlay J, Shin HR, Bray F, et al: GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.)Brunicardi_Ch10_p0305-p0354.indd 31122/02/19 2:14 PM 312BASIC CONSIDERATIONSPART Icompletion of the S and M phases, respectively. When cells cease proliferation, they exit the cell cycle and enter the quies-cent state referred to as G0. The two key classes of regulatory molecules that regulate cellular progress through the cell cycle are the cyclins and the cyclin-dependent kinases (CDKs), which associate to form an activated heterodimer. CDKs are expressed constitutively and have a catalytic activity (phosphorylation of downstream proteins), whereas the cyclins serve a regula-tory function and are synthesized at specific times during the cell cycle. Two families of genes, the cip/kip (CDK interact-ing protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) family Aerobic glycolysisinhibitorsSustainingproliferativesignalingEvadinggrowthsuppressorsEnablingreplicativeimmortalityActivatinginvasion &metastasisInducingangiogenesisGenomeinstability &mutationResistingcelldeathDeregulatingcellularenergeticsTumor-promotinginflammationAvoidingimmunedestructionEGFRinhibitorsCyclin-dependentkinase inhibitorsPARPinhibitorsInhibitors ofVEGF signalingInhibitors ofHGF/c-MetTelomeraseInhibitorsSelective anti-inflammatory drugsProapoptoticBH3 mimeticsImmune activatinganti-CTLA4 oranti-PD-1 mAbFigure 10-4. Hallmarks of cancer and their therapeutic implications. Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression are in clinical trials and in some cases approved for clinical use in treating forms of human cancer. The drugs listed are illustrative examples. (Reproduced with permission from Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation, CCell. 2011 Mar 4;144(5):646-674.)First Hit: APCSomatic Mutation(Sporadic CRC)First Hit: APCGermline Mutation(FAP)K-rasGenomic InstabilitySmad 4p53OtherAlterations˜-CateninNormalEpitheliumDysplasticACFEarlyAdenomaIntermediateAdenomaLateAdenomaCarcinomaMetastasisFigure 10-5. The adenoma-carcinoma model of human colorectal carcinogenesis. The neoplastic process is initiated by mutations in the adenomatous polyposis coli (APC) or b-catenin genes. Tumor progression results from mutations in other genes (e.g., K-ras, Smad 4 and p53) and the development of genomic instability. Patients with familial adenomatous polyposis inherit mutations in the APC gene and develop multiple aberrant crypt foci. Some of these may progress to cancer as they acquire other genetic mutations. (Reproduced with permission from Li C-J, Zhang, X, Fan G-W. Updates in colorectal cancer stem cell research, J Cancer Res Ther. 2014 Dec;10 Suppl:233-239.)Brunicardi_Ch10_p0305-p0354.indd 31222/02/19 2:14 PM 313ONCOLOGYCHAPTER 10prevent the progression of the cell cycle. Mutation or altered expression of these genes can lead to tumor formation.OncogenesNormal cellular genes that contribute to cancer when abnormal are called oncogenes. The normal counterpart of such a gene is referred to as a proto-oncogene. Oncogenes are usually designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the prefix “v-” for virus or “c-” for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased pro-tein levels) by translocation (e.g., abl), promoter insertion (e.g., c-myc), mutation (e.g., ras), or amplification (e.g., HER2/neu). More than 100 oncogenes have been identified.Oncogenes may be growth factors (e.g., platelet-derived growth factor), growth factor receptors (e.g., HER2), intracel-lular signal transduction molecules (e.g., ras), nuclear tran-scription factors (e.g., c-myc), or other molecules involved in the regulation of cell growth and proliferation. Growth factors are ubiquitous proteins that are produced and secreted by cells locally and that stimulate cell proliferation by binding specific cell-surface receptors on the same cells (autocrine stimula-tion) or on neighboring cells (paracrine stimulation). Persis-tent overexpression of growth factors can lead to uncontrolled autostimulation and neoplastic transformation. Alternatively, growth factor receptors can be aberrantly activated (turned on) through mutations or overexpressed (continually presenting cells with growth-stimulatory signals, even in the absence of growth factors), which leads cells to respond as if growth factor levels are altered. The growth-stimulating effect of growth fac-tors and other mitogens is mediated through postreceptor signal Cell with duplicated chromosomesChromosome separationMitosisCell divisionCell with chromosomes in the nucleusDNA synthesisChromosome duplicationMG1SG2CDKCyclinFigure 10-6. Schematic representation of the phases of the cell cycle. Mitogenic growth factors can drive a quiescent cell from G0 into the cell cycle. Once the cell cycle passes beyond the restric-tion point, mitogens are no longer required for progression into and through S phase. The DNA is replicated in S phase, and the chromo-somes are condensed and segregated in mitosis. In early G1 phase, certain signals can drive a cell to exit the cell cycle and enter a quies-cent phase. Cell-cycle checkpoints have been identified in G1, S, G2, and M phases. CDK = cyclin-dependent kinase.transduction molecules. These molecules mediate the passage of growth signals from the outside to the inside of the cell and then to the cell nucleus, initiating the cell cycle and DNA transcrip-tion. Aberrant activation or expression of cell-signaling mol-ecules, cell-cycle molecules, or transcription factors may play an important role in neoplastic transformation. Protein tyrosine kinases account for a large portion of known oncogenes. One of the best-studied oncogenes, HER2 is discussed as an example later.HER2, also known as neu or c-erbB-2, is a member of the epidermal growth factor receptor (EGFR) family and is one of the best-characterized tyrosine kinases. Unlike other recep-tor tyrosine kinases, HER2/neu does not have a direct soluble ligand. It plays a key role in signaling, however, because it is the preferred partner in heterodimer formation with all the other EGFR family members (EGFR/c-erbB-1, HER2/c-erbB-3, and HER3/c-erbB-4), which bind at least 30 ligands, including epidermal growth factor (EGF), transforming growth factor α (TGFα), heparin-binding EGF-like growth factor, amphiregu-lin, and heregulin.11 Heterodimerization with HER2 potenti-ates recycling of receptors rather than degradation, enhances signal potency and duration, increases affinity for ligands, and increases catalytic activity.11HER2 can interact with different members of the HER fam-ily and activate mitogenic and antiapoptotic pathways (Fig. 10-7). The specificity and potency of the intracellular signals are affected by the identity of the ligand, the composition of the receptors, and the phosphotyrosine-binding proteins associated with the erbB molecules. The Rasand Shc-activated mitogen-activated protein kinase (MAPK) pathway is a target of all erbB ligands, which increase the transcriptional activity of early response genes such as c-myc, c-fos, and c-jun.12 MAPK-independent pathways such as the phosphoinositide-3 kinase (PI3K) pathway also are activated by most erbB dimers, although the potency and kinetics of activation may differ. Stimulation of the PI3K pathway through HER2 signaling also can lead to activation of survival molecule Akt, which suppresses apoptosis through mul-tiple mechanisms.The mutant rat neu gene was first recognized as an oncogene in neuroblastomas from carcinogen-treated rats.13 The HER2 gene is frequently amplified and the protein over-expressed in many cancers, including breast, ovarian, lung, gastric, and oral cancers. Overexpression of HER2 results in ligand-independent activation of HER2 kinase, which leads to mitogenic signaling. HER2 overexpression is associated with increased cell proliferation and anchorage-independent growth as well as resistance to proapoptotic stimuli. Further, overex-pression of HER2 increases cell migration and upregulates the activities of matrix metalloproteinases (MMPs) and in vitro invasiveness. In animal models, HER2 increases tumorigenic-ity, angiogenesis, and metastasis. These results all suggest that HER2 plays a key role in cancer biology. More recently, HER2 mutations have also been reported in human cancer, including 3% of patients with lung cancer.14-17 A phase 2 study of the irre-versible kinase inhibitor neratinib showed it to have efficacy in HER2-mutated breast cancer lacking HER amplification.18The critical role of HER2 in cancer biology has been lever-aged for therapeutics, leading to several HER2-targeted drugs with different mechanism of action approved by the Food and Drug Administration (FDA): monoclonal antibodies trastu-zumab and pertuzumab, small molecule inhibitor lapatinib, and antibody-drug conjugate ado-trastuzumab emtansine. Anti-HER2 agents first showed efficacy in the metastatic setting but Brunicardi_Ch10_p0305-p0354.indd 31322/02/19 2:14 PM 314BASIC CONSIDERATIONSPART Iare now routinely used as adjuvant therapy of breast cancer and also as neoadjuvant treatments (“up-front chemotherapy”).Alterations in Apoptosis in Cancer CellsApoptosis is a genetically regulated program to dispose of cells. Cancer cells must avoid apoptosis if tumors are to arise. The growth of a tumor mass is dependent not only on an increase in proliferation of tumor cells but also on a decrease in their apoptotic rate. Apoptosis is distinguished from necrosis because it leads to several characteristic changes. Soon after undergoing apoptosis, membrane phosphatidylserine translocates from the inner face of the plasma membrane to the cell surface where it can be detected via the use of a fluorescent conjugate of Annexin V, a protein that exhibits a high affinity for phosphatidylserine. Late in apoptosis there are characteristic changes in nuclear morphology, such as chromatin condensation, nuclear frag-mentation, and DNA laddering, as well as membrane blebbing. Apoptotic cells are then engulfed and degraded by phagocytic cells. The effectors of apoptosis are a family of proteases called caspases (cysteine-dependent and aspartate-directed proteases). The initiator caspases (e.g., 8, 9, and 10), which are upstream, cleave the downstream executioner caspases (e.g., 3, 6, and 7) that carry out the destructive functions of apoptosis.Two principal molecular pathways signal apoptosis by cleaving the initiator caspases with the potential for crosstalk: the mitochondrial pathway and the death receptor pathway. In the mitochondrial (or intrinsic) pathway, death results from the release of cytochrome c from the mitochondria. Cytochrome c, procaspase 9, and apoptotic protease activating factor 1 (Apaf-1) form an enzyme complex, referred to as the apoptosome, that activates the effector caspases. In addition to these proteins, the mitochondria contain other proapoptotic proteins such as Smac/DIABLO (second mitochondria-derived activator of cas-pase/direct inhibitor of apoptosis-binding protein with low pI). The mitochondrial pathway can be stimulated by many factors, including DNA damage, reactive oxygen species, or the with-drawal of survival factors. The permeability of the mitochon-drial membrane determines whether the apoptotic pathway will proceed. The Bcl-2 family of regulatory proteins includes both proapoptotic proteins (e.g., Bax, BAD, and Bak) and antiapop-totic proteins (e.g., Bcl-2 and Bcl-xL). The activity of the Bcl-2 proteins is centered on the mitochondria, where they regulate LigandsPI3KILKEZH2GSK3MDM2ForkheadCaspase-9CaspasesFas-LAktIKKBadI˜Bp27p214E-BP1TSC1/2sosGrb2ShcsrcMEKKMEKSEKMAPKSAPKELKMYCCREBJUNS6KS6elF4EAlterations in geneexpressionMigrationGrowthProliferationAngiogenesisSurvivalNF-˜BBcl-xLPLC-°IP31,2 diacyl-glycerolCa++mobilizationProteinkinase CRaf-1AdhesionmTORHER1/3/4HER2FAKRasFigure 10-7. The HER2 signaling pathway. HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways. 4E-BP1 = eIF4E binding protein 1; CREB = cyclic adenosine monophosphate element binding; eIF4E = eukaryotic initiation factor 4E; EZH = enhancer of zeste homolog; FAK = focal adhesion kinase; Fas-L = Fas ligand; GSK3 = glycogen synthase kinase-3; HER = human epidermal growth receptor; IKK = IκB kinase; ILK= integrin-linked kinase; IP3 = inositol triphosphate; IκB = inhibitor of NF-κB; MAPK = mitogen-activated protein kinase; MDM2 = mouse double minute 2 homologue; MEK = mitogen-activated protein/extracel-lular signal regulated kinase kinase; MEKK = MEK kinase; mTOR = mammalian target of rapamycin; NF-κB = nuclear factor κB; PI3K = phosphoinositide-3 kinase; PLC-γ = phospholipase Cγ; SAPK = stress-activated protein kinase; SEK = SAPK/extracellular signal regulated kinase kinase; TSC = tuberous sclerosis complex. (Modified with permission from Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy, Clin Cancer Res. 2006 Nov 1;12(21):6326-6330.)Brunicardi_Ch10_p0305-p0354.indd 31422/02/19 2:14 PM 315ONCOLOGYCHAPTER 10membrane permeability. Growth factors promote survival sig-naling through the PI3K/Akt pathway, which phosphorylates and inactivates proapoptotic BAD. In contrast, growth fac-tor withdrawal may promote apoptosis through signaling by unphosphorylated BAD. The heat shock proteins, including Hsp70 and Hsp27, are also involved in inhibition of down-stream apoptotic pathways by blocking formation of the apop-tosome complex and inhibiting release of cytochrome c from the mitochondria.19The second principal apoptotic pathway is the death recep-tor pathway, sometimes referred to as the extrinsic pathway. Cell-surface death receptors include Fas/APO1/CD95, tumor necrosis factor receptor 1, and KILL-ER/DR5, which bind their ligands Fas-L, tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL), respectively. When the receptors are bound by their ligands, they form a death-induc-ing signaling complex (DISC). At the DISC, procaspase 8 and procaspase 10 are cleaved, yielding active initiator caspases.20 The death receptor pathway may be regulated at the cell sur-face by the expression of “decoy” receptors for Fas (DcR3) and TRAIL (TRID and TRUNDD). The decoy receptors are closely related to the death receptors but lack a functional death domain; therefore, they bind death ligands but do not transmit a death signal. Another regulatory group is the FADD-like interleukin-1 protease-inhibitory proteins (FLIPs). FLIPs have homology to caspase 8; they bind to the DISC and inhibit the activation of caspase 8. Finally, inhibitors of apoptosis proteins (IAPs) block caspase 3 activation and have the ability to regulate both the death receptor and the mitochondrial pathway.In human cancers, aberrations in the apoptotic program include increased expression of Fas and TRAIL decoy receptors; increased expression of antiapoptotic Bcl-2; increased expres-sion of the IAP-related protein survivin; increased expression of c-FLIP; mutations or downregulation of proapoptotic Bax, cas-pase 8, APAF1, XAF1, and death receptors CD95, TRAIL-R1, and TRAIL-R2; alterations of the p53 pathway; overexpression of growth factors and growth factor receptors; and activation of the PI3K/Akt survival pathway.20Autophagy in Cancer CellsAutophagy (self-eating) is a major cellular pathway for protein and organelle turnover. The autophagic pathway is a mechanism for the delivery of cellular materials to lysosomes for degra-dation. This process leads to the basal turnover of cell com-ponents and provides energy and macromolecular precursors. This process helps maintain a balance between anabolism and catabolism for normal cell growth and development. Inability to activate autophagy in response to nutrient deprivation, or consti-tutive activation of autophagy in response to stress, can lead to cell death; thus, autophagy is sometimes referred to as a second form of programmed cell death. Autophagy plays an essential role during starvation, cellular differentiation, cell death, and aging. Autophagy is also involved in the elimination of cancer cells by triggering a nonapoptotic cell death program, which suggests a negative role in tumor development. Mouse models that are heterozygotes for the beclin 1 gene, an important gene for autophagy, have altered autophagic response and show a high incidence of spontaneous tumors, which establishes a role for autophagy in tumor suppression.21 This also suggests that mutations in other genes operating in this pathway may con-tribute to tumor formation through deregulation of autophagy. However, autophagy also acts as a stress response mechanism to protect cancer cells from low nutrient supply or therapeu-tic insults. Thus, in cancer, autophagy can have opposing and context-dependent roles, and interventions to both stimulate and inhibit autophagy have been proposed as possible antican-cer treatments. Studies on the molecular controls of autophagy are ongoing and are expected to generate novel therapeutic strategies. Chloroquin is an antimalarial drug that acts as an autophagic inhibitor by blocking the autophagosome and has been tested for its anticancer properties.Cancer InvasionA feature of malignant cells is their ability to invade the sur-rounding normal tissue. Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer, whereas tumors in which the malig-nant cells are demonstrated to breach the basement membrane, penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility, and proteolysis of the extracellular matrix (ECM).Cell-to-cell adhesion in normal cells involves interactions between cell-surface proteins. Calcium adhesion molecules of the cadherin family (E-cadherin, P-cadherin, and N-cadherin) are thought to enhance the cells’ ability to bind to one another and suppress invasion. Migration occurs when cancer cells pen-etrate and attach to the basal matrix of the tissue being invaded; this allows the cancer cell to pull itself forward within the tissue. Attachment to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated by tumor cell integrin recep-tors. Integrins are a family of glycoproteins that form heterodi-meric receptors for ECM molecules. The integrins can form at least 25 distinct pairings of their α and β subunits, and each pairing is specific for a unique set of ligands. In addition to regulating cell adhesion to the ECM, integrins relay molecular signals regarding the cellular environment that influence shape, survival, proliferation, gene transcription, and migration.Factors that are thought to play a role in cancer cell motil-ity include autocrine motility factor, autotaxin, scatter factor (also known as hepatocyte growth factor), TGFα, EGF, and insulin-like growth factors. Also, serine, cysteine, and aspar-tic proteinases and MMPs have all been implicated in cancer invasion. Urokinase and tissue plasminogen activators (uPA and tPA) are serine proteases that convert plasminogen into plasmin. Plasmin, in return, can degrade several ECM components. Plas-min also may activate MMPs. uPA has been more closely corre-lated with tissue invasion and metastasis than tPA. Plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) are produced in tissues and counteract the activity of plasminogen activators.MMPs comprise a family of metal-dependent endopepti-dases. Upon activation, MMPs degrade a variety of ECM com-ponents. Although MMPs often are referred to by their common names, which reflect the ECM component for which they have specificity, a sequential numbering system has been adopted for standardization. For example, collagenase-1 is now referred to as MMP-1. The MMPs are further classified as secreted and membrane-type MMPs. Most of the MMPs are synthesized as inactive zymogens (pro-MMP) and are activated by proteolytic removal of the propeptide domain outside the cell by other active MMPs or serine proteinases.MMPs are upregulated in almost every type of cancer. Some of the MMPs are expressed by cancer cells, whereas others are expressed by the tumor stromal cells. Experimental models have demonstrated that MMPs promote cancer progression by Brunicardi_Ch10_p0305-p0354.indd 31522/02/19 2:14 PM 316BASIC CONSIDERATIONSPART Iincreasing cancer cell growth, migration, invasion, angiogenesis, and metastasis. MMPs exert these effects by cleaving not only structural components of the ECM but also growth factor–binding proteins, growth factor precursors, cell adhesion molecules, and other proteinases to provide a growth advantage. The activity of MMPs is regulated by their endogenous inhibitors and tissue inhibitors of MMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4).AngiogenesisAngiogenesis is the establishment of new blood vessels from a preexisting vascular bed. This neovascularization is essential for tumor growth and metastasis. Tumors develop an angiogenic phenotype as a result of accumulated genetic alterations and in response to local selection pressures such as hypoxia. Many of the common oncogenes and tumor-suppressor genes have been shown to play a role in the induction of angiogenesis.In response to the angiogenic switch, pericytes retract and the endothelium secretes several growth factors such as basic fibroblast growth factor, platelet-derived growth fac-tor (PDGF), and insulin-like growth factor. The basement membrane and stroma around the capillary are proteolytically degraded, a process that is mediated in most part by uPA. The endothelium then migrates through the degraded matrix, ini-tially as a solid cord and later forming lumina. Finally, sprout-ing tips anastomose to form a vascular network surrounded by a basement membrane.Angiogenesis is mediated by factors produced by various cells, including tumor cells, endothelial cells, stromal cells, and inflammatory cells. The first proangiogenic factor was identi-fied by Folkman and colleagues in 1971.22 Since then, several other factors have been shown to be proangiogenic or antian-giogenic. Of the angiogenic stimulators, the best studied are the vascular endothelial growth factors (VEGFs). The VEGF fam-ily consists of six growth factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor) and three receptors (VEGFR1 or Flt-1, VEGFR2 or KDR/FLK-1, and VEGFR3 or Flt-4).23 Neuropilin 1 and 2 also may act as recep-tors for VEGF.24 VEGF is induced by hypoxia and by different growth factors and cytokines, including EGF, PDGF, TNF-α, TGFβ, and interleukin-1β. VEGF has various functions, includ-ing increasing vascular permeability, inducing endothelial cell proliferation and tube formation, and inducing endothelial cell synthesis of proteolytic enzymes such as uPA, PAI-1, uroki-nase plasminogen activator receptor, and MMP-1. Furthermore, VEGF may mediate blood flow by its effects on the vasodila-tor nitric oxide and act as an endothelial survival factor, thus protecting the integrity of the vasculature. The proliferation of new lymphatic vessels, lymphangiogenesis, is also thought to be controlled by the VEGF family. Signaling in lymphatic cells is thought to be modulated by VEGFR3.25 Experimental studies with VEGF-C and VEGF-D have shown that they can induce tumor lymphangiogenesis and direct metastasis via the lymphatic vessels and lymph nodes.25,26PDGFs A, B, C, and D also play important roles in angio-genesis. PDGFs are produced by tumor cells as well as support-ing cells in the tumor microenvironment. PDGFs can enhance endothelial cell proliferation directly, and they can also upreg-ulate VEGF expression in vascular smooth muscle cells, pro-moting endothelial cell survival via a paracrine effect.23 The angiopoietins, angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), are thought to regulate blood vessel maturation. Ang-1 and Ang-2 both bind to the angiopoietin-1 receptor (also known as tyrosine-protein kinase receptor TIE-2), but only the binding of Ang-1 activates signal transduction; thus Ang-2 is an Ang-1 antagonist. Ang-1, via the Tie-2 receptor, induces remodel-ing and stabilization of blood vessels. Therefore, the balance between these factors determines the angiogenetic capacity of a tumor.Tumor angiogenesis is regulated by several factors in a coordinated fashion. In addition to upregulation of proangiogenic molecules, angiogenesis also can be encouraged by suppression of naturally occurring inhibitors. Such inhibitors of angiogen-esis include thrombospondin 1 and angiostatin. Angiogenesis is a prerequisite not only for primary tumor growth but also for metastasis. Angiogenesis in the primary tumor, as determined by microvessel density, has been demonstrated to be an inde-pendent predictor of distant metastatic disease and survival in several cancers. Expression of angiogenic factors such as VEGFs has had prognostic value in many studies. These findings further emphasize the importance of angiogenesis in cancer biology.MetastasisMetastases arise from the spread of cancer cells from the pri-mary site and the formation of new tumors in distant sites. The metastatic process consists of a series of steps that need to be completed successfully (Fig. 10-8).27 First, the primary cancer must develop access to the circulation through either the blood circulatory system or the lymphatic system. After the cancer cells are shed into the circulation, they must survive. Next, the circulating cells lodge in a new organ and extravasate into the new tissue. Next, the cells need to initiate growth in the new tis-sue and eventually establish vascularization to sustain the new tumor. Overall, metastasis is an inefficient process, although the initial steps of hematogenous metastasis (the arrest of tumor cells in the organ and extravasation) are believed to be per-formed efficiently. Only a small subset of cancer cells is then able to initiate micrometastases, and an even smaller portion goes on to grow into macrometastases.Metastases can sometimes arise several years after the treatment of primary tumors. For example, although most breast cancer recurrences occur within the first 10 years after the initial treatment and recurrences are rare after 20 years, breast cancer recurrences have been reported decades after the original tumor. This phenomenon is referred to as dormancy, and it remains one of the biggest challenges in cancer biology. Persistence of solitary cancer cells in a secondary site such as the liver or bone marrow is one possible contributor to dormancy.28 Another explanation of dormancy is that cells remain viable in a qui-escent state and then become reactivated by a physiologically perturbing event. Interestingly, primary tumor removal has been proposed to be a potentially perturbing factor.29 An alternate explanation is that cells establish preangiogenic metastases in which they continue to proliferate but that the proliferative rate is balanced by the apoptotic rate. Therefore, when these small metastases acquire the ability to become vascularized, substan-tial tumor growth can be achieved at the metastatic site, leading to clinical detection. More recently, it has been proposed that dormancy may be the result of the host losing immunologic con-trol of subclinical metastatic foci of disease either through loss of immune cell populations with antigen-specific capabilities or via the mutation of tumor cells such that their immunogenicity is altered.30Several types of tumors metastasize in an organ-specific pattern. One explanation for this is mechanical and is based on Brunicardi_Ch10_p0305-p0354.indd 31622/02/19 2:14 PM 317ONCOLOGYCHAPTER 10the different circulatory drainage patterns of the tumors. When different tumor types and their preferred metastasis sites were compared, 66% of organ-specific metastases were explained on the basis of blood flow alone. The other explanation for pref-erential metastasis is what is referred to as the “seed and soil” theory, the dependence of the seed (the cancer cell) on the soil (the secondary organ). According to this theory, once cells have reached a secondary organ, their growth efficiency in that organ is based on the compatibility of the cancer cell’s biology with its new microenvironment. For example, breast cancer cells may grow more efficiently in bone than in some other organs because of favorable molecular interactions that occur in the bone microenvironment. The ability of cancer cells to grow in a specific site likely depends on features inherent to the cancer cell, features inherent to the organ, and the interplay between the cancer cell and its microenvironment.31Many of the oncogenes discovered to date, such as HER2 and ras, are thought to potentiate not only malignant transforma-tion but also one or more of the steps required in the metastatic process. Experimental models have suggested a role for several molecules, including RhoC, osteopontin and interleukin-11, and Twist, in tumor metastasis. Metastasis also may involve the loss of metastasis-suppressor genes. Laboratory work involving cancer cell lines that have been selected to have a higher meta-static potential have led to the realization that these more highly metastatic cells have a different gene expression profile than their less metastatic parental counterparts. This in turn has led to the currently held belief that the ability of a primary tumor to metastasize may be predictable by analysis of its gene expres-sion profile. Indeed, several studies have focused on identify-ing a gene expression profile or a molecular signature that is associated with metastasis. It has been shown that such a gene expression profile can be used to predict the probability that the patient will remain free of distant metastasis.32 This suggests that the metastatic potential of a tumor is already predetermined by the genetic alterations that the cancer cells acquire early in tumorigenesis. Notably, this hypothesis differs from the mul-tistep tumorigenesis theory in that the ability to metastasize is considered an inherent quality of the tumor from the beginning. It is assumed that metastasis develops not from a few rare cells in the primary tumor that acquire the ability to metastasize but that all cells in tumors with such molecular signatures develop the ability to metastasize. The reality probably lies in between since some early genetic changes detectable in the entire tumor can give tumors an advantage in the metastatic process, whereas additional genetic changes can give a clone of cells additional advantages, thus allowing them to succeed in metastasis.Epithelial-Mesenchymal TransitionA regulatory program referred to as epithelial-mesenchymal transition (EMT) is a fundamental event in morphogenesis. During EMT, epithelial cells are converted to migratory and Figure 10-8. A schematic representation of the metastatic process. A. The metastatic process begins with an in situ cancer surrounded by an intact basement membrane. B. Invasion requires reversible changes in cell-cell and cell-extracellular matrix adherence, destruction of proteins in the matrix and stroma, and motility. C. Metastasizing cells can enter the circulation via the lymphatics. D. They can also directly enter the circulation. E. Intravascular survival of the tumor cells and extravasation of the circulatory system follow. F. Metastatic single cells can colonize sites and remain dormant for years as occult micrometastases. G. Subsequent progression and neovascularization leads to clinically detectable metastases and progressively growing, angiogenic metastases. (Reproduced with permission Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells, Nat Rev Cancer. 2003 Jan;3(1):55-63.)Brunicardi_Ch10_p0305-p0354.indd 31722/02/19 2:14 PM 318BASIC CONSIDERATIONSPART Iinvasive mesenchymal cells.33 EMT has also been implicated as the mechanism through which epithelial cells acquire the abil-ity to migrate, invade, resist apoptosis, and metastasize in the setting of cancer. EMT is a developmental process, and a set of pleiotropically acting transcriptional factors, including Snail, Twist, Slug, and Zeb1/2 orchestrate EMT. Several of these tran-scription factors can directly repress E-cadherin gene expression reducing levels of this key suppressor of motility and invasive-ness in cancer cells. This process also entails the induction of mesenchymal markers such as vimentin. It has been proposed that the process of invasion and metastases requires significant plasticity, suggesting that EMT is required for invasion, intrava-sation, and extravasation. Thus, suppression of EMT regulators (and consequently EMT reversion, or MET) can be important for metastatic outgrowth.34-36Cancer Stem CellsStem cells are cells that have the ability to perpetuate them-selves through self-renewal and to generate mature cells of a particular tissue through differentiation.37 It has been proposed that stem cells themselves may be the target of transformation. It was first documented for leukemia and multiple myeloma that only a small subset of cancer cells is capable of extensive prolif-eration. It has subsequently also been shown for many solid can-cers that only a small proportion of cells is clonogenic in culture and in vivo. Similarly, in many solid tumor types only a small proportion of cells is clonogenic in culture and in vivo. If indeed tumor growth and metastasis are driven by a small population of cancer stem cells, this may alter our current approaches to cancer therapy. Currently available drugs can shrink metastatic tumors but often cannot eradicate them. The failure of these treatments usually is attributed to the acquisition of drug resistance by the cancer cells; however, the cancer stem cell hypothesis raises the possibility that existing therapies may simply fail to kill cancer stem cells effectively. Therapeutic approaches targeting stem cells specifically are under study.CANCER ETIOLOGYCancer GenomicsOne widely held opinion is that cancer is a genetic disease that arises from an accumulation of genomic alterations that leads to the selection of cells with increasingly aggressive behavior. These alterations may lead either to a gain of function by onco-genes or to a loss of function by tumor-suppressor genes. These acquired gene alterations present within the tumor are termed somatic mutations to distinguish them from germline mutations that are inherited from parents and transmitted to offspring. Somatic mutations in a cancer genome may consist of several classes of DNA sequence changes. These include substitutions of one base by another; insertions or deletions of small or large segments of DNA; rearrangements, in which the DNA sequence has been broken and then rejoined to another DNA segment; copy number losses that may result in complete absence of a DNA sequence; and copy number gains over and above the two copies present in the normal diploid genome.Somatic mutations in a cancer cell genome have accumu-lated over the lifetime of the patient (Fig. 10-9).38 DNA in normal cells is continuously damaged by internal and external mutagens. Most of this damage is repaired; however, a small fraction may remain as fixed mutations. Mutation rates increase in the pres-ence of substantial exogenous mutagenic exposures, such as tobacco carcinogens or various forms of radiation, including ultraviolet light. These exposures are associated with increased rates of lung and skin cancer, respectively, and somatic muta-tions within such cancers often exhibit the distinctive mutational signatures known to be associated with the mutagen.39 The rates of somatic mutations are also increased in several rare inher-ited diseases, such as Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum, which are associated with increased risks of cancer.40,41 The rest of the somatic mutations in a can-cer cell have been acquired after the cancer cell already shows phenotypic evidence of neoplastic change. Whether the somatic AdulthoodEarly clonalexpansionBenigntumorEarly invasivecancerLate invasivecancerChemotherapy-resistantrecurrenceFertilized eggIntrinsicmutation processesPassenger mutationDriver mutationChemotherapyresistance mutationEnvironmentaland lifestyle exposures10s–1,000s of mitosesdepending on the organ10s–100s of mitosesdepending on the cancer10s–100,000 of morepassenger mutationsMutatorphenotypeChemotherapy1–10 or moredriver mutationsGestationInfancyChildhoodFigure 10-9. Accumulation of somatic mutations acquired by the cancer cell. Mutations may be acquired while the cell lineage is phenotypi-cally normal, reflecting intrinsic mutations acquired during normal cell division as well as the effects of exogenous mutagens. Other processes such as example DNA repair defects may contribute to the mutational burden. Passenger mutations do not have any effect on the cancer cell, but driver mutations cause clonal expansion. Relapse after chemotherapy can be associated with resistance mutations that may predate the initiation of treatment. (Reproduced with permission from Stratton MR, Campbell PJ, Futreal PA. The cancer genome, Nature. 2009 Apr 9;458(7239):719-724.)Brunicardi_Ch10_p0305-p0354.indd 31822/02/19 2:14 PM 319ONCOLOGYCHAPTER 10mutation rate is always higher during this part of the lineage is controversial. This is clearly the case for some cancers. For instance, colorectal and endometrial cancers with defective DNA mismatch repair due to abnormalities in genes such as MLH1 and MSH2, exhibit increased rates of single nucleotide changes and small insertions/deletions at repetitive noncoding polynucleotide tracts known as microsatellites.42 It has been proposed that one early step in tumor progression is the development of a “mutator phenotype” that is the result of mutations in genes that normally function in the maintenance of genetic stability. This hypothesis was formulated in order to account for the disparity between the low frequency of spontaneous mutations in normal cells as com-pared to the large number of mutations seen in human tumors.To date about 300 genes that have been reported to be mutated and causally implicated in cancer development.43 Ninety percent of cancer genes are mutated at the somatic or tumor level, 20% show germline mutations, and 10% show both. The most common class of genomic alterations among the known cancer genes is a chromosomal translocation that creates a chi-meric gene. Many more cancer genes have been found in leuke-mias, lymphomas, and sarcomas than in other types of cancer; and these genes are usually altered by chromosomal transloca-tion. The most common cancer genes are protein kinases. Several domains that are involved in DNA binding and transcriptional regulation are also common in proteins encoded by cancer genes. Somatic mutations in a cancer genome may be classified according to its consequences for cancer development. “Driver” mutations confer a growth advantage to the cells carrying them and have been positively selected during the evolution of the cancer. The remainder of mutations are “bystanders” or “pas-sengers” that do not confer growth advantage. It is likely that most somatic mutations are passenger mutations. Each tumor may have dozens to hundreds of genomic alterations, making it critical to determine which alterations are indeed drivers, and potentially better therapeutic targets.There have been many recent advancements in large-scale databases and tools to catalogue and interpret genomic vari-ants in cancer patient populations. Currently, the NCI Genomic Data Commons provides a unified data repository, The Cancer Genome Atlas (TCGA), the NCI Center for Cancer Genomics (CCG), and the childhood cancer initiative entitled Therapeu-tically Applicable Research to Generate Effective Treatments (TARGET), as well as a suite of tools for users to interact with the GDC data and provide their own data. Other cancer genome repositories include the Catalogue of Somatic Mutations in Can-cer (COSMIC) and the International Cancer Genome Consor-tium (ICGC).44 The Precision Medicine Initiative launched in 2016 that includes the All of Us Research Program, which will collect genetic data, biologic samples, and other clinical informa-tion from at least 1 million volunteer participants. To facilitate the clinical and biologic interpretation of genomic variants in cancer genomes, several open-access tools have been developed and expanded, including MuSiC, MutSigCV, and OncodriveFM. Other curated database resources used to annotate clinical pheno-types to variants observed in cancer genomes include ClinVAR, Clinical Interpretation of Variants in Cancer (CiVic), and the Precision Medicine Knowledgebase (PMKB). These resources and tools are being utilized to conduct pan-cancer analyses to characterize genomic variation and other molecular aberra-tions observed across tumors to define cancer drivers, clinically actionable targets, and prognostic and predictive signatures. This information is being integrated into clinical practice in many UnknownKIF5B-RETROS1 fusionsNRASMAP2K1AKT1PIK3CABRAFHER2ALKfusionsKRASEGFRFigure 10-10. Molecular subsets of lung adenocarcinoma. Pie chart shows the percentage of tumors with each potentially action-able alteration. (Reproduced with permission from Pao W, Hutchinson KE. Chipping away at the lung cancer genome, Nat Med. 2012 Mar 6;18(3):349-351.)Hereditary:Nonhereditary:TumorTumorFigure 10-11. Tumor heterogeneity. A. Patients with tumors with similar histologies may differ in genetic mutation status and other molecular features B. Cells within the primary tumor can acquire or lose genomic alterations in different metastatic sites. C. Intra-tumoral spatial heterogeneity: common initiating genomic events usually exist in all tumor cells but additional spatially separated heterogeneous somatic mutations or copy number changes may accumulate within an individual tumor. (Reproduced with permis-sion from Knudson AG: Two genetic hits (more or less) to cancer, Nat Rev Cancer. 2001 Nov;1(2):157-162.)tumor types, such as lung cancer, where molecular drivers are being taken into consideration when selecting systemic therapies (Fig. 10-10). TCGA data was recently leveraged in a study to identify TRK fusions in tumors from six different cancer types, which led to the development of novel TRK inhibitor therapies.Tumor Heterogeneity and Molecular EvolutionThere is increasing recognition that tumors are heterogeneous; this represents an important challenge to utilizing genomic alterations to personalize cancer therapy (Fig. 10-11).45 First, Brunicardi_Ch10_p0305-p0354.indd 31922/02/19 2:14 PM 320BASIC CONSIDERATIONSPART Ithere may be significant heterogeneity between cancer patients, such that patients with tumors that seem similar histologically, may differ in genomic alterations and in malignant potential.46-48 Second, during cancer progression, subclones frequently arise, resulting in differences in the proportion and pattern of genomic alterations between the primary tumor and the metastases or local-regional recurrences.45 Third, there may also be signifi-cant heterogeneity within any one tumor deposit, with spatially separated heterogeneous somatic mutations and chromosomal imbalances.49 Such spatial heterogeneity of subclones within the primary tumor or metastases provides an additional challenge, as it has been proposed that sequencing of a biopsy specimen or only a portion of the tumor could miss therapeutically rel-evant genomic alterations. The genomic alterations found in a tumor can also change under the selective pressure of a targeted therapy, adding to the challenge of implementing genomically informed personalized therapy.Genes Associated With Hereditary Cancer RiskMost of our information on human cancer genes has been gained from hereditary cancers. In the case of hereditary cancers, the individual carries a particular germline mutation in every cell. To date, over 70 genes have been associated with hereditary cancers (Table 10-3).43 A few of these hereditary cancer genes are oncogenes, but most are tumor-suppressor genes. Although hereditary cancer syndromes are rare, somatic mutations that occur in sporadic cancer have been found to disrupt the cellular pathways altered in hereditary cancer syndromes, which sug-gests that these pathways are critical to normal cell growth, cell cycle, and proliferation. Recently, the results of a genome-wide association study of breast cancer in over 120,000 cases and 100,000 controls identified 65 new loci that are associated with overall breast cancer risk.50The following factors may suggest the presence of a hereditary cancer51:1. Tumor development at a much younger age than usual2. Presence of bilateral disease3. Presence of multiple primary malignancies4. Presentation of a cancer in the less affected sex (e.g., male breast cancer)5. Clustering of the same cancer type in relatives6. Occurrence of cancer in association with other conditions such as mental retardation or pathognomonic skin lesionsIt is crucial that all surgeons caring for cancer patients be aware of hereditary cancer syndromes, because a patient’s genetic background has significant implications for patient and family counseling, planning of surgical therapy, and cancer screening and prevention. Some of the more commonly encoun-tered hereditary cancer syndromes are discussed here.rb1Gene. The retinoblastoma gene rb1 was the first tumor sup-pressor to be cloned. The rb1 gene product, the Rb protein, is a regulator of transcription that controls the cell cycle, differen-tiation, and apoptosis in normal development.52 Retinoblastoma has long been known to occur in hereditary and nonhereditary forms. Interestingly, although most children with an affected parent develop bilateral retinoblastoma, some develop unilateral retinoblastoma. Furthermore, some children with an affected parent are not affected themselves but then have an affected child, which indicates that they are rb1 mutation carriers. These findings led to the theory that a single mutation is not sufficient for tumorigenesis. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, of which one is germ-line and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations (Fig. 10-12).53 Thus, both heredi-tary and nonhereditary forms of retinoblastoma involve the same number of mutations, a hypothesis known as Knudson’s “two-hit” hypothesis. A “hit” may be a point mutation, a chro-mosomal deletion referred to as allelic loss, or a loss of hetero-zygosity, or silencing of an existing gene. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma.p53 and Li-Fraumeni Syndrome. Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia.54 Criteria for classic LFS in an individual (the proband) include: (a) a bone or soft tissue sarcoma when younger than 45 years, (b) a first-degree relative with cancer before age 45 years, and (c) another firstor second-degree relative with either a sar-coma diagnosed at any age or any cancer diagnosed before age 45 years.55 Approximately 70% of LFS families have been shown to have germline mutations in the tumor-suppressor gene p53.56 Breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms’ tumor, and phyllodes tumor of the breast are strongly associated; pancre-atic cancer is moderately associated; and leukemia and neuro-blastoma are weakly associated with germline p53 mutations.57 Mutations of p53 have not been detected in approximately 30% of LFS families, and it is hypothesized that genetic alterations in other proteins interacting with p53 function may play a role in these families.Of the known genes in human cancer, p53 is the most commonly mutated within cancer cells. The p53 protein regu-lates cell-cycle progression as well as apoptotic cell death as part of stress response pathways after exposure to ionizing or ultraviolet (UV) irradiation, chemotherapy, acidosis, growth factor deprivation, or hypoxia. When cells are exposed to stress-ors, p53 acts as a transcription factor for genes that induce cell-cycle arrest or apoptosis. A majority of p53 mutations are found within a central DNA recognition motif and disrupt DNA bind-ing by p53. Families with germline missense mutations in the DNA-binding domain show a more highly penetrant phenotype than families with other p53 mutations.58 Furthermore, proband cancers are linked with significantly younger age at diagnosis in patients with missense mutations in the DNA-binding domain.58 It has become apparent that children and adults with LFS will benefit from intensive surveillance aimed at early detection of cancers and a modified version of the “Toronto protocol” that includes a combination of physical exams, blood tests, and imaging is recommended.BRCA1, BRCA2, and Hereditary Breast-Ovarian Cancer Syndrome. It is estimated that 5% to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (age 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genes BRCA1 or BRCA2.59 Mutation carriers are more prevalent among women who have a firstor second-degree relative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of a BRCA mutation is higher in patients who belong to a population in which founder Brunicardi_Ch10_p0305-p0354.indd 32022/02/19 2:14 PM 321ONCOLOGYCHAPTER 10Table 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMEALKanaplastic lymphoma kinase (Ki-1)NeuroblastomaFamilial neuroblastomaAPCadenomatous polyposis of the colon geneColorectal, pancreatic, desmoid, hepatoblastoma, glioma, other CNSAdenomatous polyposis coli; Turcot syndromeATMataxia telangiectasia mutatedLeukemia, lymphoma, medulloblastoma, gliomaAtaxia-telangiectasiaBLMBloom syndromeLeukemia, lymphoma, skin squamous cell, other cancersBloom syndromeBMPR1Abone morphogenetic protein receptor, type IAGastrointestinal polypsJuvenile polyposisBRCA1familial breast/ovarian cancer gene 1Breast, ovarianHereditary breast/ovarian cancerBRCA2familial breast/ovarian cancer gene 2Breast, ovarian, pancreaticHereditary breast/ovarian cancerBRIP1BRCA1 interacting protein C-terminal helicase 1AML, leukemia, breastFanconi anemia J, breast cancer susceptibilityBUB1BBUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)RhabdomyosarcomaMosaic variegated aneuploidyCDH1cadherin 1, type 1, E-cadherin (epithelial) (ECAD)Gastric, lobular cancerFamilial gastric carcinomaCDK4cyclin-dependent kinase 4MelanomaFamilial malignant melanomaCDKN2Acyclin-dependent kinase inhibitor 2A (p16[INK4a]) geneMelanoma, pancreaticFamilial malignant melanomaCDKN2a(p14)cyclin-dependent kinase inhibitor 2A– p14ARF proteinMelanoma, pancreaticFamilial malignant melanomaCHEK2CHK2 checkpoint homolog (S pombe)BreastFamilial breast cancerCYLDfamilial cylindromatosis geneCylindromaFamilial cylindromatosisDDB2damage-specific DNA binding protein 2Skin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (E)DICER1dicer 1, ribonuclease type IIIPleuropulmonary blastomaFamilial pleuropulmonary blastomaEGFRepidermal growth factor receptor (erythroblastic leukemia viral [v-erb-b] oncogene homolog, avian)NSCLCFamilial lung cancerERCC2, 3, 4, 5excision repair cross-complementing rodent repair deficiency, complementation groupSkin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (D, B, F, G)EXT1multiple exostoses type 1 geneexostoses, osteosarcomaexostoses, osteosarcomaFANCA, C, D2, E, F, GFanconi anemia, complementation groupAML, leukemiaFanconi anemia A, C, D2, E, F, GFHfumarate hydrataseleiomyomatas, renalHereditary leiomyomatosis and renal cell cancerGPC3glypican 3Wilms’ tumorSimpson-Golabi-Behmel syndromeHRASv-Ha-ras Harvey rat sarcoma viral oncogene homologv-Ha-ras Harvey rat sarcoma viral oncogene homologCostello syndromeHRPT2Hyperparathyroidism 2 (parafibromin)parathyroid adenoma, multiple ossifying jaw fibromaHyperparathyroidism-jaw tumor syndrome(Continued)Brunicardi_Ch10_p0305-p0354.indd 32122/02/19 2:14 PM 322BASIC CONSIDERATIONSPART ITable 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMEKITv-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologGIST, epitheliomaFamilial gastrointestinal stromal tumorMADH4Homolog of Drosophila Mothers Against Decapentaplegic 4 geneGastrointestinal polypsJuvenile polyposisMEN1multiple endocrine neoplasia type 1 geneParathyroid adenoma, pituitary adenoma, pancreatic islet cell, carcinoidParathyroid adenoma, pituitary adenoma, pancreatic islet cell, carcinoidMLH1E coli MutL homolog geneColorectal, endometrial, ovarian, CNSHereditary nonpolyposis colorectal cancer, Turcot syndromeMPLmyeloproliferative leukemia virus oncogene, thrombopoietin receptorMPDFamilial essential thrombocythemiaMSH2mutS homolog 2 (E coli)colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerMSH6mutS homolog 6 (E coli)colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerMUTYHmutY homolog (E coli)ColorectalAdenomatous polyposis coliNBS1Nijmegen breakage syndrome 1 (nibrin)NHL, glioma, medulloblastoma, rhabdomyosarcomaNijmegen breakage syndromeNF1neurofibromatosis type 1 geneNeurofibroma, gliomaNeurofibromatosis type 1NF2neurofibromatosis type 2 geneMeningioma, acoustic neuromaNeurofibromatosis type 2PALB2partner and localizer of BRCA2Wilms tumor, medulloblastoma, AML, breastFanconi anemia N, breast cancer susceptibilityPHOX2Bpaired-like homeobox 2bNeuroblastomaFamilial neuroblastomaPMS1PMS1 postmeiotic segregation increased 1 (S cerevisiae)Colorectal, endometrial, ovarianHereditary non-polyposis colorectal cancerPMS2PMS2 postmeiotic segregation increased 2 (S cerevisiae)Colorectal, endometrial, ovarian, medulloblastoma, gliomaHereditary nonpolyposis colorectal cancer, Turcot syndromePRKAR1Aprotein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)Myxoma, endocrine, papillary thyroidCarney complexPTCHHomolog of Drosophila Patched geneSkin basal cell, medulloblastomaNevoid basal cell carcinoma syndromePTENphosphatase and tensin homolog geneHamartoma, glioma, prostate, endometrialCowden syndrome, Bannayan-Riley-Ruvalcaba syndromeRB1retinoblastoma geneRetinoblastoma, sarcoma, breast, small cell lungFamilial retinoblastomaRECQL4RecQ protein-like 4Osteosarcoma, skin basal and squamous cellRothmund-Thompson syndromeRETret proto-oncogeneMedullary thyroid, papillary thyroid, pheochromocytomaMultiple endocrine neoplasia 2A/2BSBDSShwachman-Bodian-Diamond syndrome proteinAML, MDSSchwachman-Diamond syndrome(Continued)(Continued)Brunicardi_Ch10_p0305-p0354.indd 32222/02/19 2:14 PM 323ONCOLOGYCHAPTER 10Table 10-3Selected genes associated with hereditary cancerSYMBOLNAMETUMOR TYPES (GERMLINE MUTATIONS)CANCER SYNDROMESDH5chromosome 11 open reading frame 79ParagangliomaFamilial paragangliomaSHD, B, Dsuccinate dehydrogenase complexParaganglioma, pheochromocytomaFamilial paragangliomaSMARCB1SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1Malignant rhabdoidRhabdoid predisposition syndromeSTK11serine/threonine kinase 11 gene (LKB1)Jejunal hamartoma, ovarian, testicular, pancreaticPeutz-Jeghers syndromeSUFUsuppressor of fused homolog (Drosophila)MedulloblastomaMedulloblastoma predispositionTCF1transcription factor 1, hepatic (HNF1)Hepatic adenoma, hepatocellular carcinomaFamilial Hepatic AdenomaTP53tumor protein p53Breast, sarcoma, adrenocortical carcinoma, glioma, multiple other tumor typesLi-Fraumeni syndromeTSC1tuberous sclerosis 1 geneHamartoma, renal cellTuberous sclerosis 1TSC2tuberous sclerosis 2 geneHamartoma, renal cellTuberous sclerosis 2TSHRthyroid stimulating hormone receptorThyroid adenoma VHLvon Hippel-Lindau syndrome geneRenal, hemangioma, pheochromocytomavon Hippel-Lindau syndromeWRNWerner syndrome (RECQL2)Osteosarcoma, meningioma, othersWerner syndromeWT1Wilms’ tumor 1 geneWilms’Denys-Drash syndrome, Frasier syndrome, Familial Wilms tumorXPA, Cxeroderma pigmentosum, complementation groupSkin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (A C)A = amplification; AEL = acute eosinophilic leukemia; AL = acute leukemia; ALCL = anaplastic large-cell lymphoma; ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; AML = acute myelogenous leukemia (primarily treatment associated); APL = acute promyelocytic leukemia; B-ALL = B-cell acute lymphocytic leukemia; B-CLL = B-cell lymphocytic leukemia; B-NHL = B-cell non-Hodgkin’s lymphoma; CLL = chronic lymphatic leukemia; CML = chronic myeloid leukemia; CMML = chronic myelomonocytic leukemia; CNS = central nervous system; D = large deletion; DFSP = dermatofibrosarcoma protuberans; DLBL = diffuse large B-cell lymphoma; DLCL = diffuse large-cell lymphoma; Dom = dominant; E = epithelial; F = frameshift; GIST = gastrointestinal stromal tumor; JMML = juvenile myelomonocytic leukemia; L = leukemia/lymphoma; M = mesenchymal; MALT = mucosa-associated lymphoid tissue lymphoma; MDS = myelodysplastic syndrome; Mis = Missense; MLCLS = mediastinal large cell lymphoma with sclerosis; MM = multiple myeloma; MPD = myeloproliferative disorder; N = nonsense; NHL = non-Hodgkin’s lymphoma; NK/T = natural killer T cell; NSCLC = non-small cell lung cancer; O = other; PMBL = primary mediastinal B-cell lymphoma; pre-B All = pre-B-cell acute lymphoblastic leukemia; Rec = recessive; S = splice site; T = translocation; T-ALL = T-cell acute lymphoblastic leukemia; T-CLL = T-cell chronic lymphocytic leukemia; TGCT = testicular germ cell tumor; T-PLL = T-cell prolymphocytic leukemia.Adapted with permission from Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes. Nat Rev Cancer. 2004 Mar;4(3):177-183.(Continued)mutations may be prevalent, such as in the Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the cumula-tive risks of developing breast cancer and ovarian cancer by age 70 have been estimated to be 87% and 44%, respectively.60 The cumulative risks of breast cancer and ovarian cancer by age 70 in families with BRCA2 mutation have been estimated to be 84% and 27%, respectively.61 Although male breast cancer can occur with either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2.61 Besides breast and ovar-ian cancer, BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate cancer.60 BRCA2 mutations confer a fivefold increased risk for prostate cancer, sevenfold in men younger than 65 years.62 Furthermore, BRCA2 mutations confer Brunicardi_Ch10_p0305-p0354.indd 32322/02/19 2:14 PM 324BASIC CONSIDERATIONSPART Ia fivefold increased risk for gallbladder and bile duct cancers, fourfold increased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma.62BRCA1 was the first breast cancer susceptibility gene identi-fied and has been mapped to 17q21. BRCA2, mapped to 13q12.3, was reported shortly afterward. BRCA1 and BRCA2 encode large nuclear proteins, 208 kDa and 384 kDa, respectively, that have been implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of the cell cycle, and transcription.63 Although early studies suggested that the two proteins function together as a complex, subsequent data demonstrated that they have distinct functions.64,65 In fact, breast cancers arising from BRCA1 or BRCA2 mutations are different at the molecular level and have been found to have distinct gene expression profiles.66 BRCA1-associated tumors are more likely to be estrogen receptor negative, whereas BRCA2-associated tumors are more likely to be estrogen receptor positive. Cur-rently, studies are ongoing to determine whether BRCA1 and BRCA2 status can be used to guide systemic therapy choices for breast cancer. Some targeted therapies are showing activity in BRCA mutation carriers with breast cancer such as PARP poly(ADP-ribose) polymerase-inhibitors.APC Gene and Familial Adenomatous PolyposisPatients affected with familial adenomatous polyposis (FAP) characteristically develop hundreds to thousands of polyps in the colon and rectum. The polyps usually appear in adolescence and, if left untreated, progress to colorectal cancer. FAP is asso-ciated with benign extracolonic manifestations that may be use-ful in identifying new cases, including congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and osteo-mas. In addition to colorectal cancer, patients with FAP are at risk for upper intestinal neoplasms (gastric and duodenal pol-yps, duodenal and periampullary cancer), hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), thyroid carcinomas, desmoid tumors, and medulloblastomas.The product of the adenomatous polyposis coli tumor-sup-pressor gene (APC) plays an important role in cell-cell interac-tions, cell adhesion, regulation of β-catenin, and maintenance of cytoskeletal microtubules. Alterations in APC lead to dys-regulation of several physiologic processes that govern colonic epithelial cell homeostasis, including cell-cycle progression, migration, differentiation, and apoptosis. Mutations in the APC have been identified in FAP and in 80% of sporadic colorectal cancers.67 Furthermore, APC mutations are the earliest known genetic alterations in colorectal cancer progression, which emphasizes its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally inactive protein. The risk of developing specific manifestations of FAP is correlated with the position of the FAP mutations, a phenomenon referred to as genotype-phenotype correlation. For example, desmoids usually are associated with mutations between codons 1403 and 1578.68,69 Mutations in the extreme 5′ or 3′ ends of APC, or in the alternatively spliced region of exon 9, are associated with an attenuated version of FAP. Better understanding of the genotype-phenotype correla-tions may assist in patient counseling and therapeutic planning.Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer. Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autoso-mal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome 1, which entails hereditary predisposition for colorectal cancer with early age of onset (approximately age 44 years) and an excess of synchronous and metachronous colonic cancers; and Lynch syndrome 2, featur-ing a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.70 The diagnostic criteria for HNPCC are referred to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-4).71 These criteria are met when three or more family members have histologically ver-ified, HNPCC-associated cancers (one of whom is a first-degree relative of the other two), two or more generations are involved, at least one individual was diagnosed before age 50 years, and no individuals have FAP.71During DNA replication, DNA polymerases may intro-duce single nucleotide mismatches or small insertion or deletion loops. These errors are corrected through a process referred to as mismatch repair. When mismatch repair genes are inactivated, DNA mutations in other genes that are critical to cell growth and proliferation accumulate rapidly. In HNPCC, germline mutations have been identified in several genes that play a key role in DNA nucleotide mismatch repair: hMLH1 (human mutL homologue 1), hMSH2 (human mutS homologue 2), hMSH6, A Heterogeneity among patientsB Heterogeneity betweenprimary and metastatic sitesC Intratumoral spatialheterogeneityFigure 10-12. “Two-hit” tumor formation in both hereditary and nonhereditary cancers. A “one-hit” clone is a precursor to the tumor in nonhereditary cancer, whereas all cells are one-hit clones in hereditary cancer. (Reproduced with permission from Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy, Nat Rev Clin Oncol. 2012 Sep;9(9):542-548.)Brunicardi_Ch10_p0305-p0354.indd 32422/02/19 2:14 PM 325ONCOLOGYCHAPTER 10and hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2), of which hMLH1 and hMSH2 are the most common.72-77 The hallmark of HNPCC is microsatellite instability, which occurs on the basis of unrepaired mismatches and small inser-tion or deletion loops. Microsatellite instability can be tested by comparing the DNA of a patient’s tumor with DNA from adja-cent normal epithelium, amplifying the DNA with polymerase chain reaction (PCR) using a standard set of markers, compar-ing the amplified genomic DNA sequences, and classifying the degree of microsatellite instability as high, low, or stable. Such microsatellite instability testing may help select patients who are more likely to have germline mutations. An analysis of patients with early-onset colorectal cancer (age less than 50) showed that 8% had an unsuspected germline mutation in a mismatch repair gene and could be considered as having Lynch syndrome. Thus, genetic counseling and testing with a multigene panel should be considered for such patients.78PTEN and Cowden DiseaseSomatic deletions or mutations in the tumor-suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) have been observed in a number of glioma breast, prostate, and renal carcinoma cell lines and several primary tumor specimens.79PTEN encodes a 403-amino-acid protein, tyrosine phos-phatase. PTEN negatively controls the PI3K signaling pathway for the regulation of cell growth and survival by dephosphory-lating phosphoinositol 3,4,5-triphosphate; thus, mutation of PTEN leads to constitutive activation of the PI3K/Akt signaling pathway. The “hot spot” for PTEN mutations has been identi-fied in exon 5. Forty-three percent of CD mutations have been identified in this exon, which contains the tyrosine phosphatase core domain. This suggests that the PTEN catalytic activity is vital for its biologic function. PTEN was identified as the sus-ceptibility gene for the autosomal dominant syndrome Cowden disease (CD) or multiple hamartoma syndrome.80 Trichilem-momas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis are pathognomonic of CD. Other common features include thyroid adenomas and multinodular goiters, breast fibroadenomas, and hamartomatous GI polyps. The diagnosis of CD is made when an individual or family has a combination of pathognomonic major and/or minor criteria pro-posed by the International Cowden Consortium.81 CD is associ-ated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25% to 50% of affected women.81p16 and Hereditary Malignant Melanoma. The gene p16, also known as INK4A, CDKN1, CDKN2A, and MTS1, is a tumor suppressor that acts by binding CDK4 and CDK6 and inhibit-ing the catalytic activity of the CDK4-CDK6/cyclin D complex that is required for phosphorylation of Rb and subsequent cell-cycle progression. Studies suggest that germline mutations in p16 can be found in 20% of melanoma-prone families.82 Muta-tions in p16 that alter its ability to inhibit the catalytic activity of the CDK4-CDK6/cyclin D complex not only increase the risk of melanoma by 75-fold but also increase the risk of pancre-atic cancer by 22-fold.83 Interestingly, p16 mutations that do not appear to alter its function increase the risk of melanoma by 38-fold and do not increase the risk of pancreatic cancer.83 Genomic characterization of primary tumors has revealed that p16 is inactivated through point mutation, promoter methyla-tion, or deletion in a significant portion of sporadic tumors, including cancers of the pancreas, esophagus, head and neck, stomach, breast, and colon, as well as melanomas.E-cadherin and Hereditary Diffuse Gastric Cancer. E-cadherin is a cell adhesion molecule that plays an important role in nor-mal architecture and function of epithelial cells. The adhesive function of E-cadherin is dependent on interaction of its cyto-plasmic domain with βand γ-catenins and may be regulated by phosphorylation of β-catenin.Hereditary diffuse gastric carcinoma is an autosomal domi-nant cancer syndrome that results from germline mutations in the E-cadherin gene, CDH1. Carriers of CDH1 mutations have a 70% to 80% chance of developing gastric cancer.84 Furthermore, mutations of CDH1 have been described in sporadic cancers of the ovary, endometrium, breast, and thyroid. However, frequent mutations have been identified in only two particular tumors: dif-fuse gastric carcinomas and lobular breast carcinomas. Invasive lobular breast carcinomas often show inactivating mutations in combination with a loss of heterozygosity of the wild-type CDH1 allele.85 Interestingly, in gastric carcinomas the predominant mutations are exon skipping causing in-frame deletions, whereas most mutations identified in lobular breast cancers are premature stop codons; this suggests a genotype-phenotype correlation.RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2The RET (rearranged during transfection) gene encodes for a transmembrane receptor tyrosine kinase that plays a role in pro-liferation, migration, and differentiation of cells derived from the neural crest. Gain-of-function mutations in the RET gene are associated with medullary thyroid carcinoma in isolation or mul-tiple endocrine neoplasia type 2 (MEN2) syndromes. MEN2A is associated with medullary thyroid carcinoma and pheochro-mocytoma (in 50%) or parathyroid adenoma (in 20%), whereas MEN2B is associated with medullary thyroid carcinoma, mar-fanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract.86 RET mutations lead to uncontrolled growth of the thyroid C cells, and in familial medullary cancer, C-cell hyperplasia progresses to bilateral, multicentric medul-lary thyroid cancer. Mutations in the RET gene have also been identified in half of sporadic medullary thyroid cancers.Genetic Modifiers of Risk. Individuals carrying identi-cal germline mutations vary in regard to cancer penetrance (whether cancer will develop or not) and cancer phenotype (the tissues involved). It is thought that this variability may be due to environmental influences or, if genetic, to genetic modifiers Table 10-4Revised criteria for hereditary nonpolyposis colon cancer (HNPCC) (Amsterdam criteria II)Three or more relatives with an HNPCC-associated cancer (colorectal cancer, endometrial cancer, cancer of the small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other twoAt least two successive generations affectedAt least one case diagnosed before age 50 yFamilial adenomatous polyposis excludedTumors verified by pathologic examinationReproduced with permission from Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun;116(6):1453-1456.Brunicardi_Ch10_p0305-p0354.indd 32522/02/19 2:14 PM 326BASIC CONSIDERATIONSPART Iof risk. Similarly, genetic modifiers of risk also can play a role in determining whether an individual will develop cancer after exposure to carcinogens.Chemical CarcinogensThe first report indicating that cancer could be caused by envi-ronmental factors was by John Hill, who in 1761 noted the association between nasal cancer and excessive use of tobacco snuff.87 Currently, approximately 60% to 90% of cancers are thought to be due to environmental factors. Any agent that can contribute to tumor formation is referred to as a carcinogen and can be a chemical, physical, or viral agent. Chemicals are clas-sified into three groups based on how they contribute to tumor formation. The first group of chemical agents, the genotoxins, can initiate carcinogenesis by causing a mutation. The second group, the cocarcinogens, by themselves cannot cause cancer but potentiate carcinogenesis by enhancing the potency of geno-toxins. The third group, tumor promoters, enhances tumor for-mation when given after exposure to genotoxins.The International Agency for Research on Cancer (IARC) maintains a registry of human carcinogens that is available through the World Wide Web (http://www.iarc.fr). The compounds are categorized into five groups based on an analysis of epidemio-logic studies, animal models, and short-term mutagenesis tests. Group 1 contains what are considered to be proven human carcinogens, based on formal epidemiologic studies among workers who were exposed for long periods (several years) to the chemicals.88 Group 2A contains what are considered to be probable human carcinogens. Suggestive epidemiologic evidence exists for compounds in this group, but the data are insufficient to establish causality. There is evidence of carcinogenicity, however, from animal studies carried out under conditions relevant to human exposure. Group 2B contains what are considered to be possible carcinogens because these substances are associated with a clear statistically and biologically significant increase in the incidence of malignant tumors in more than one animal species or strain. Group 3 agents are not classifiable, and Group 4 agents are prob-ably not carcinogenic to humans. Selected substances that have been classified as proven carcinogens (group 1) by the IARC in an expert panel review are listed in Table 10-5.89Physical CarcinogensPhysical carcinogenesis can occur through induction of inflam-mation and cell proliferation over a period of time or through exposure to physical agents that induce DNA damage. Foreign bodies can cause chronic irritation that can expose cells to carci-nogenesis due to other environmental agents. In animal models, for example, subcutaneous implantation of a foreign body can lead to the development of tumors that have been attributed to chronic irritation from the foreign objects. In humans, clinical sce-narios associated with chronic irritation and inflammation such as chronic nonhealing wounds, burns, and inflammatory bowel syn-drome have all been associated with an increased risk of cancer. H pylori infection is associated with gastritis and gastric cancer, and thus, its carcinogenicity may be considered physical carci-nogenesis. Infection with the liver fluke Opisthorchis viverrini similarly leads to local inflammation and cholangiocarcinoma.The induction of lung and mesothelial cancers by asbes-tos fibers and nonfibrous particles such as silica are other examples of foreign body-induced physical carcinogenesis.90 Animal experiments have demonstrated that the dimensions and durability of the asbestos and other fibrous minerals are the key determinants of their carcinogenicity.91 Short fibers can be inactivated by phagocytosis, whereas long fibers (>10 μm) are cleared less effectively and are encompassed by proliferat-ing epithelial cells. The long fibers support cell proliferation and have been shown to preferentially induce tumors. Asbestosassociated biologic effects also may be mediated through reactive oxygen and nitrogen species. Furthermore, an inter-action occurs between asbestos and silica and components of cigarette smoke. Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are metabolized by epithelial cells and form DNA adducts. If PAH is coated on asbestos, PAH uptake is increased.90 Both PAH and asbestos impair lung clearance, potentially increasing uptake further. Therefore, physical car-cinogens may be synergistic with chemical carcinogens.Radiation is the best-known agent of physical carcinogens and is classified as ionizing radiation (X-rays, gamma rays, and alpha and beta particles) or nonionizing radiation (UV). The car-cinogenic potential of ionizing radiation was recognized soon after Wilhelm Conrad Roentgen’s discovery of X-rays in 1895. Within the next 20 years, a large number of radiation-related skin cancers were reported. Long-term follow-up of survivors of the atomic bombing of Hiroshima and Nagasaki revealed that virtually all tissues exposed to radiation are at risk for cancer.Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide bases and cross-linking, and DNA singleand double-strand breaks (DSBs). Misrepaired DSBs are the principal lesions of importance in the induction of chromosomal abnormalities and gene mutations. DSBs in irradiated cells are repaired primarily by a nonhomologous end-joining process, which is error prone; thus, DSBs facilitate the production of chromosomal rearrangements and other large-scale changes such as chromosomal deletions. It is thought that radiation may initiate cancer by inactivating tumor-suppressor genes. Activation of oncogenes appears to play a lesser role in radiation carcinogenesis.Although it has been assumed that the initial genetic events induced by radiation constitute direct mutagenesis from radiation, other indirect effects may contribute to carcinogenesis. For exam-ple, radiation induces genomic instability in cells that persists for at least 30 generations after irradiation. Therefore, even if cells do not acquire mutations at initial irradiation, they remain at risk for developing new mutations for several generations. Moreover, even cells that have not been directly irradiated appear to be at risk, a phenomenon referred to as the bystander effect.Nonionizing UV radiation is a potent DNA-damaging agent and is known to induce skin cancer in experimental ani-mals. Most nonmelanoma human skin cancers are thought to be induced by repeated exposure to sunlight, which leads to a series of mutations that allow the cells to escape normal growth control. Patients with inherited xeroderma pigmentosum lack one or more DNA repair pathways, which confers susceptibility to UV-induced cancers, especially on sun-exposed body parts. Patients with ataxia telangiectasia mutated syndrome also have a radiation-sensitive phenotype.Viral CarcinogensOne of the first observations that cancer may be caused by trans-missible agents was by Peyton Rous in 1910 when he demon-strated that cell-free extracts from sarcomas in chickens could transmit sarcomas to other animals injected with these extracts.92 This was subsequently discovered to represent viral transmission of cancer by the Rous sarcoma virus. At present, several human viruses are known to have oncogenic properties, and several Brunicardi_Ch10_p0305-p0354.indd 32622/02/19 2:14 PM 327ONCOLOGYCHAPTER 10Table 10-5Group 1 chemical carcinogens and evidence for carcinogenicity in humans and for genotoxicity as the main mechanism TUMOR SITES OR TYPES WITH SUFFICIENT EVIDENCE IN HUMANSEVIDENCE OF GENOTOXICITY AS THE MAIN MECHANISM4-AminobiphenylUrinary bladderStrongBenzidineUrinary bladderStrongDyes metabolized to benzidine⋅⋅Stronga4,4’-Methylenebis(2-chloroaniline)⋅⋅Stronga2-NapthylamineUrinary bladderStrongOrtho-toluidineUrinary bladderModerateAuramine productionUrinary bladderWeak/lack of databMagenta productionUrinary bladderWeak/lack of databBenzo[α]pyrene⋅⋅StrongaSoot (chimney sweeping)Skin, lungModerateCoal gasificationLungStrongCoal-tar distillationSkinStrongCoke productionLungStrongCoal-tar pitches (paving, roofing)LungStrongAluminum productionLung, urinary bladderWeak/moderateb,cAflatoxinsHepatocellular carcinomaStrongBenzeneANLLStrongBis (chloromethyl)ether/chloromethyl methyletherLungModerate/strong1,3-ButadieneHaematolymphatic organsStrongDioxin (2,3,7,8-TCDD)All cancers combinedaSee textd2,3,4,7,8-Pentachlorodibenzofuran⋅⋅See texta,d3,3’,4,4’,5-Pentachlorobiphenyl (PCB-126)⋅⋅See texta,dEthylene oxide⋅⋅StrongaFormaldehydeNasopharynxLeukemiagStrongModerateSulfur mustardLungStrongVinyl chlorideHepatic angiosarcoma, hepatocellular carcinomaStrongIron and steel foundingLungWeak/moderateIsopropyl alcohol manufacture using strong acidsNasal cavityWeak/lack of dataMineral oilsSkinWeak/lack of dataOccupational exposure as a painterLung, urinary bladder, pleural mesotheliomaStrongcRubber-manufacturing industryLeukaemia, lymphoma,g urinary bladder, lung,g stomachgStrongcShale oilsSkinWeak/lack of dataStrong inorganic acid mistsLarynxWeak/lack of dataANLL = acute nonlymphocytic leukemia; ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia; MM = multiple myeloma; NH = non-Hodgkin lymphoma; STS = soft-tissue sarcoma.aAgents classified in Group 1 on the basis of mechanistic information.bWeak evidence in workers, but strong evidence for some chemicals in this industry.cDue to the diversity and complexity of these exposures, other mechanisms may also be relevant.dStrong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism.eParticularly myeloid leukemia.fAfter maternal exposure (before or during pregnancy, or both).gNew epidemiological findings.Reproduced with permission from Baan R, Grosse Y, Straif K, et al. A review of human carcinogens–part F: chemical agents and related occupations, Lancet Oncol. 2009 Dec;10(12):1143-1144.Brunicardi_Ch10_p0305-p0354.indd 32722/02/19 2:14 PM 328BASIC CONSIDERATIONSPART ITable 10-6Selected viral carcinogensaVIRUSPREDOMINANT TUMOR TYPEbEpstein-Barr virusBurkitt’s lymphoma Hodgkin’s disease Immunosuppression-related lymphoma Sinonasal angiocentric T-cell lymphoma Nasopharyngeal carcinomaHepatitis B virusHepatocellular carcinomaHepatitis C virusHepatocellular carcinomaHIV type 1Kaposi’s sarcoma Cervical cancer Non-Hodgkin’s lymphomaHuman herpes virus 8Kaposi’s sarcomaHuman papillomavirus 16 and 18 Cervical cancerVulvar and vaginal cancer Penile cancer Oropharyngeal cancer (commonly base of tongue and tonsil) Anal cancerHuman T-cell lymphotropic virusesAdult T-cell leukemia/lymphomaMerkel cell polyoma virusMerkel cell carcinomaaData based on information in the International Agency for Research on Cancer monographs.bOnly tumor types for which causal relationships are established are listed. Other cancer types may be linked to the agents with a lower frequency or with insufficient data to prove causality.have been causally linked to human cancers (Table 10-6).88 It is estimated that 15% of all human tumors worldwide are caused by viruses.93Viruses may cause or increase the risk of malignancy through several mechanisms, including direct transformation, expression of oncogenes that interfere with cell-cycle check-points or DNA repair, expression of cytokines or other growth factors, and alteration of the immune system. Oncogenic viruses may be RNA or DNA viruses. Oncogenic RNA viruses are retro-viruses and contain a reverse transcriptase. After the viral infec-tion, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then integrated into the chromosomal DNA of the cell. Retroviral infection of the cell is permanent; thus, integrated DNA sequences remain in the host chromosome. Oncogenic transforming retroviruses carry onco-genes derived from cellular genes. These cellular genes, referred to as proto-oncogenes, usually are involved in mitogenic signal-ing and growth control, and include protein kinases, G proteins, growth factors, and transcription factors (Table 10-7).93Integration of the provirus upstream of a proto-oncogene may produce chimeric virus-cell transcripts and recombination during the next round of replication that could lead to incorpo-ration of the cellular gene into the viral genome.93 Then again, many retroviruses do not possess oncogenes but can cause tumors in animals regardless. This occurs by integration of the provirus near a normal cellular proto-oncogene and activation of the expression of these genes by the strong promoter and enhancer sequences in the integrated viral sequence.Unlike the oncogenes of the RNA viruses, those of the DNA tumor viruses are viral, not cellular, in origin. These genes are required for viral replication using the host cell machinery. In permissive hosts, infection with an oncogenic DNA virus may result in a productive lytic infection, which leads to cell death and the release of newly formed viruses. In nonpermis-sive cells, the viral DNA can be integrated into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, which leads to transformation of cells to a neoplastic state. The binding of viral oncoproteins to cellu-lar tumor-suppressor proteins p53 and Rb is fundamental to the carcinogenesis induced by most DNA viruses, although some target different cellular proteins.Like other types of carcinogenesis, viral carcinogenesis is a multistep process. Some retroviruses contain two cellular onco-genes, rather than one, in their genome and are more rapidly tumorigenic than single-gene transforming retroviruses, which emphasizes the cooperation between transforming genes. Further-more, some viruses encode genes that suppress or delay apoptosis.Although immunocompromised individuals are at ele-vated risk, most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs sev-eral years after the viral infection. It is estimated, for example, that the risk of hepatocellular carcinoma (HCC) among individu-als infected with hepatitis C virus is 1% to 3% after 30 years.94 There may be synergy between various environmental factors and viruses in carcinogenesis.Recognition of a viral origin for some tumors has led to the pursuit of vaccination as a preventive strategy. The use of childhood hepatitis B vaccination has already translated into a decrease in liver cancer incidence in the East Asia.5 Similarly, it is recognized that cervical cancer and its obligate precursors, cervical intraepithelial neoplasia grades 2 and 3, and adenocar-cinoma in situ, are caused by oncogenic human papillomavirus (HPV); administration of HPV vaccine to HPV-naive women, substantially reduces the incidence of HPV16/18-related cervi-cal precancers and cervical cancer.95 Studies suggest that HPV vaccination may also reduce oral HPV infections that are a risk factor for the development of oropharyngeal cancer.96 The American Cancer Society recommends routine HPV vaccina-tion for girls and boys starting at age 11 or 12. The vaccination series can be started as early as age 9. HPV vaccination is also recommended for females 13 to 26 years old and for males 13 to 21 years old who have not started the vaccines, or who have started but have not completed the series. Males 22 to 26 years old may also be vaccinated. HPV vaccination is also recom-mended up until age 26 for men who have sex with men and for people with weakened immune systems (including people with HIV infection), if they have not previously been vaccinated. It is important for patients to know that vaccination at older ages is less effective in lowering cancer risk.97CANCER RISK ASSESSMENTCancer risk assessment is an important part of the initial evalua-tion of any patient. A patient’s cancer risk not only is an impor-tant determinant of cancer screening recommendations but also Brunicardi_Ch10_p0305-p0354.indd 32822/02/19 2:14 PM 329ONCOLOGYCHAPTER 10Table 10-7Selected cellular oncogenes in retrovirusesONCOGENEVIRUS NAMEORIGINPROTEIN PRODUCTablAbelson murine leukemia virusMouseTyrosine kinasefesST feline sarcoma virusCatTyrosine kinasefpsFujinami sarcoma virusChickenTyrosine kinasesrcRous sarcoma virusChickenTyrosine kinaseerbBAvian erythroblastosis virusChickenEpidermal growth factor receptorfmsMcDonough feline sarcoma virusCatColony-stimulating factor receptorkitHardy-Zuckerman 4 feline sarcoma virusCatStem cell factor receptormilAvian myelocytoma virusChickenSerine/threonine kinasemosMoloney murine sarcoma virusMouseSerine/threonine kinaserafMurine sarcoma virus 3611MouseSerine/threonine kinasesisSimian sarcoma virusMonkeyPlatelet-derived growth factorH-rasHarvey murine sarcoma virusRatGDP/GTP bindingK-rasKirsten murine sarcoma virusRatGDP/GTP bindingerbAAvian erythroblastosis virusChickenTranscription factor (thyroid hormone receptor)etsAvian myeloblastosis virus E26ChickenTranscription factorfosFBJ osteosarcoma virusMouseTranscription factor (AP1 component)junAvian sarcoma virus 17ChickenTranscription factor (AP1 component)mybAvian myeloblastosis virusChickenTranscription factormycMC29 myelocytoma virusChickenTranscription factor (NF-κB family)AP1 = activator protein 1; FBJ = Finkel-Biskis-Jinkins; GDP = guanosine diphosphate; GTP = guanosine triphosphate; NF-κB = nuclear factor κB.Data from Coffin JM, Hughes SH, Varmus HE: Retroviruses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1997.may alter how aggressively an indeterminant finding will be pursued for diagnosis. A “probably benign” mammographic lesion, for example, defined as one with <2% probability of malignancy (American College of Radiology category III) is usually managed with a 6-month follow-up mammogram in a patient at baseline cancer risk, but obtaining a tissue diagnosis may be preferable in a patient at high risk for breast cancer.98Cancer risk assessment starts with taking a complete his-tory that includes history of environmental exposures to potential carcinogens and a detailed family history. Risk assessment for breast cancer, for example, includes obtaining a family history to determine whether another member of the family is known to carry a breast cancer susceptibility gene; whether there is famil-ial clustering of breast cancer, ovarian cancer, thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, brain tumors, dermatologic manifestations, leukemia, or lymphoma; and whether the patient is from a population at increased risk, such as individuals of Ashkenazi Jewish descent. Patients who have a family history suggestive of a cancer susceptibility syn-drome such as hereditary breast-ovarian syndrome, Li-Fraumeni Syndrome, or Cowden’s Disease would benefit from genetic counseling and possibly genetic testing.There are several models that can estimate risk based on complex family histories and assist clinicians in estimat-ing breast cancer risk or the likelihood that a BRCA mutation is present, including the Claus model, Tyrer-Cuzick model, BRCAPRO model, and the Breast and Ovarian Analysis of Dis-ease Incidence and Carrier Estimation Algorithm (BOADICEA) model.99-102 Patients who do have a strong hereditary component of risk can be evaluated on the basis of their age, race, per-sonal history, and exposures. One of the most commonly used models for risk assessment in breast cancer is the Gail model.103 Gail and colleagues analyzed the data from 2852 breast cancer cases and 3146 controls from the Breast Cancer Detection and Demonstration Project, a mammography screening project conducted in the 1970s, and developed a model for project-ing breast cancer incidence. The model uses risk factors such as an individual’s age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsy specimens, and whether the biopsy speci-men results revealed atypical ductal hyperplasia (Table 10-8).103 This model has led to the development of a breast cancer risk assessment tool, which is available on the World Wide Web.104 This tool incorporates the risk factors used in the Gail model, as well as race and ethnicity, and allows a health professional to project a woman’s individualized estimated risk for invasive breast cancer over a 5-year period and over her lifetime (to age 90 years). Notably, these risk projections assume that the woman is undergoing regular clinical breast examinations and screen-ing mammograms. Also of note is that this program underes-timates the risk for women who have already had a diagnosis of invasive or noninvasive breast cancer and does not take into account specific genetic predispositions such as mutations in BRCA1 or BRCA2. However, risk assessment tools such as this have been validated and are now in widespread clinical use. Similar models are in development or are being validated for Brunicardi_Ch10_p0305-p0354.indd 32922/02/19 2:14 PM 330BASIC CONSIDERATIONSPART ITable 10-8Assessment of risk for invasive breast cancerRISK FACTORRELATIVE RISK (%)Age at menarche (years)  >141.00 12–131.10 <121.21Age at first live birth (years) Patients with no first-degree relatives with cancer  <201.00 20–241.24 25–29 or nulliparous1.55 ≥301.93Patients with one first degree-relative with cancer  <201.00 20–242.64 25–29 or nulliparous2.76 ≥302.83Patients with ≥2 first-degree relatives with cancer  <206.80 20–245.78 25–29 or nulliparous4.91 ≥304.17Breast biopsies (number) Patients aged <50 y at counseling  01.00 11.70 ≥22.88Patients aged ≥50 y at counseling  01.00 11.27 ≥21.62Atypical hyperplasia  No biopsies1.00 At least 1 biopsy, no atypical  hyperplasia0.93 No atypical hyperplasia,  hyperplasiastatus unknown for at least 1 biopsy1.00 Atypical hyperplasia in at least  1 biopsy1.82Modified with permission from Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually, J Natl Cancer Inst. 1989 Dec 20;81(24):1879-1886.as presence or absence of single nucleotide polymorphisms which each may confer low or intermediate cancer risk. Risk models that include biologic as well as environmental factors may accurately predict cancer risk, providing better guidance as to which patients should undergo more intensive screening (e.g., screening with magnetic resonance imaging of the breast, computerized tomography screening of the lung), and should be considered for preventive strategies.CANCER SCREENINGEarly detection is the key to success in cancer therapy. Screen-ing for common cancers using relatively noninvasive tests is expected to lead to early diagnosis, allow more conservative surgical therapies with decreased morbidity, and potentially improve surgical cure rates and overall survival rates. Key factors that influence screening guidelines are how prevalent the cancer is in the population, what risk is associated with the screening measure, and whether early diagnosis actually affects outcome. The value of a widespread screening measure is likely to go up with the prevalence of the cancer in a population, which often determines the age cutoffs for screening and explains why screening is done only for common cancers. The risks asso-ciated with the screening measure are a significant consider-ation, especially with more invasive screening measures such as colonoscopy. The consequences of a false-positive screening test result also need to be considered. For example, when 1000 screening mammograms are taken, only 2 to 4 new cases of cancer will be identified; this number is slightly higher (6 to 10 prevalent cancers per 1000 mammograms) for initial screen-ing mammograms.106 However, as many as 10% of screening mammograms may be potentially suggestive of an abnormal-ity, which requires further imaging (i.e., a 10% recall rate). Of those women with abnormal mammogram findings, only 5% to 10% will be determined to have a breast cancer. Among women for whom biopsy specimen is recommended, 25% to 40% will have a breast cancer. A false-positive screening result is likely to induce significant emotional distress in patients, leads to unnecessary biopsy specimens, and has cost implications for the health care system.American Cancer Society guidelines for the early detec-tion of cancer are listed in Table 10-9.96 These guidelines are updated periodically to incorporate emerging technologies and new data on the efficacy of screening measures. Besides the American Cancer Society, several other professional bodies make recommendations for screening. Although the screening guidelines differ somewhat, most organizations do not empha-size one screening strategy as superior to another, but all empha-size the importance of age-appropriate screening.Screening guidelines are developed for the general base-line-risk population. These guidelines need to be modified for patients who are at high risk. For example, more intensive colorectal cancer screening is recommended for individuals at increased risk because of a history of adenomatous polyps, a personal history of colorectal cancer, a family history of either colorectal cancer or colorectal adenomas diagnosed in a first-degree relative before age 60 years, a personal history of inflam-matory bowel disease of significant duration, or a family history or genetic test result indicating FAP or HNPCC. For some dis-eases, in higher risk populations, both the screening modality and the screening intensity may be altered. For example, breast magnetic resonance imaging is recommended as an adjunct to other cancers. For example, a lung cancer risk prediction model, which includes age, sex, asbestos exposure history, and smoking history, has been found to predict risk of lung cancer.105 There is now growing interest in using each individuals genotype, such Brunicardi_Ch10_p0305-p0354.indd 33022/02/19 2:14 PM 331ONCOLOGYCHAPTER 10Table 10-9American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individualsCANCER SITEPOPULATIONTEST OR PROCEDUREFREQUENCYBreastWomen age 40 and aboveMammographyWomen with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years. Women age 45 to 54 years should be screened annually. Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually. Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer. The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age.CervixWomen, age 21–65 yPap test and HPV DNA testCervical cancer screening should begin at age 21 y. For women age 21–29 y, screening should be done every 3 y with conventional or liquid-based Pap tests. For women age 30–65 y, screening should be done every 5 y with both the HPV test and the Pap test (preferred), or every 3 y with the Pap test alone (acceptable). Women age >65 y who have had ≥3 consecutive negative Pap tests or ≥2 consecutive negative HPV and Pap tests within the last 10 y, with the most recent test occurring within the last 5 y, and women who have had a total hysterectomy should stop cervical cancer screening.ColorectalMen and women age ≥50 ygFOBT, or FIT, or sDNA with a high sensitivity for cancerAnnual, starting at age 50 y.  FSIG, orEvery 5 y, starting at age 50 y. FSIG can be performed alone, or consideration can be given to combining FSIG performed every 5 y with a highly sensitive guaiac-based FOBT or FIT performed annually.  DCBE, orEvery 5 y, starting at age 50 y.  ColonoscopyEvery 10 y, starting at age 50 y.  CT colonographyEvery 5 yr, starting at age 50 y.EndometrialWomen, at menopause At the time of menopause, women at average risk should be informed about the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians.LungCurrent or former smokers age 50–74 in good health with at least a 30 pack/year historyLDCTClinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about lung cancer screening with apparently healthy patients age 55–74 y who have at least a 30 pack-y smoking history, and who currently smoke or have quit within the past 15 y. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with LDCT should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation.(Continued)Brunicardi_Ch10_p0305-p0354.indd 33122/02/19 2:14 PM 332BASIC CONSIDERATIONSPART ITable 10-9American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individualsCANCER SITEPOPULATIONTEST OR PROCEDUREFREQUENCYProstateMen, age ≥50 yDRE and PSAMen who have at least a 10-y life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer, after receiving information about the potential benefits, risks, and uncertainties associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at age 50 years. Men in higher risk groups should receive this information before age 50 years. Men should either receive this information directly from their health care providers or be referred to reliable and culturally appropriate sources. Patient decision aids are helpful in preparing men to make a decision whether to be tested.Cancer-related checkupMen and women age ≥20 y On the occasion of a periodic health examination, the cancer-related checkup should include examination for cancers of the thyroid, testicles, ovaries, lymph nodes, oral cavity, and skin, as well as health counseling about tobacco, sun exposure, diet and nutrition, risk factors, sexual practices, and environmental and occupational exposures.ACS = American Cancer Society; BSE = breast self-examination; CBE = clinical breast examination; Pap = Papanicolaou; HPV = human papillomavirus; gFOBT = guaiac-based fecal occult blood test; FIT = fecal immunochemical test; sDNA, stool DNA; DRE = digital rectal examination; FSIG = flexible sigmoidoscopy; DCBE = double-contrast barium enema; CT = computed tomography; LDCT = low-dose helical CT; PSA = prostate-specific antigen.Reproduced with permission from Smith RA, Brooks D, Cokkinides V, et al: Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening, CA Cancer J Clin. 2013 Mar-Apr;63(2):88-105.mammography for breast cancer screening in BRCA mutation carriers, first-degree relatives of carriers, and women with a life-time breast cancer risk of 20% to 25% or higher.107The National Lung Screening Trial demonstrated a 20% reduction in lung cancer deaths in adults age 55 to 74 years who were at high risk of lung cancer and randomized to low-dose helical computed tomography (LDCT) screening compared with screening with annual CXR.108 In 2013, the American Cancer Society updated their lung cancer screening recommendations to emphasize that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should ascertain the smoking history of their patients 55 to 74 years of age, and should discuss lung cancer screening with those who have at least a 30 pack per year smoking history, currently smoke, or have quit within the past 15 years, and who are in relatively good health.109 It is recommended that this discussion include the benefits, uncertainties, and harms associated with screening for lung cancer with LDCT.CANCER DIAGNOSISThe definitive diagnosis of solid tumors is obtained by perform-ing a biopsy specimen of the lesion. Biopsy findings determine the tumor histology and grade and thus, assist in definitive ther-apeutic planning. Biopsy specimens of mucosal lesions usually are obtained endoscopically (e.g., via colonoscope, broncho-scope, or cystoscope). Lesions that are easily palpable, such as those of the skin, can either be excised or sampled by punch biopsy specimen. Deep-seated lesions can be localized with computed tomographic (CT) scan or ultrasound guidance for acquisition of a biopsy specimen.A sample of a lesion can be obtained with a needle or with an open incisional or excisional biopsy specimen. Fine-needle aspiration is easy and relatively safe, but has the disad-vantage of not giving information on tissue architecture. For example, fine-needle aspiration biopsy specimen of a breast mass can make the diagnosis of malignancy but cannot dif-ferentiate between an invasive and noninvasive tumor. There-fore core-needle biopsy specimen is more advantageous when the histologic findings will affect the recommended therapy. Core biopsy specimen, like fine-needle aspiration, is relatively safe and can be performed either by direct palpation (e.g., a breast mass or a soft tissue mass) or can be guided by an imag-ing study (e.g., stereotactic core biopsy specimen of the breast). Core biopsy specimens, like fine-needle aspirations, have the disadvantage of introducing sampling error. For example, 19% to 44% of patients with a diagnosis of atypical ductal hyperpla-sia based on core biopsy specimen findings of a mammographic abnormality are found to have carcinoma upon excision of the entire lesion.110 It is crucial to ensure that the histologic find-ings are consistent with the clinical scenario and to know the appropriate interpretation of each histologic finding. A needle biopsy specimen for which the report is inconsistent with the clinical scenario should be either repeated or followed by an open biopsy procedure.Open biopsy specimens have the advantage of providing more tissue for histologic evaluation and the disadvantage of being an operative procedure. Incisional biopsy specimens are (Continued)Brunicardi_Ch10_p0305-p0354.indd 33222/02/19 2:14 PM 333ONCOLOGYCHAPTER 10reserved for very large lesions in which a definitive diagnosis cannot be made by needle biopsy specimen. Excisional biopsy specimens are performed for lesions for which either core biopsy specimen is not possible or the results are nondiagnostic. Excisional biopsy specimens should be performed with curative intent, that is, by obtaining adequate tissue around the lesion to ensure negative surgical margins. Marking of the orientation of the margins by sutures or clips by the surgeon and inking of the specimen margins by the pathologist will allow for determina-tion of the surgical margins and will guide surgical reexcision if one or more of the margins are positive for microscopic tumor or are close. The biopsy specimen incision should be oriented to allow for excision of the biopsy specimen scar if repeat opera-tion is necessary. Furthermore, the biopsy specimen incision should directly overlie the area to be removed rather than tun-neling from another site, which runs the risk of contaminating a larger field. Meticulous hemostasis during a biopsy specimen is essential because a hematoma can lead to contamination of the tissue planes and can make subsequent follow-up with physical examinations much more challenging.In the case where an enlarged lymph node is being inves-tigated due to a suspicion of lymphoma, it will usually be nec-essary for the surgeon to remove an entire lymph node through an open biopsy in order to permit an analysis of lymph node architecture and provide sufficient tissue for molecular and flow cytometric analyses.CANCER STAGINGCancer staging is a system used to describe the anatomic extent of a malignant process in an individual patient. Staging sys-tems may incorporate relevant clinical prognostic factors such as tumor size, location, extent, grade, and dissemination to regional lymph nodes or distant sites. Accurate staging is essen-tial in designing an appropriate treatment regimen for an indi-vidual patient. Staging of the lymph node basin is considered a standard part of primary surgical therapy for most surgical procedures and is discussed later in this chapter. Cancer patients who are considered to be at high risk for distant metastasis usu-ally undergo a preoperative staging work-up. This involves a set of imaging studies of sites of preferential metastasis for a given cancer type. For a patient with breast cancer, for example, a staging work-up would include a chest radiograph, bone scan, and liver ultrasound, or CT scans to evaluate for lung, bone, and liver metastases, respectively. A distant staging work-up usually is performed only for patients likely to have metastasis based on the characteristics of the primary tumor; for example, a staging work-up for a patient with ductal carcinoma in situ of the breast or a small invasive breast tumor is likely to be low yield and not cost effective.Recently there also is increased usage of molecular imag-ing with positron emission tomography (PET) scanning, or PET/CT, for cancer staging. Most commonly PET scanning is performed with fluorine 18 incorporated into fluorodeoxy-glucose (FDG). FDG PET assesses the rate of glycolysis. FDG uptake is increased in most malignant tissues but also in benign pathologic conditions such as inflammatory disorders, trauma, infection, and granulomatous disease. PET/CT combines a PET scanner and an X-ray CT scanner in a single gantry, in order to acquire sequential images from both devices in the same ses-sion. These separate images are combined into a single coreg-istered image that gives information on the size and shape of abnormal masses in conjunction with their metabolic activity. It has been especially useful in the staging and management of lymphoma, lung cancer, and colorectal cancer. The role of PET in evaluating many other cancers is evolving, and additional molecular tracers, such as 3′-deoxy-3′ (18F)-fluorothymidine, used to assess proliferation, are being actively pursued.A PET scan can be useful in staging a cancer that poten-tially can be treated radically, such as small cell lung cancer. In the case of some cancers such as GIST, a PET scan can be used to establish baseline staging before commencing targeted therapy and assessing the overall response to therapy. Another use for PET scanning is the evaluation of an indeterminate lesion as in the case of a solitary pulmonary nodule that is suspected to be malignant in nature. In testicular cancer (seminoma) and lymphoma, this imaging modality has been shown to be effec-tive in assessing suspected disease recurrence, relapse, and/or residual disease. Finally, PET scans have been effective in guid-ing biopsies in the setting of mesothelioma. Standardization of staging systems is essential to allow comparison of results from different studies from different institutions and worldwide. The staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (International Union Against Cancer, or UICC) are among the most widely accepted staging systems. Both the AJCC and the UICC have adopted a shared tumor, node, and metastasis (TNM) staging system that defines the cancer in terms of the anatomic extent of disease and is based on assessment of three components: the size of the primary tumor (T), the presence (or absence) and extent of nodal metastases (N), and the presence (or absence) and extent of distant metastases (M).The TNM staging applies only to tumors that have been microscopically confirmed to be malignant. Standard TNM staging (clinical and pathologic) is completed at initial diag-nosis. Clinical staging (cTNM or TNM) is based on informa-tion gained up until the initial definitive treatment. Pathologic staging (pTNM) includes clinical information and information obtained from pathologic examination of the resected primary tumor and regional lymph nodes. Tumor size following neo-adjuvant chemotherapy is designated as ypT, and should be based on the largest single focus of residual invasive cancer. Other classifications, such as staging at the time of retreatment for recurrence (rTNM) or autopsy staging (aTNM), should be clearly identified as such.The clinical measurement of tumor size (T) is the one judged to be the most accurate for each individual case based on physical examination and imaging studies. For example, in breast cancer the size of the tumor could be obtained from a physical examination, mammogram, or ultrasound, and the tumor size is based only on the invasive component.If even one lymph node is involved by tumor, the N com-ponent is at least N1. For many solid tumor types, simply the absence or presence of lymph node involvement is recorded, and the tumor is categorized either as N0 or N1. For other tumor types, the number of lymph nodes involved, the size of the lymph nodes or the lymph node metastasis, or the regional lymph node basin involved also has been shown to have prog-nostic value. In these cancers, the designations N1, N2, and N3 suggest an increasing abnormality of lymph nodes based on size, characteristics, and location. NX indicates that the lymph nodes cannot be fully assessed.Cases in which there is no distant metastasis are designated M0, cases in which one or more distant metastases are detected Brunicardi_Ch10_p0305-p0354.indd 33322/02/19 2:14 PM 334BASIC CONSIDERATIONSPART Iare designated M1, and cases in which the presence of distant metastasis cannot be assessed are designated MX. In clinical practice, negative findings on clinical history and examination are sufficient to designate a case as M0. However, in clinical trials, routine follow-up often is performed to standardize the detection of distant metastases.The practice of dividing cancer cases into groups accord-ing to stage is based on the observation that the survival rates are higher for localized (lower-stage) tumors than for tumors that have extended beyond the organ of origin. Therefore, staging assists in selection of therapy, estimation of prognosis, evalu-ation of treatments, and exchange of information among treat-ment centers. Notably, the AJCC regularly updates its staging system to incorporate advances in prognostic technology to improve the predictive accuracy of the TNM system. There-fore, it is important to know which revision of a staging system is being used when evaluating studies.TUMOR MARKERSPrognostic and Predictive Tissue MarkersTumor markers are substances that can be detected in higher than normal amounts in the serum, urine, or tissues of patients with certain types of cancer. Tumor markers are produced either by the cancer cells themselves or by the body in a response to the cancer.Over the past decade, there has been an especially high interest in identifying tissue tumor markers that can be used as prognostic or predictive markers. Although the terms prognostic marker and predictive marker are sometimes used interchange-ably, the term prognostic marker generally is used to describe molecular markers that predict disease-free survival, disease-specific survival, and overall survival, whereas the term predic-tive marker often is used in the context of predicting response to certain therapies.The goal is to identify prognostic markers that can give information on prognosis independent of other clinical charac-teristics and therefore can provide information to supplement the projections based on clinical presentation. This would allow practitioners to further classify patients as being at higher or lower risk within clinical subgroups and to identify patients who may benefit most from adjuvant therapy. For example, ideal prognostic tumor markers would be able to help determine which patients with node-negative breast cancer are at higher risk of relapse so that adjuvant systemic therapy could be given only to that group. However, although a large number of studies have identified potential novel prognostic markers, most have not been tested with enough vigor to be shown to be of clinical util-ity. In the 2017, American Society of Clinical Oncology (ASCO) guidelines, it was decided that level of uPA/PAI-1 measured by enzyme-linked immunosorbent assay could be used to determine prognosis in cases of newly diagnosed node-negative, hormone receptor positive breast cancer.111 In contrast, the data for many other markers, including Ki-67, p27, HER1/EGFR, and p53 were felt to be insufficient to support their use in the management of these breast cancer patients.111 Similarly, guidelines are avail-able for the management of patients with colorectal cancer and emphasize the processes that need to be in place for accurate measurement of abnormalities in DNA mismatch repair genes as well as EGFR and BRAF mutational status.112Predictive markers are markers that can prospectively identify patients who will benefit from a certain therapy. For Low-riskgroupIntermediate-risk groupHigh-riskgroup005510101515202025253030353540404550Rate of distant recurrence at 10 y(% of patients)Recurrence scoreFigure 10-13. Distant recurrence as a continuous function of the recurrence score derived from tumor levels of expression of 21 genes. (Redrawn from Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer, N Engl J Med. 2004 Dec 30;351(27):2817-2826.)example in breast cancer, estrogen receptor (ER), and HER2 assessment can identify patients who can benefit from anti-estrogen therapies (e.g., tamoxifen) and anti-HER2 targeted therapies (e.g., trastuzumab), respectively, and the ASCO guide-lines recommend that these markers be routinely assessed.111 High-throughput techniques such as transcriptional profiling allow for assessment of the relative mRNA levels of thou-sands of genes simultaneously in a given tumor using micro-array technology. With the advent of such molecular profiling technologies, researchers have focused on identifying expres-sion profiles that are prognostic for different cancer types. For breast cancer, although many such multiparameter tests are under development, few have reached the large-scale valida-tion stage.113 In 2007, ASCO guidelines suggested that one of these, the Oncotype DX assay, can be used to predict recurrence in women with node-negative, ER-positive breast cancer who are treated with tamoxifen.111 Oncotype DX is a quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) test that used paraffin-fixed tissue. A 21-gene recurrence score (RS) is generated based on the expression of 16 cancer genes and 5 reference genes. The levels of expression are used to derive an RS that ranges from 0 to 100, using a prospectively defined mathematical algorithm. This novel quantitative approach to the evaluation of the best-known molecular pathways in breast cancer has produced impressive results. Use of this multigene assay to predict recurrence was validated in the National Surgi-cal Adjuvant Breast and Bowel Project (NSABP) B-14 trial, in which ER-positive, node-negative patients had received tamoxifen.114 By multivariate Cox proportional analysis, RS was found to be independently associated with recurrence risk, with a hazard ratio of 3.21 (95% confidence interval of 2.23 to 4.65, P <.001). The RS was indeed able to stratify patients by freedom from distant recurrence (Fig. 10-13).114 The Trial Assessing Individualized Options for Treatment for breast cancer (TAILORx) is evaluating the utility of Oncotype DX for predicting prognosis in patients with ER-positive, node-negative tumors and will focus on women with intermediate RS scores in whom the role of chemotherapy is unclear. Several other multigene predictors for breast cancer are available including MammaPrint, a gene expression profiling platform assessing a Brunicardi_Ch10_p0305-p0354.indd 33422/02/19 2:14 PM 335ONCOLOGYCHAPTER 1070-gene transcriptional signature.115 This assay was approved by the Food and Drug Administration (FDA) in February 2007. The usefulness of this assay in making therapy-related decisions was tested prospectively in a large-scale study, the Microarray in Node-Negative Disease May Avoid Chemotherapy (MIND-ACT) trial. Among women with early-stage breast cancer who were determined to be at high clinical risk and low genomic risk for cancer recurrence, the receipt of no adjuvant chemotherapy on the basis of the 70-gene signature result led to a 5-year metas-tasis survival rate that was 1.5% lower than the rate in patients who had received chemotherapy. In light of these findings, 45% of women with breast cancer who are considered to be at high clinical risk might not require adjuvant chemotherapy.116Multigene profiles to predict prognosis are in development or in validation phases for many other solid tumor types, includ-ing lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, and melanoma. Gene signatures and genomic alterations also are being studied for their ability to predict response to specific chemotherapy regimens or targeted therapies. Many of these multigene marker sets will likely be incorporated into clinical practice in the years to come.Serum MarkersSerum markers are under active investigation because they may allow early diagnosis of a new cancer or may be used to follow cancer response to therapy or monitor for recurrence. Unfor-tunately, identification of serum markers of clinical value has been challenging. Many of the tumor markers proposed so far have had low sensitivities and specificities.113 Tumor marker levels may not be elevated in all patients with cancer, especially in the early stages, when a serum marker would be most use-ful for diagnosis. Therefore, when a tumor marker is used to monitor recurrence, it is important to be certain that the level of the tumor marker was elevated before primary therapy. More-over, tumor marker levels can be elevated in benign conditions. Many tumor markers are not specific for a certain type of cancer and can be elevated with more than one type of tumor. Since there may be significant laboratory variability, it is important to obtain serial results from the same laboratory. In spite of these many clinical limitations, several serum markers are in clinical use. A few of the commonly measured serum tumor markers are discussed in the following sections.Prostate-Specific Antigen. Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by the pros-tate epithelium. PSA is normally present in low concentrations in the blood of all adult males. PSA levels may be elevated in the blood of men with benign prostate conditions such as pros-tatitis and benign prostatic hyperplasia, as well as in men with prostate cancer. PSA levels have been shown to be useful in evaluating the effectiveness of prostate cancer treatment and monitoring for recurrence after therapy. In monitoring for recur-rence, a trend of increasing levels is considered more significant than a single absolute elevated value.Although PSA has been widely used for prostate cancer screening, the utility of PSA screening remains controversial. There is concern that the number of men who avoid dying from prostate cancer due to screening is small, while the harms related to the treatment of screen-detected cancers, including inconti-nence and erectile dysfunction are at least moderate. In 2012, the U.S. Preventive Services Task Force concluded with moder-ate certainty that the harms of PSA testing outweigh the benefits and on that basis recommended against PSA-based screening for all men.117 In 2010, the American Cancer Society updated its guidelines for the early detection of prostate cancer to state that men who have at least a 10-year life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer with digital rectal exam and serum PSA, after receiving information about the benefits, risks, and uncertainties associated with pros-tate cancer screening118; this recommendation was reinforced in their most recent guidelines.96Carcinoembryonic Antigen. Carcinoembryonic antigen (CEA) is a glycoprotein found in the embryonic endodermal epithelium. Elevated CEA levels have been detected in patients with primary colorectal cancer as well as in patients with breast, lung, ovarian, prostate, liver, and pancreatic cancer. Levels of CEA also may be elevated in benign conditions, including diverticulitis, peptic ulcer disease, bronchitis, liver abscess, and alcoholic cirrhosis, especially in smokers and in elderly persons.CEA measurement is most commonly used in the man-agement of colorectal cancer. However, the appropriate use of CEA testing in patients with colorectal cancer has been debated. Use of CEA level as a screening test for colorectal cancer is not recommended. CEA levels may be useful if obtained pre-operatively and postoperatively in patients with a diagnosis of colorectal cancer. Preoperative elevation of CEA level is an indicator of poor prognosis. However, the ASCO clinical prac-tice guidelines state that the data are insufficient to support the use of CEA to determine whether to give a patient adjuvant therapy; the data are stronger for the use of CEA for monitoring for postoperative recurrence.111 CEA measurement is the most cost-effective approach for detecting metastasis, with over 60% of recurrences being detected first by an elevation in CEA level. Therefore, in cases in which the patient would be a candidate for resection of recurrent colorectal cancer or systemic therapy, the ASCO guidelines recommend that postoperative CEA testing be performed every 3 months in patients with stage II or III disease for at least 3 years.112 CEA is the marker of choice for monitor-ing metastatic colorectal cancer during systemic therapy.112Alpha-Fetoprotein. Alpha-fetoprotein (AFP) is a glycoprotein normally produced by a developing fetus. AFP levels decrease soon after birth in healthy adults. An elevated level of AFP sug-gests the presence of either primary liver cancer or a germ cell tumor of the ovary or testicle. Rarely, other types of cancer such as gastric are associated with an elevated AFP level. Benign conditions that can cause elevations of AFP include cirrhosis, hepatic necrosis, acute hepatitis, chronic active hepatitis, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and pregnancy.119The sensitivity of an elevated AFP level for detecting HCC is approximately 60%. AFP is considered to be sensitive and specific enough to be used for screening for HCC in high-risk populations. Current consensus recommendations are to screen healthy hepatitis B virus carriers with annual or semi-annual measurement of AFP level and to screen carriers with cirrhosis or chronic hepatitis and patients with cirrhosis of any etiology with twice-yearly measurement of AFP level and liver ultrasonography.120 Although AFP testing has been used widely for a long time, its efficacy in early diagnosis of HCC is limited. With improvements in imaging technology, a larger proportion of patients diagnosed with HCC are now AFP seronegative.Cancer Antigen 19-9. Cancer antigen 19-9 (CA 19-9) is a tumor-related antigen that was originally defined by a monoclo-nal antibody produced by a hybridoma prepared from murine Brunicardi_Ch10_p0305-p0354.indd 33522/02/19 2:14 PM 336BASIC CONSIDERATIONSPART Ispleen cells immunized with a human colorectal cancer cell line.112 The data are insufficient to recommend use of CA 19-9 for screening, diagnosis, surveillance, or monitoring of therapy for colon cancer.112 Based on the 2006 ASCO guidelines, there are also insufficient data to recommend use of CA 19-9 for screening, diagnosis, or determination of the operability of pan-creatic cancer.112 However, for patients with locally advanced or metastatic cancer receiving active therapy, CA 19-9 can be measured at the start of therapy and every 1 to 3 months while therapy is given; elevations in serial CA 19-9 levels may indi-cate progressive disease and should be confirmed by additional studies.112Cancer Antigen 15-3. Cancer antigen 15-3 (CA 15-3) is an epitope of a large membrane glycoprotein encoded by the MUC1 gene that tumor cells shed into the bloodstream. The CA 15-3 epitope is recognized by two monoclonal antibodies in a sandwich radioimmunoassay. CA 15-3 levels are most useful in following the course of treatment in women diagnosed with advanced breast cancer. CA 15-3 levels are infrequently elevated in early-stage breast cancer. CA 15-3 levels can be increased in benign conditions such as chronic hepatitis, tuberculosis, sar-coidosis, pelvic inflammatory disease, endometriosis, systemic lupus erythematosus, pregnancy, and lactation, and in other types of cancer such as lung, ovarian, endometrial, and GI cancers.The sensitivity of CA 15-3 is higher for metastatic disease, and in these cases studies have shown sensitivity to be between 54% and 87%, with specificity as high as 96%. This has led to interest in using CA 15-3 for monitoring patients with advanced breast cancer for recurrence. Elevated CA 15-3 levels have been reported before relapse in 54% of patients, with a lead time of 4.2 months. Therefore, detection of elevated CA 15-3 levels dur-ing follow-up should prompt evaluation for recurrent disease. However, 6% to 8% of patients without recurrence will have ele-vated CA 15-3 levels that require evaluation. Furthermore, moni-toring with the use of CA 15-3 levels has shown no demonstrated impact on survival. Therefore, the 2007 ASCO guidelines state that the routine use of CA 15-3 for screening, diagnosis, stag-ing, or surveillance of breast cancer is not recommended because available data are insufficient.111 For monitoring patients during active therapy, CA 15-3 can be used in conjunction with diag-nostic imaging and history and physical examination.111 In the absence of measurable disease, an increase may be interpreted to indicate treatment failure. However, caution is advised when interpreting rising levels in the first 4 to 6 weeks of therapy.111Cancer Antigen 27-29. The MUC-1 gene product in the serum may be quantitated by using radioimmunoassay with a monoclonal antibody against the cancer antigen 27-29 (CA 27-29). CA 27-29 levels can be elevated in breast cancer as well as in cancers of the colon, stomach, kidney, lung, ovary, pan-creas, uterus, and liver. First-trimester pregnancy, endometrio-sis, benign breast disease, kidney disease, and liver disease also may be associated with elevated CA 27-29 levels.CA 27-29 has been reported to have a sensitivity of 57%, a specificity of 98%, a positive predictive value of 83%, and a negative predictive value of 93% in detecting breast cancer recurrences.121 Although CA 27-29 has been found to predict recurrence an average of 5.3 months before other symptoms or tests, testing of CA 27-29 levels has not been demonstrated to affect disease-free and overall survival rates.121,122 Therefore, the ASCO guidelines state that, as with CA 15-3, the routine use of CA 27-29 for screening, diagnosis, staging, or surveillance of breast cancer is not recommended because available data are insufficient.111 CA 27-29 levels can be used together with diag-nostic imaging and history and physical examination to monitor patients during active therapy.111 When no measurable disease is present, an increase in level may be considered to indicate treat-ment failure. However, rising levels in the first 4 to 6 weeks of therapy should be interpreted with caution.111Circulating Tumor CellsCirculating tumor cells (CTCs) are cells present in the blood that possess antigenic or genetic characteristics of a specific tumor type.111 One CTC detection methodology is capture and quantita-tion of CTCs with immunomagnetic beads coated with antibody specific for cell-surface, epithelial, or cancer antigens. Another methodology used to detect cancer cells in the peripheral blood is RT-PCR. It has been suggested that measurement of CTCs can be an effective tool for selecting patients who have a high risk of relapse and for monitoring efficacy of cancer therapy.CTCs have probably been most extensively studied in breast cancer.111 The most promising data come from the use of CTC measures in metastatic breast cancer. In a prospective multicenter trial, the number of CTCs (≥5 CTCs vs. <5 CTCs per 7.5 mL of whole blood) before treatment of metastatic breast cancer was an independent predictor of progression-free and overall survival rates.123 The presence of >5 CTCs after the first course of therapy predicted lack of response to treatment. This technology, known as CellSearch, has been approved by the FDA for clinical use. In a well-designed single institutional study, detection of one or more CTCs in stage I to III breast cancer patients was associated with both decreased progres-sion-free survival and overall survival.124 A large clinical trial was launched by the German SUCCESS study group to evalu-ate the prognostic significance of CTCs in early breast cancer. Blood samples were obtained from over 2000 average-to-high-risk nonmetastatic breast cancer patients before chemotherapy and nearly 1500 patients post chemotherapy and examined for CTCs. Women with detectable CTCs before chemotherapy had significantly worse disease-free and overall survival, and those with five or more CTCs had the highest relapse risk.125 How-ever, there is limited data to prove that the use of CTC testing leads to improved survival or improved quality of life; thus, the ASCO 2017 guidelines update did not recommend the use of CTC measurement in any clinical setting.111 The clinical util-ity of measuring CTC response to initial therapy is now being tested prospectively in multiple clinical trials. The ability to conduct comprehensive analyses of cancer genomes within indi-vidual cells is becoming a real possibility, although the clinical utility of such information is still evolving. In addition to CTC, it has become possible in recent years to conduct a so-called “liquid tumor biopsy” by measuring levels of circulating tumor DNA and also circulating microRNAs. These new techniques are investigational but have the potential to provide prognos-tic and diagnostic information via their presumed correlation with tumor progression and the development of genomic altera-tions.126 The prognostic implications of detection of CTCs by RT-PCR have been intensively studied for melanoma. In the recent multicenter Sunbelt Melanoma Trial, serial RT-PCR was performed on peripheral blood samples using four markers—tyrosinase, melanoma antigen reacting to T cell (MART-1), melanoma antigen 3 (MAGE3), and gp 100—to detect occult Brunicardi_Ch10_p0305-p0354.indd 33622/02/19 2:14 PM 337ONCOLOGYCHAPTER 10melanoma cells in the bloodstream.127 Although there were no differences in survival rates among patients in whom at least one marker was detected and those in whom no markers were detected, the disease-free survival and distant disease-free sur-vival rates were worse for patients in whom more than one marker was detected at any time during follow-up.127Bone Marrow MicrometastasesMicrometastatic disease in the bone marrow, also referred to as minimal residual disease, continues to be investigated as a potential prognostic marker. Bone marrow micrometastatic disease usually is detected by staining bone marrow aspirates with monoclonal antibodies to cytokeratin, but other method-ologies such as flow cytometry and RT-PCR are in use. Breast cancer patients with bone marrow micrometastasis have larger tumors, tumors with a higher histologic grade, more lymph node metastases, and more hormone receptor-negative tumors than patients without bone marrow micrometastasis. In 4700 patients with stage I, II, or III breast cancer, micrometastasis was a sig-nificant prognostic factor associated with poor overall survival, breast cancer-specific survival, disease-free survival, and distant disease-free survival during a 10-year observation period.128 The American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study to determine the association between survival and metastases detected by immunochemical staining of bone marrow specimens from patients with early-stage breast cancer.129 Of 3413 bone mar-row specimens examined by immunocytochemistry, only 104 (3.0%) were positive for tumor. Bone marrow involvement was associated with a decreased overall survival, but this association was not significant on multivariable analysis. The prognostic implication of bone marrow involvement continues to be stud-ied by the National Surgical Adjuvant Breast and Bowel Project.At this time, the routine use of bone marrow testing is not recommended.111 Ongoing clinical trials are evaluating the role of routine assessment of bone marrow status in the care of patients with early and advanced breast cancer. The utility of assessment of bone marrow micrometastasis has also been evaluated in other tumor types, including gastric, esophageal, colorectal, lung, cervical, and ovarian cancer.130SURGICAL APPROACHES TO CANCER THERAPYMultidisciplinary Approach to CancerAlthough surgery is an effective therapy for most solid tumors, patients who die from cancer usually die of metastatic disease. Therefore, to improve patient survival rates, a multimodality approach, including systemic therapy and radiation therapy, is key for most tumors. It is important that surgeons involved in cancer care not only know the techniques for performing a cancer operation but also know the alternatives to surgery and be well versed in reconstructive options. It is also crucial that the surgeon be familiar with the indications for and complications of preoperative and postoperative chemotherapy and radiation therapy. Although the surgeon may not be delivering these other therapies, as the first physician to see a patient with a cancer diagnosis, he or she is ultimately responsible for initiating the appropriate consultations. For this reason, the surgeon often is responsible for determining the most appropriate adjuvant ther-apy for a given patient as well as the best sequence for therapy. In most instances, a multidisciplinary approach beginning at the patient’s initial presentation is likely to yield the best result.Surgical Management of Primary TumorsThe goal of surgical therapy for cancer is to achieve oncologic cure. A curative operation presupposes that the tumor is confined to the organ of origin or to the organ and the regional lymph node basin. Patients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable disease. The operability of primary tumors is best determined before surgery with appropriate imaging studies that can define the extent of local-regional disease. For example, a preoperative thin-section CT scan is obtained to determine resectability of pancreatic cancer, which is based on the absence of extrapancre-atic disease, the absence of tumor extension to the superior mes-enteric artery and celiac axis, and a patent superior mesenteric vein-portal vein confluence.131 Disease involving multiple distant metastases is deemed inoperable because it is usually not curable with surgery of the primary tumor. Therefore, patients who are at high risk of having distant metastasis should undergo a staging work-up before surgery for the primary tumor. On occasion, pri-mary tumors are resected in these patients for palliative reasons, such as improving the quality of life by alleviating pain, infec-tion, or bleeding. An example of this is toilet mastectomies for large ulcerated breast tumors. Patients with limited metastases from a primary tumor on occasion are considered surgical candi-dates if the natural history of isolated distant metastases for that cancer type is favorable or the potential complications associated with leaving the primary tumor intact are significant.In the past, it was presumed that the more radical the sur-gery, the better the oncologic outcome would be. Over the past three decades, this has been recognized as not necessarily being true, which has led to more conservative operations, with wide local excisions replacing compartmental resections of sarcomas, and partial mastectomies, skin-sparing mastectomies, and breast-conserving therapies replacing radical mastectomies for breast cancer. The uniform goal for all successful oncologic operations seems to be achieving widely negative margins with no evidence of macroscopic or microscopic tumor at the surgical margins. The importance of negative surgical margins for local tumor control and/or survival has been documented for many tumor types, including sarcoma, breast cancer, pancreatic cancer, and rectal cancer. Thus, it is clear that every effort should be made to achieve microscopically negative surgical margins. Inking of the margins, orientation of the specimen by the surgeon, and immediate gross evaluation of the margins by a pathologist using frozen-section analysis when necessary may assist in achiev-ing negative margins at the first operation. In the end, although radiation therapy and systemic therapy can assist in decreasing local recurrence rates in the setting of positive margins, adjuvant therapy cannot substitute for adequate surgery.Although it is clear that the surgical gold standard is nega-tive surgical margins, the appropriate surgical margins for optimal local control are controversial for many cancer types. In contrast, in melanoma the optimal margin width for any tumor depth has been better defined, owing to the systematic study of this ques-tion in randomized clinical trials.132,133 Although such randomized studies may not be possible for all tumor types, it is important to determine optimal surgical margins for each cancer type so that adjuvant radiation and systemic therapy can be offered to patients deemed to be at increased risk for local treatment failure.Brunicardi_Ch10_p0305-p0354.indd 33722/02/19 2:14 PM 338BASIC CONSIDERATIONSPART IFigure 10-14. Lymphatic mapping and sen-tinel lymph node biopsy specimen for breast cancer. A. Peritumoral injection of blue dye. B. Blue dye draining into the sentinel lymph node.Surgical Management of the Regional Lymph Node BasinMost neoplasms have the ability to metastasize via the lymphat-ics. Therefore, most oncologic operations have been designed to remove the primary tumor and draining lymphatics en bloc. This type of operative approach usually is undertaken when the lymph nodes draining the primary tumor site lie adjacent to the tumor bed, as is the case for colorectal cancers and gastric can-cers. For tumors in which the regional lymph node basin is not immediately adjacent to the tumor (e.g., melanomas), lymph node surgery can be performed through a separate incision. Unlike most carcinomas, soft tissue sarcomas rarely metasta-size to the lymph nodes (<5%); therefore, lymph node surgery usually is not necessary.It is generally accepted that a formal lymphadenectomy is likely to minimize the risk of regional recurrence of most cancers. For example, the introduction of total mesorectal excision of rectal cancer has been associated with a large decline in local-regional recurrence, and this procedure has become the new standard of operative management.134 On the other hand, there have been two opposing views regarding the role of lymphadenectomy in survival of cancer patients. The traditional Halsted view states that lymphadenectomy is important for staging and survival. The opposing view coun-ters that cancer is systemic at inception and that lymphade-nectomy, although useful for staging, does not affect survival. For most cancers, involvement of the lymph nodes is one of the most significant prognostic factors. Interestingly, in some studies removal of a larger number of lymph nodes has been found to be associated with an improved overall survival rate for many tumors, including breast cancer, colon cancer, and lung cancer. Although this seems to support the Halsted the-ory that more extensive lymphadenectomy yielding of nodes reduces the risk of regional recurrence, there may be alterna-tive explanations for the same finding. For example, the sur-geon who performs a more extensive lymphadenectomy may obtain wider margins around the tumor or even provide better overall care, such as ensuring that patients receive the appropri-ate adjuvant therapy or undergo a more thorough staging work-up. Alternatively, the pathologist may perform a more thorough examination, identifying more nodes and more accurately stag-ing the nodes. The effect of appropriate staging on survival is twofold. Patients with nodal metastases may be offered adjuvant therapy, which improves their survival chances. Further, the enhanced staging can improve perceived survival rates through a “Will Rogers effect.” Such a phenomenon is observed when moving an element from one set to another set raises the average value of both sets. When commenting on the 1930s migration of poor farmers from a dustbowl state to a more prosperous west-ern state, humorist Will Rogers quipped that this event raised the average intelligence of both states. Thus, identification of small metastases that had formerly been silent and unidenti-fied leads to stage migration for these patients and thus to a perceived improvement in chances of survival for the higher stage. In addition, there is improved survival for the lower stage, which is now minus the patients with low volume nodal disease. Clearly the impact of lymphadenectomy on survival will con-tinue to be a topic of clinical research.Surgical management of the clinically negative regional lymph node basin has evolved with the introduction of lym-phatic mapping technology (Fig. 10-14).135 Lymphatic mapping and sentinel lymph node biopsy specimen were first reported in 1977 by Cabanas for penile cancer.136 Now, sentinel node biopsy specimen is the standard of care for the management of melanoma and breast cancer. The utility of sentinel node biopsy is being explored in other cancer types such as head and neck squamous cell cancer and vulvar cancer.The first node to receive drainage from the tumor site is termed the sentinel node. This node is the node most likely to contain metastases, if metastases to that regional lymph node basin are present. The goal of lymphatic mapping and senti-nel lymph node biopsy specimen is to identify and remove the lymph node most likely to contain metastases in the least inva-sive fashion. The practice of sentinel lymph node biopsy speci-men followed by regional lymph node dissection for selected patients with a positive sentinel lymph node avoids the morbid-ity of lymph node dissections in patients with negative nodes. An additional advantage of the sentinel lymph node technique is that it directs attention to a single node, which allows more careful analysis of the lymph node most likely to have a positive yield and increases the accuracy of nodal staging. Two criteria are used to assess the efficacy of a sentinel lymph node biopsy specimen: the sentinel lymph node identification rate and the false-negative rate. The sentinel lymph node identification rate Brunicardi_Ch10_p0305-p0354.indd 33822/02/19 2:14 PM 339ONCOLOGYCHAPTER 10is the proportion of patients in whom a sentinel lymph node was identified and removed among all patients undergoing an attempted sentinel lymph node biopsy specimen. The false-negative rate is the proportion of patients with regional lymph node metastases in whom the sentinel lymph node was found to be negative. False-negative biopsy specimen results may be due to identifying the wrong node or to missing the sentinel node (i.e., surgical error) or they may be due to the cancer cells’ establishing metastases not in the first node encountered but in a second-echelon node (i.e., biologic variation). Alternatively, false-negative biopsy specimen results may be due to inadequate histologic evaluation of the lymph node. The false-negative rates for sentinel lymph node biopsy specimen in study series range between 0% and 11%. Both increases in the identification rate and decreases in the false-negative rate have been observed as surgeons gain experience with the technique.Lymphatic mapping is performed by using isosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combi-nation of both techniques to detect sentinel nodes. The combina-tion of blue dye and technetium has been reported to improve the capability of detecting sentinel lymph nodes. The nodal drainage pattern usually is determined with a preoperative lym-phoscintigram, and the “hot” and/or blue nodes are identified with the assistance of a gamma probe and careful nodal basin exploration. Careful manual palpation is a crucial part of the procedure to minimize the false-negative rate.The nodes are evaluated with serial sectioning, hematoxy-lin and eosin staining, and immunohistochemical analysis with S-100 protein and homatropine methylbromide staining for mel-anoma and cytokeratin staining for breast cancer. The utility of molecular techniques such as RT-PCR to assess the sentinel nodes is still being explored.Another area of active investigation is the prognostic value of minimal nodal involvement. For example, in breast cancer, nodes with isolated tumor cell deposits of <0.2 mm are considered to be N0 by the sixth edition of the AJCC staging manual. However, some retrospective studies have suggested that even this amount of nodal disease burden has negative prognostic implications.137 Molecular ultrastaging with RT-PCR for patients with node-negative disease was assessed in a pro-spective multicenter trial and was found not to be prognostic in malignant melanoma.127 However, a recent meta-analysis of 22 studies enrolling 4019 patients found that PCR positivity was associated with worse overall and disease-free survival.138 Fur-ther study of the utility of ultrastaging of nodes in breast cancer, melanoma, and several other tumor types is ongoing.Until recently, in breast cancer management, when senti-nel node mapping revealed a positive sentinel node, this was fol-lowed by a completion axillary lymph node dissection. Results of the American College of Surgeons Oncology Group Z0011 trial, challenged this practice. ACOSOG Z11 was a phase 3 mul-ticenter noninferiority trial conducted to determine the effects of complete axillary lymph node dissection on survival of patients with sentinel lymph node metastasis of breast cancer.129 Patients were women with clinical T1-T2 invasive breast cancer, no pal-pable adenopathy, and 1 to 2 SLNs containing metastases identi-fied by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. All patients underwent breast-conserving surgery and tangential whole-breast irradiation. Those with sentinel node metastases identified by sentinel node biopsy specimen were randomized to undergo axillary lymph node dissection or no further axillary treatment. At a median follow-up of 6.3 years, 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with axillary lymph node dissection and 92.5% (95% CI, 90.0%–95.1%) with sen-tinel node alone. The 5-year disease-free survival was 82.2% (95% CI, 78.3%–86.3%) with axillary lymph node dissection, and 83.9% (95% CI, 80.2%–87.9%) with sentinel node alone. Thus, ACOSOGZ11 demonstrated that among breast cancer patients with limited sentinel node metastasis treated with breast conservation and systemic therapy, the use of sentinel node alone compared with axillary lymph node dissection did not result in inferior survival. This study challenges the traditional surgical dictum of regional management, and has led to a selec-tive utilization of completion axillary lymph node dissection in breast cancer patients undergoing breast conservation. The role of completion lymph node dissections in melanoma is under investigation. In the MSLT-II clinical trial, melanoma patients with sentinel-node metastases were randomized to immediate completion lymph-node dissection or nodal observation with ultrasonography. The primary end point of this study was mela-noma-specific survival. Immediate completion lymph-node dis-section led to increased regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with intermediate-thickness melanoma and sentinel-node metastases.139Surgical Management of Distant MetastasesThe treatment of a patient with distant metastases depends on the number and sites of metastases, the cancer type, the rate of tumor growth, the previous treatments delivered and the responses to these treatments, and the patient’s age, physical condition, and desires. Although once a tumor has metastasized it usually is not curable with surgical therapy, such therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, or brain.Patient selection is the key to the success of surgical therapy for distant metastases. The cancer type is a major determinant in surgical decision making. A liver metastasis from a colon cancer is more likely to be an isolated and thus resectable lesion than a liver metastasis from a pancreatic carcinoma. The growth rate of the tumor also plays an important role and can be determined in part by the disease-free interval and the time between treatment of the primary tumor and detection of the distant recurrence. Patients with longer disease-free intervals have a higher survival rate after surgical metastasectomy than those with a short disease-free interval. Similarly, patients who have synchronous metastases (metastases diagnosed at the initial cancer diagnosis) do worse after metastasectomy than patients who develop metachronous metastases (metastasis diagnosed after a disease-free interval). The natural history of metastatic disease is so poor for some tumors (e.g., pancreatic cancer) that there is no role at this time for surgical metastasectomy. In cancers with a more favorable outlook, observation for several weeks or months, potentially with initial treatment with systemic therapy, can allow the sur-geon to monitor for metastases at other sites.In curative surgery for distant metastases, as with surgery for primary tumors, the goal is to resect the metastases with negative margins. In patients with hepatic metastases that are unresectable because their location near intrahepatic blood ves-sels precludes a margin-negative resection, or because they are multifocal or hepatic function is inadequate, tumor ablation with cryotherapy or radiofrequency ablation is an alternative.140,141 Curative resections or ablative procedures should be attempted Brunicardi_Ch10_p0305-p0354.indd 33922/02/19 2:14 PM 340BASIC CONSIDERATIONSPART Ionly if the lesions are accessible and the procedure can be per-formed safely.CHEMOTHERAPYClinical Use of ChemotherapyIn patients with documented distant metastatic disease, chemo-therapy is usually the primary modality of therapy. The goal of therapy in this setting is to decrease the tumor burden, thus prolonging survival. It is rare to achieve cure with chemother-apy for metastatic disease for most solid tumors. Chemotherapy administered to a patient who is at high risk for distant recur-rence but has no evidence of distant disease is referred to as adjuvant chemotherapy. The goal of adjuvant chemotherapy is eradication of micrometastatic disease, with the intent of decreasing relapse rates and improving survival rates.Adjuvant therapy can be administered after surgery (post-operative chemotherapy) or before surgery (preoperative che-motherapy, neoadjuvant chemotherapy, or induction therapy). A portion or all of the planned adjuvant chemotherapy can be administered before the surgical removal of the primary tumor. Preoperative chemotherapy has three potential advantages. The first is that preoperative regression of tumor can facilitate resection of tumors that were initially inoperable or allow more conservative surgery for patients whose cancer was operable to begin with. In the NSABP B-18 project, for example, women were randomly assigned to receive adjuvant doxorubicin and cyclophosphamide preoperatively or postoperatively. More patients treated before surgery than after surgery underwent breast-conserving surgery (68% vs. 60%).142 The second advan-tage of preoperative chemotherapy is the treatment of microme-tastases without the delay of postoperative recovery. The third advantage is the ability to assess a cancer’s response to treat-ment clinically, after a number of courses of chemotherapy, and pathologically, after surgical resection. This is especially impor-tant if alternative treatment regimens are available to be offered to patients whose disease responded inadequately. Molecular characterization of the residual disease may also give insight into mechanisms of chemoresistance and possible therapeutic targets.There are some potential disadvantages to preoperative chemotherapy, however. Although disease progression while the patient is receiving preoperative chemotherapy is rare in chemotherapy-sensitive tumors such as breast cancer, it is more frequent in relatively chemotherapy-resistant tumors such as sarcomas.143 Thus, patient selection is critical to ensure that the opportunity to treat disease surgically is not lost by giving pre-operative chemotherapy. Often, rates of postoperative wound infection, flap necrosis, and delays in postoperative adjuvant therapy do not differ between patients who are treated with preoperative chemotherapy and patients who are treated with surgery first. However, preoperative chemotherapy can intro-duce special challenges to tumor localization, margin analysis, lymphatic mapping, and pathologic staging.Response to chemotherapy is monitored clinically with imaging studies as well as physical examinations. Response usually is defined as complete response, partial response, stable disease, or progression. Response generally is assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.144 Objective tumor response assessment is critical because tumor response is used as a prospective endpoint in clinical trials and tumor response is a guide to clinicians regard-ing continuation of current therapy.Principles of ChemotherapyChemotherapy destroys cells by first-order kinetics, which means that with the administration of a drug a constant percent-age of cells is killed, not a constant number of cells. If a patient with 1012 tumor cells is treated with a dose that results in 99.9% cell kill (3-log cell kill), the tumor burden will be reduced from 1012 to 109 cells (or 1 kg to 1 g). If the patient is retreated with the same drug, which theoretically could result in another 3-log cell kill, the cells would decrease in number from 109 to 106 (1 g to 1 mg) rather than being eliminated totally.Chemotherapeutic agents can be classified according to the phase of the cell cycle during which they are effective. Cell-cycle phase-nonspecific agents (e.g., alkylating agents) have a linear dose-response curve, such that the fraction of cells killed increases with the dose of the drug.145 In contrast, the cell-cycle phase-specific drugs have a plateau with respect to cell killing ability, and cell kill will not increase with further increases in drug dose.Anticancer AgentsAlkylating Agents. Alkylating agents are cell-cycle– nonspecific agents, that is, they are able to kill cells in any phase of the cell cycle. They act by cross-linking the two strands of the DNA helix or by causing other direct damage to the DNA. The damage to the DNA prevents cell division and, if severe enough, leads to apoptosis. The alkylating agents are composed of three main subgroups: classic alkylators, nitrosoureas, and miscellaneous DNA-binding agents (Table 10-10).Antitumor Antibiotics. Antitumor antibiotics are the prod-ucts of fermentation of microbial organisms. Like the alkylat-ing agents, these agents are cell-cycle nonspecific. Antitumor antibiotics damage the cell by interfering with DNA or RNA synthesis, although the exact mechanism of action may differ by agent.Antimetabolites. Antimetabolites are generally cell-cycle–specific agents that have their major activity during the S phase of the cell cycle and have little effect on cells in G0. These drugs are most effective, therefore, in tumors that have a high growth fraction. Antimetabolites are structural analogues of naturally occurring metabolites involved in DNA and RNA synthesis. Therefore, they interfere with normal synthesis of nucleic acids by substituting for purines or pyrimidines in the metabolic path-way to inhibit critical enzymes in nucleic acid synthesis. The antimetabolites include folate antagonists, purine antagonists, and pyrimidine antagonists.Plant Alkaloids. Plant alkaloids are derived from plants such as the periwinkle plant, Vinca rosea (e.g., vincristine, a vinca alkaloid), or the root of American mandrake, Podophyllum peltatum (e.g., etoposide, a podophyllotoxin).145 Vinca alkaloids affect the cell by binding to tubulin in the S phase. This blocks microtubule polymerization, which results in impaired mitotic spindle formation in the M phase. Taxanes such as paclitaxel, on the other hand, cause excess polymerization and stability of microtubules, which blocks the cell cycle in mitosis. The epi-podophyllotoxins (e.g., etoposide) act to inhibit a DNA enzyme called topoisomerase II by stabilizing the DNA-topoisomerase II complex. This results in an inability to synthesize DNA, and thus the cell cycle is stopped in the G1 phase.145Brunicardi_Ch10_p0305-p0354.indd 34022/02/19 2:14 PM 341ONCOLOGYCHAPTER 10Combination ChemotherapyCombination chemotherapy may provide greater efficacy than single-agent therapy by three mechanisms: (a) it provides maxi-mum cell kill within the range of toxicity for each drug that can be tolerated by the host, (b) it offers a broader range of coverage of resistant cell lines in a heterogeneous population, and (c) it prevents or delays the emergence of drug-resistant cell lines.145 When combination regimens are devised, drugs known to be active as single agents usually are selected. Drugs with different mechanisms of action are combined to allow for additive or syn-ergistic effects. Combining cell-cycle–specific and cell-cycle–nonspecific agents may be especially advantageous. Drugs with differing dose-limiting toxic effects are combined to allow for each drug to be given at therapeutic doses. Drugs with differ-ent patterns of resistance are combined whenever possible to minimize cross-resistance. The treatment-free interval between cycles is kept to the shortest possible time that will allow for recovery of the most sensitive normal tissue.Drug ToxicityTumors are more susceptible than normal tissue to chemothera-peutic agents, in part because they have a higher proportion of dividing cells. Normal tissues with a high growth fraction, such as the bone marrow, oral and intestinal mucosa and hair follicles are sensitive to chemotherapeutic effects. Therefore, treatment with chemotherapeutic agents can produce toxic effects such as bone marrow suppression, stomatitis, ulceration of the GI tract, and alopecia. Toxic effects usually are graded from 0 to 4 on the basis of World Health Organization standard criteria.146 Significant drug toxicity may necessitate a dosage reduction. A toxic effect requiring a dose modification or change in dose intensity is referred to as a dose-limiting toxic effect. Because maintaining dose intensity is important to preserve as high a tumor cell kill as possible, several supportive strategies have been developed, such as administration of colony-stimulating factors and erythropoietin to treat poor bone marrow reserve and administration of cytoprotectants such as mesna and amifostine to prevent renal dysfunction. Some toxicities, such as neuropa-thy, are not as easily reversible, and their potential effects on lifestyle must be considered when evaluating a patient prior to the initiation of chemotherapy.Administration of ChemotherapyChemotherapy usually is administered systemically (IV, IM, SC, or PO). Systemic administration treats micrometastases at widespread sites and prevents systemic recurrence. However, it increases the drug’s toxicity to a wide range of organs through-out the body. One method to minimize systemic toxicity while enhancing target organ delivery of chemotherapy is regional administration of chemotherapy. Many of these approaches require surgical access, such as intrahepatic delivery of chemo-therapy for hepatic carcinomas or metastatic colorectal cancer using a hepatic artery infusion pump, limb perfusion for extrem-ity melanoma and sarcoma, and intraperitoneal hyperthermic Table 10-10Classification of chemotherapeutic agentsAlkylating agents Classic alkylating agents  Busulfan  Chlorambucil  Cyclophosphamide  Ifosfamide  Mechlorethamine (nitrogen mustard)  Melphalan  Mitomycin C  Triethylene thiophosphoramide (thiotepa) Nitrosoureas  Carmustine (BCNU)  Lomustine (CCNU)  Semustine (MeCCNU)  Streptozocin Miscellaneous DNA-binding agents  Carboplatin  Cisplatin  Dacarbazine (DTIC)  Hexamethylmelamine  ProcarbazineAntitumor antibiotics Bleomycin Dactinomycin (actinomycin D) Daunorubicin Doxorubicin Idarubicin Plicamycin (mithramycin)Antimetabolites Folate analogues  Methotrexate  Purine analogues   Azathioprine   Mercaptopurine   Thioguanine   Cladribine (2-chlorodeoxyadenosine)   Fludarabine   Pentostatin  Pyrimidine analogues   Capecitabine   Cytarabine   Floxuridine   Gemcitabine  Ribonucleotide reductase inhibitors   Hydroxyurea Plant alkaloids  Vinca alkaloids   Vinblastine   Vincristine   Vindesine   Vinorelbine  Epipodophyllotoxins   Etoposide   Teniposide  Taxanes   Paclitaxel   Docetaxel Miscellaneous agents   Asparaginase   Estramustine   MitotaneBrunicardi_Ch10_p0305-p0354.indd 34122/02/19 2:14 PM 342BASIC CONSIDERATIONSPART Iperfusion for pseudomyxoma peritonei. Alternately, percutane-ous access may be utilized, such as limb infusion with percuta-neously placed catheters.HORMONAL THERAPYSome tumors, most notably breast and prostate cancers, origi-nate from tissues whose growth is under hormonal control. The first attempts at hormonal therapy were through surgical ablation of the organ producing the hormones involved, such as oophorectomy for breast cancer. Currently, hormonal anti-cancer agents include androgens, antiandrogens, antiestrogens, estrogens, glucocorticoids, gonadotropin inhibitors, progestins, aromatase inhibitors, and somatostatin analogues. Hormones or hormone-like agents can be administered to inhibit tumor growth by blocking or antagonizing the naturally occurring sub-stance, such as with the estrogen antagonist tamoxifen. Other substances that block the synthesis of the natural hormone can be administered as alternatives. Aromatase inhibitors, for exam-ple, block the peripheral conversion of endogenous androgens to estrogens in postmenopausal women. Hormonal therapy pro-vides a highly tumor-specific form of therapy in sensitive tis-sues. In breast cancer, estrogen and progesterone receptor status is used to predict the success of hormonal therapy. Androgen receptor is also being pursued as a therapeutic target for breast cancer treatment.TARGETED THERAPYOver the past decade, increased understanding of cancer biol-ogy has fostered the emerging field of molecular therapeutics. The basic principle of molecular therapeutics is to exploit the molecular differences between normal cells and cancer cells to develop targeted therapies. Thus, targeted therapies usually are directed at the processes involved in tumor growth rather than directly targeting the tumor cells. The ideal molecular target would be exclusively expressed in the cancer cells, be the driv-ing force of the proliferation of the cancer cells, and be critical to their survival. A large number of molecular targets are cur-rently being explored, both preclinically and in clinical trials. The major groups of targeted therapy agents are inhibitors of growth factor receptors, inhibitors of intracellular signal trans-duction, cell-cycle inhibitors, apoptosis-based therapies, and anti-angiogenic compounds.Protein kinases have come to the forefront as attrac-tive therapeutic targets with the success of imatinib mesylate (Gleevec) in treating chronic myelogenous leukemia and GI stromal tumors, and trastuzumab (Herceptin) in treating breast cancer, and vemurafanib in treating melanoma. These drugs work by targeting bcr-abland c-kit (imatinib) and HER2 and BRAF, respectively. For example, a phase 3 randomized trial demonstrated that, compared with dacarbazine, standard of care chemotherapy option for patients with metastatic melanoma with a V600E BRAF mutation, the BRAF inhibitor vemurafenib led to significantly higher response rates (48% vs. 5%).147 At 6 months, overall survival was 84% (95% CI, 78–89) in the vemurafenib group and 64% (95% CI, 56–73) in the dacarba-zine group. The hazard ratio for tumor progression in the vemu-rafenib group was 0.26 (95% CI, 0.20–0.33; P<0.001). The estimated median progression-free survival was 5.3 months in the vemurafenib group and 1.6 months in the dacarbazine group. This trial highlights the fact that in at least some tumor types targeted therapies that inhibit a genomic alteration that is a driver is likely to be more effective than an unselected thera-peutic option.Sequencing of the human genome has revealed approxi-mately 500 protein kinases. Several tyrosine kinases have been shown to have oncogenic properties and many other protein kinases have been shown to be aberrantly activated in cancer cells.93 Therefore, protein kinases involved in these aberrantly activated pathways are being aggressively pursued in molecular therapeutics. Potential targets like HER2 can be targeted via dif-ferent strategies, such as transcriptional downregulation, targeting of mRNA, RNA inhibition, antisense strategies, direct inhibition of protein activity, and induction of immunity against the protein. Most of the compounds in development are monoclonal antibod-ies like trastuzumab or small-molecule kinase inhibitors like ima-tinib or vemurafanib. Some other agents, such as sunitinib, are multitargeted kinase inhibitors. Selected FDA-approved targeted therapies are listed in Table 10-11. Many of the promising path-ways, such as the PI3K/Akt/mTOR pathway, are being pursued as therapeutic targets with several drugs in development, targeting different aspects of the pathway (Fig. 10-15).148Development of molecularly targeted agents for clinical use presents several unique challenges. Once an appropriate compound is identified and confirmed to have activity in pre-clinical testing, predictive markers for activity in the preclinical setting must be defined. Expression of a target may not be suf-ficient to predict response because the pathway of interest may not be activated or critical to the cancer’s survival. Although in traditional phase 1 trials the goal is to identify the maximum tol-erated dosage, the maximum dosage of biologic agents may not be necessary to achieve the desired biologic effect. Thus, assays to verify modulation of the target need to be developed to deter-mine at what dosage the desired effect is achieved. When phases 2 and 3 clinical trials are initiated, biomarker modulation studies should be integrated into the trial to determine whether clinical response correlates with target modulation and thus to identify additional parameters that impact response. Rational dose selec-tion and limitation of study populations to patients most likely to respond to the molecular therapy as determined by predictive markers are most likely to lead to successful clinical transla-tion of a product. Finally, most biologic agents are cytostatic, not cytotoxic. Thus, rational combination therapy mixing new biologic agents with either established chemotherapeutic agents that have synergy or with other biologic agents is more likely to lead to cancer cures.IMMUNOTHERAPYThe aim of immunotherapy is to induce or potentiate inherent antitumor immunity that can destroy cancer cells. Central to the process of antitumor immunity is the ability of the immune sys-tem to recognize tumor-associated antigens present on human cancers and to direct cytotoxic responses through humoral or T-cell–mediated immunity. Overall, T-cell–mediated immunity appears to have the greater potential of the two for eradicating tumor cells. T cells recognize antigens on the surfaces of target cells as small peptides presented by class I and class II MHC molecules.Several antitumor strategies are under investigation. One approach to antitumor immunity is nonspecific immunotherapy, which stimulates the immune system as a whole through admin-istration of bacterial agents or their products, such as bacille Brunicardi_Ch10_p0305-p0354.indd 34222/02/19 2:14 PM 343ONCOLOGYCHAPTER 10Table 10-11Selected FDA-approved targeted therapiesGENERIC NAMETRADE NAMETARGETFDA-APPROVED INDICATIONSAdo-trastuzumab emtansineKadcylaHER2Breast cancerAxitinibInlytaKIT, FDGFRβ, VEGFR1/2/3RCCBevacizumabAvastinVEGFColorectal cancer, lung cancer, glioblastoma, NSCLCRCCBortezomibVelcadeProteasomeMyelomaBosutinibBosulifABLCML (Philadelphia chromosome+)CabozantinibCometriqFLT3, KIT, MET, RET, VEGR2Medullary thyroid cancerCetuximabErbituxEGFRColorectal cancer (KRAS wild-type)Squamous cell cancer of the head and neckCrizotinibXalkoriALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitorNon-small cell lung carcinomaDabrafenibTafinolarBRAF V600E mutationMelanomaDasatinibSprycelABL, src family, KIT, EPHA2, PDGFR-βCMLErlotinibTarcevaEGFRNSCLC,Pancreatic cancerEverolimusAfinitormTORPNET,RCC,Breast cancer.Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosisGefitinibIressaEGFRNSCLC with known/previous benefit from gefitinib (limited approval)IbrutinibImbruvicaBruton’s Tyrosine KinaseChronic lymphocytic leukemiaImatinibGleevecKIT, ABL, PDGFRCML,GIST (KIT+),Dermatofibrosarcoma protuberansLapatinibTykerbEGFR and HER2Breast cancer (HER2+)NilotinibTasignaABLCML (Philadelphia chromosome+)PanitumumabVectibixEGFRColorectal cancer (KRAS wild type)PazopanibVotrientVEGFR, PDGFR, KITRCCPertuzumabPerjetaHER2Breast cancer (HER+)PonatinibIclusigABL, FGFR1-3, FLT3, VEGFR2CML, ALL (Philadelphia chromosome+)RegorafenibStivargaKIT, PDGFRβ, RAF, RET, VEGFR1/2/3Colorectal cancer, GISTSorafenibNexavarVEGFR, PDGFR, KIT, RAFHCCRCCSunitinibSutentVEGFR PDGFR KIT, Flt-3, RETGIST,RCC,PNETTemsirolimusToriselmTORRCCTrastuzumabHerceptinHER2Breast cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF V600E mutant)VorinostatZolinzaHistone deacetylasesCutaneous T-cell lymphomaCML = chronic myelogenous leukemia; EGFR = epidermal growth factor receptor; EPHA2 = ephrin A2; FDA = Food and Drug Administration; Flt-3 = fms-related tyrosine kinase 3; GIST = GI stromal tumor; HCC = hepatocellular cancer, HER2 = human epidermal growth factor receptor 2; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer, PDGF = platelet-derived growth factor; PDGFR = platelet-derived growth factor receptor; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma; RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC CONSIDERATIONSPART IGlucoseAminoAcidsIRS1PI3KPDK1PIP2PIP3ATPAMPKActivatorsMAP4K3AMPKRapalogsFKBP12AktTSC2TSC1PI3KInhibitorsAktInhibitorsPTENmTORC2ProctorRICTORmTORmLST8SIN1GSK3FOXOBADASK1GDPGTPRhebRhebmTORC1PRAS40mTORRAPTORmLST84EBP1S6KeIF4EPDCD4eEF3KS6eIF4BmTORKinase InhibitorsDual Pl3K/mTORKinase InhibitorsPPFigure 10-15. Targeting PI3K/Akt/mTOR signaling. This central pathway is altered in many tumor types and is being pursued as a therapeu-tic target through development of numerous pathway inhibitors targeting PI3K, Akt, mTOR, and dual inhibitors as well as several upstream and downstream regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast Cancer. 2010 Nov;10 Suppl 3:S59-S65.)Calmette-Guérin. This approach is thought to activate the effec-tors of antitumor response such as natural killer cells and macro-phages, as well as polyclonal lymphocytes.149 Another approach to nonspecific immunotherapy is systemic administration of cytokines such as interleukin-2, interferon-α, and interferon-γ. Interleukin-2 stimulates proliferation of cytotoxic T lympho-cytes and maturation of effectors such as natural killer cells into lymphokine-activated killer cells. Interferons, on the other hand, exert antitumor effects directly by inhibiting tumor cell prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression on tumor cells.149Antigen-specific immunotherapy can be active, as is achieved through antitumor vaccines, or passive. In pas-sive immunotherapy, antibodies to specific tumor-associated antigens can be produced by hybridoma technique and then administered to patients whose cancers express these antigens, inducing antibody-dependent cellular cytotoxicity.The early attempts at vaccination against cancers used allo-geneic cultured cancer cells, including irradiated cells, cell lysates, and shed antigens isolated from tissue culture supernatants. An alternate strategy is the use of autologous tumor vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for preparation, which restricts eligibility of patients for this modality. Strategies to enhance immunogenicity of tumor cells include the introduction of genes encoding cytokines or chemokines, and fusion of the tumor cells to allogeneic MHC class II-bearing cells.150 Alternatively, heat shock proteins derived from a patient’s tumor can be used because heat shock protein peptide complexes are readily taken up by dendritic cells for presentation to T cells.150Identification of tumor antigens has made it possible to perform antigen-specific vaccination. For example, in the case of melanoma, several antigens have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested usually are over-expressed or mutated in cancer cells. Tissue specificity and immunogenicity are important determinants in choosing an appropriate target. Vaccines directed at defined tumor antigens aim to combine selected tumor antigens and appropriate routes for delivering these antigens to the immune system to optimize antitumor immunity.152 Several different vaccination approaches have been studied, including tumor cell-based vaccines, pep-tide-based vaccines, recombinant virus-based vaccines, DNA-based vaccines, and dendritic cell vaccines.In adoptive transfer, antigen-specific effector cells (i.e., cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a patient. These effector cells can be obtained from the tumor (tumor-infiltrating lymphocytes) or the peripheral blood.Clinical experience in patients with metastatic disease has shown objective tumor responses to a variety of immunothera-peutic modalities. It is thought, however, that the immune sys-tem is overwhelmed with the tumor burden in this setting, and thus adjuvant therapy may be preferable, with immunotherapy reserved for decreasing tumor recurrences. Trials to date sug-gest that immunotherapy is a potentially useful approach in the adjuvant setting. How to best select patients for this approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor responses.153 Recently, several pathways that modulate tolerance and approaches to manipulat-ing these pathways have been identified: pathways that activate professional antigen-presenting cells such as Toll-like receptors, growth factors, and the CD40 pathway; cytokines to enhance immunoactivation; and pathways that inhibit T-cell inhibitory signals or block the activity of immune-suppressive regulatory T cells (Tregs).153A new and highly effective strategy to activate the T-cell arm of anticancer immunity is the use of monoclonal antibodies to block inhibitory signaling pathways employed by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing antibod-ies and result in an effective antigen-specific anti-tumor response.CTLA-4 is an inhibitory receptor expressed by activated T cells that belongs to the immunoglobulin superfamily. CTLA4 is related to the T-cell costimulatory receptor, CD28, and both are bound by CD80 and CD86 (also known as B7-1 and B7-2) which are expressed on antigen-presenting cells. CTLA-4 con-veys an inhibitory signal to the T cell, whereas engagement of CD28 with ligand sends a stimulatory signal. CTLA-4 is able to outcompete CD28 for CD80 and CD86 ligands and therefore is able to dominate immune signaling in the setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1 trans-membrane protein that is thought to play an important role in suppressing the immune system. PD-L1 binds to its receptor, PD-1, which is found on activated T cells. The PD1/PDL1 path-way is increasingly recognized as a key contributor to tumor-mediated immune suppression. The interaction between PD-1 leads to reduced proliferation, altered production of stimulatory cytokines, and reduced T-cell lytic activity. Thus, both anti-PD1 and anti-PD-L1 strategies are actively being pursued for cancer therapy.155The FDA-approved CTLA-4 blocking antibody ipi-limumab has shown efficacy in patients with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which checkpoint inhibitors have found utility include melanoma, renal cell car-cinoma, bladder carcinoma, squamous cell carcinoma of the head and neck, and carcinoma of the lung. These agents pro-duce durable shrinkage of advanced disease in 20% to 40% of patients, and combination strategies that employ checkpoint inhibitors with cytokines, vaccines, cellular therapies, and other targeted agents are under active investigation.GENE THERAPYGene therapy is being pursued as a possible approach to modify-ing the genetic program of cancer cells as well as treating meta-bolic diseases. The field of cancer gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models, approaches such as replacement of tumor-suppressor genes leads to growth arrest or apoptosis. However, the translation of these findings into clinically useful tools presents special challenges.One of the main difficulties in getting gene therapy tech-nology from the laboratory to the clinic is the lack of a perfect delivery system. An ideal vector would be administered through a noninvasive route and would transduce all of the cancer cells and none of the normal cells. Furthermore, the ideal vector would have a high degree of activity, that is, it would produce an adequate amount of the desired gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer requires either that the therapeutic gene be delivered to all of the cancer cells or that a therapeutic effect be achieved on nontransfected cells as well as transfected cells through a bystander effect. However, treatment of a meta-bolic disease requires prolonged gene expression, whereas tran-sient expression may be sufficient for cancer therapy.Several vector systems are under study for gene ther-apy; however, none is considered ideal. One of the promising approaches to increase the number of tumor cells transduced is the use of a replication-competent virus like a parvovirus, human reovirus, or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes exploits tumor-specific expression elements, such as the MUC-1, PSA, CEA, or VEGF promoters, that can be used to achieve tissue-specific or tumor-specific expression of the desired gene.Because the goal in cancer therapy is to eradicate systemic disease, optimization of delivery systems is the key to success for gene therapy strategies. Gene therapy is likely to be most successful when combined with standard therapies, but it will provide the advantage of customization of therapy based on the molecular status of an individual’s tumor.MECHANISMS OF INTRINSIC AND ACQUIRED DRUG RESISTANCESeveral tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell clones. This has been used as an argument for giv-ing chemotherapy as soon as possible in treatment to reduce the likelihood that resistant clones will emerge. Tumor size is another important variable. Larger tumors may have greater het-erogeneity, although heterogeneity may also differ based on bio-logic subtype. Tumor growth may be described by a Gompertz curve, named after Benjamin Gompertz, which has the form of a sigmoid function. Gompertzian models have thus been used to describe changes in tumor cell numbers over time where growth is slowest at the start and end of a time period, but are quite rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC CONSIDERATIONSPART Iphase), and then the growth slows down owing to hypoxia and decreased nutrient supply. Because of the larger proportion of cells dividing, smaller tumors may be more chemosensitive.Multiple mechanisms of systemic therapy resistance have been identified (Table 10-12).160 Cells may exhibit reduced sen-sitivity to drugs by virtue of their cell-cycle distribution. For example, cells in the G0 phase are resistant to drugs active in the S phase. This phenomenon of “kinetic resistance” usually is temporary, and if the drug level can be maintained, all cells will eventually pass through the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may occur when tumor cells are located in sites where effective drug concentrations are difficult to achieve (such as the central nervous system) or can be due to enhanced metabolism of the drug after its administration, decreased conversion of the drug to its active form, or decrease in the intracellular drug level caused by increased removal of the drug from the cell associated with enhanced expression of P-glycoprotein (Pgp). Pgp is the protein product of multidrug resis-tance gene 1 and extrudes cytotoxic drugs at the expense of ATP hydrolysis. Other mechanisms of resistance include decreased affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is inadequate dosing. Relative dose intensity (RDI) is defined as the actual amount of a particular chemotherapy given over a specific time in relation to what was ordered and is usually expressed as a percentage. An RDI below 80% is considered suboptimal and may impact survival in the adjuvant setting.145Cancer cells demonstrate adaptive responses to targeted therapy, like activating alternate pathways of survival; thus, these alterations may blunt therapeutic efficacy. Cancer cells also acquire resistance upon prolonged treatment with targeted therapy through a variety of mechanisms. One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients who were treated with neoadjuvant trastuzumab-based chemo-therapy.161 Post neoadjuvant treatment, a third of the samples from patients who did not have a complete pathologic response displayed loss of the HER2 amplification that had been pres-ent in their pretreatment-biopsy specimens.161 Another means by which cancers develop resistance is the acquisition of addi-tional genomic aberrations. In lung cancer, a second mutation in EGFR (T790M) and MET amplification have been described as two main mechanisms of drug resistance to EGFR inhibi-tors erlotinib and gefinitib.162-164 Other mechanisms like novel genetic changes, including HER2 and EGFR amplification, PIK3CA mutations, and markers of epithelial-to-mesenchymal transition have also been reported in EGFR inhibitor resistant lung.165,166 Analysis of metastases from patients with colorectal cancer who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% of the cases.167 These studies emphasize the utility of repeat tumor biopsy specimens at the time of relapse or progression to iden-tify mechanisms of resistance and best combinatorial therapies.RADIATION THERAPYPhysical Basis of Radiation TherapyIonizing radiation is energy strong enough to remove an orbital electron from an atom. This radiation can be electromagnetic, like a high-energy photon, or particulate, such as an electron, proton, neutron, or alpha particle. Radiation therapy is delivered primar-ily as high-energy photons (gamma rays and X-rays) and charged particles (electrons). Gamma rays are photons that are released from the nucleus of a radioactive atom. X-rays are photons that are created electronically, such as with a clinical linear accelerator. Currently, high-energy radiation is delivered to tumors primarily with linear accelerators. X-rays traverse the tissue, depositing the maximum dose beneath the surface, and thus spare the skin. Elec-trons are used to treat superficial skin lesions, superficial tumors, or surgical beds to a depth of 5 cm. Gamma rays typically are produced by radioactive sources used in brachytherapy.The dose of radiation absorbed correlates with the energy of the beam. The basic unit is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray (Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past.Biologic Basis of Radiation TherapyRadiation deposition results in DNA damage manifested by singleand double-strand breaks in the sugar phosphate back-bone of the DNA molecule.168 Cross-linking between the DNA strands and chromosomal proteins also occurs. The mecha-nism of DNA damage differs by the type of radiation deliv-ered. Electromagnetic radiation is indirectly ionizing through the actions of short-lived hydroxyl radicals, which are pro-duced primarily by the ionization of cellular hydrogen perox-ide (H2O2).168 Protons and other heavy particles are directly ionizing and directly damage DNA.Table 10-12General mechanisms of drug resistanceCellular and biochemical mechanisms Decreased drug accumulation  Decreased drug influx  Increased drug efflux  Altered intracellular trafficking of drug Decreased drug activation Increased inactivation of drug or toxic intermediate Increased repair of drug-induced damage to:  DNA  Protein  Membranes Alteration of drug targets (quantitatively or qualitatively) Alteration of cofactor or metabolite levels Alteration of gene expression  DNA mutation, amplification, or deletion  Altered transcription, posttranscription processing, or  translation  Altered stability of macromoleculesMechanisms relevant in vivo Pharmacologic and anatomic drug barriers  (tumor sanctuaries) Host-drug interactions  Increased drug inactivation by normal tissues  Decreased drug activation by normal tissues  Relative increase in normal tissue drug sensitivity  (toxicity)Host-tumor interactionsReproduced with permission from Bast R, Kufe D, Pollock R: Cancer Medicine. Hamilton: BC Decker, Inc; 2000.Brunicardi_Ch10_p0305-p0354.indd 34622/02/19 2:14 PM 347ONCOLOGYCHAPTER 10Radiation damage is manifested primarily by the loss of cellular reproductive integrity. Most cell types do not show signs of radiation damage until they attempt to divide, so slowly proliferating tumors may persist for months and appear viable. Some cell types, however, undergo apoptosis.The extent of DNA damage after radiation exposure is dependent on several factors. The most important of these is cellular oxygen. Hypoxic cells are significantly less radiosensi-tive than aerated cells. The presence of oxygen is thought to pro-long the half-life of free radicals produced by the interaction of X-rays and cellular H2O2, and thus indirectly ionizing radiation is less efficacious in tumors with areas of hypoxia.168 In contrast, radiation damage from directly ionizing radiation is independent of cellular oxygen levels.The extent of DNA damage from indirectly ionizing radiation is dependent on the phase of the cell cycle. The most radiation-sensitive phases are G2 and M, whereas G1 and late S phases are less sensitive. Thus, irradiation of a population of tumor cells results in killing of a greater proportion of cells in G2 and M phases. However, delivery of radiation in divided doses, a concept referred to as fractionation, allows the surviv-ing G1 and S phase cells to progress to more sensitive phases, a process referred to as reassortment. In contrast to DNA dam-age after indirectly ionizing radiation, that after exposure to directly ionizing radiation is less dependent on the cell-cycle phase.169Several chemicals can modify the effects of ionizing radia-tion. These include hypoxic cell sensitizers such as metronida-zole and misonidazole, which mimic oxygen and increase cell kill of hypoxic cells.168 A second category of radiation sensitiz-ers are the thymidine analogues iododeoxyuridine and bromo-deoxyuridine. These molecules are incorporated into the DNA in place of thymidine and render the cells more susceptible to radiation damage; however, they are associated with consid-erable acute toxicity. Several other chemotherapeutic agents sensitize cells to radiation through various mechanisms, includ-ing 5-fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan, doxorubicin, and vinorelbine.168 The development of novel radiosensitizers is an active area of research and mul-tiple small molecules as well as novel nanomaterials are under investigation.170Radiation Therapy PlanningRadiation therapy is delivered in a homogeneous dose to a well-defined region that includes tumor and/or surrounding tissue at risk for subclinical disease. The first step in planning is to define the target to be irradiated as well as the dose-limiting organs in the vicinity.171 Treatment planning includes evaluation of alter-native treatment techniques, which is done through a process referred to as simulation. Once the beam distribution that will best achieve homogeneous delivery to the target volume and minimize the dose to the normal tissue is determined, immo-bilization devices and markings or tattoos on the patient’s skin are used to ensure that each daily treatment is given in the same way. Conventional fractionation is 1.8 to 2 Gy/d, administered 5 days each week for 3 to 7 weeks.Radiation therapy may be used as the primary modality for palliation in certain patients with metastatic disease, pri-marily patients with bony metastases. In these cases, radiation is recommended for symptomatic metastases only. However, lytic metastases in weight-bearing bones such as the femur, tibia, or humerus also are considered for irradiation. Another circumstance in which radiation therapy might be appropriate is spinal cord compression due to metastases to the vertebral body that extend posteriorly to the spinal canal.The goal of adjuvant radiation therapy is to decrease local-regional recurrence rates. Adjuvant radiation therapy can be given before surgery, after surgery, or, in selected cases, during surgery. Preoperative radiation therapy has several advantages. It may minimize seeding of the tumor during surgery and it allows for smaller treatment fields because the operative bed has not been contaminated with tumor cells. Also, radiation therapy for inoperable tumors may achieve adequate reduction to make them operable. The disadvantages of preoperative therapy are an increased risk of postoperative wound healing problems and the difficulty in planning subsequent radiation therapy in patients who have positive surgical margins. If radiation therapy is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radia-tion therapy is that the surgical specimen can be evaluated histo-logically and radiation therapy can be reserved for patients who are most likely to benefit from it. Further, the radiation therapy can be modified on the basis of margin status. The disadvantages of postoperative radiation therapy are that the volume of nor-mal tissue requiring irradiation may be larger owing to surgical contamination of the tissue planes and that the tumor may be less sensitive to radiation owing to poor oxygenation. Postlapa-rotomy adhesions may decrease the mobility of the small bowel loops, increasing the risk for radiation injury in abdominal or pel-vic irradiation. Given the potential advantages and disadvantages of both approaches, the roles of preoperative and postoperative radiation therapy are being actively evaluated and compared for many cancer types.Another mode of postoperative radiation therapy is brachytherapy. In brachytherapy, unlike in external beam therapy, the radiation source is in contact with the tissue being irradiated. The radiation source may be cesium, gold, iridium, or radium. Brachytherapy is administered via temporary or per-manent delivery implants such as needles, seeds, or catheters. Temporary brachytherapy catheters are placed either during open surgery or percutaneously soon after surgery. The implants are loaded interstitially, and treatment usually is given postop-eratively for a short duration, such as 1 to 3 days. Although brachytherapy has the disadvantages of leaving scars at the cath-eter insertion site and requiring special facilities for inpatient brachytherapy, the advantage of patient convenience owing to the shorter treatment duration has made intracavitary treatment approaches popular for the treatment of breast cancer.Another short delivery approach is intraoperative radio-therapy (IORT), often used in combination with external beam therapy. The oncologic consequences of the limited treatment volume and duration associated with brachytherapy and IORT are not well understood. Accelerated partial breast irradiation with interstitial brachytherapy, intracavitary brachytherapy (MammoSite), IORT, and three-dimensional conformal external beam radiotherapy is being compared with whole breast irra-diation in an intergroup phase 3 trial (NSABP B-39/Radiation Therapy Oncology Group 0413). Several additional studies of adjuvant IORT also are ongoing internationally. There has also been increased interest in utilizing intensity-modulated radiation therapy (IMRT). IMRT is a complex technique for the delivery of radiation therapy preferentially to target structures while mini-mizing doses to adjacent normal critical structures.172 It is widely utilized for the treatment of a variety of tumor types, including Brunicardi_Ch10_p0305-p0354.indd 34722/02/19 2:14 PM 348BASIC CONSIDERATIONSPART Ithe central nervous system, head and neck, breast, prostate, gas-trointestinal tract, and gynecologic organs, as well as in patients where previous radiation therapy has been delivered. Stereotac-tic radiosurgery uses extremely accurate image-guidance and patient positioning to deliver a high dose of radiation to a small tumor with well-defined margins. In this manner, the dose of radiation being applied to normal tissues can be minimized. It is most commonly used for the treatment of brain and spinal tumors. Protons are a charged particle that can be also used in external beam radiation therapy. Proton therapy employs a beam of protons as a means of delivering radiation to a tumor. In con-trast to photons, which deposit energy continuously during their passage through tissue, protons deposit a large amount of their energy near the end of their path (known as the Bragg peak) and release less energy along the way. Thus, proton therapy could theoretically reduce the exposure of normal tissue to radiation, allowing the delivery of higher doses of radiation to a tumor. It is thought that chemotherapy given concurrently with radiation improves survival rates. Chemotherapy before radiation has the advantage of reducing the tumor burden, which facilitates radia-tion therapy. On the other hand, some chemotherapy regimens, when given concurrently with radiation, may sensitize the cells to radiation therapy. Chemoradiation is being investigated in many tumor types, including rectal cancer, pancreatic cancer, and esophageal cancer.173-175 In a Cochrane review of six ran-domized controlled trials, it was demonstrated that in patients with T3/4 rectal cancer, chemoradiation was associated with a significantly lower local recurrence rate compared with radiation therapy alone (OR 0.56, 95% CI 0.42–0.75, P <0.0001) but was not associated with improved survival.173Side EffectsBoth tumor and normal tissue have radiation dose-response rela-tionships that can be plotted as a sigmoidal curve (Fig. 10-16).171 A minimum dose of radiation must be given before any response is seen. The response to radiation then increases slowly with an increase in dose. At a certain dose level the curves become exponential, with increases in tumor response and normal tissue toxicity with each incremental dose increase. The side effects of radiation therapy can be acute, occurring during or 2 to 3 weeks after therapy, or chronic, occurring weeks to years after therapy. The side effects depend on the tissue included in the target volume. Some of the major acute and chronic sequelae of radiation are summarized in Table 10-13.171,176 In addition to these effects, a small increase in the risk for secondary malignancies is attribut-able to radiation therapy.CANCER PREVENTIONThe truth of the old axiom “An ounce of prevention is worth a pound of cure” is being increasingly recognized in oncology. Cancer prevention can be divided into three categories: (a) pri-mary prevention (i.e., prevention of initial cancers in healthy indi-viduals), (b) secondary prevention (i.e., prevention of cancer in individuals with premalignant conditions), and (c) tertiary pre-vention (i.e., prevention of second primary cancers in patients cured of their initial disease).The systemic or local administration of therapeutic agents to prevent the development of cancer, called chemoprevention, is being actively explored for several cancer types. In breast can-cer, the NSABP Breast Cancer Prevention Trial demonstrated that tamoxifen administration reduces the risk of breast cancer by one half and reduces the risk of estrogen receptor-positive tumors by 69% in high-risk patients.177 Therefore, tamoxifen has been approved by the FDA for breast cancer chemoprevention. The subsequent NSABP P-2 trial demonstrated that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and is associated with a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer; these findings led the FDA to approve raloxifene for prevention as well. Several other agents are also under investigation.178 Celecoxib (a cyclooxygenase 2 [COX-2] inhibitor) has been shown to reduce polyp number and polyp burden in patients with FAP, which led to its approval by the FDA for these patients. However, celecoxib is no longer widely used as a primary preventative treatment in this setting due to the association between COX-2 inhibitors and coronary artery disease. In head and neck cancer, 13-cis-retinoic acid has been shown both to reverse oral leukoplakia and to reduce sec-ond primary tumor development.179,180 However, a large phase 3 clinical trial that utilized low-dose 13-cis-retinoic acid in patients with early stage squamous cell carcinoma of the head and neck showed no significant difference in the incidence of tumor recurrence or the second primary tumors between the pla-cebo and chemoprevention arms.181 Thus, the chemoprevention trials completed so far have had mixed results. Much remains to be done over the next few years to improve outcomes and decrease therapy-related toxic effects. It is important for sur-geons to be aware of these preventive options because they are likely to be involved in the diagnosis of premalignant and malig-nant conditions and will be the ones to counsel patients about their chemopreventive options.In selected circumstances, the risk of cancer is high enough to justify surgical prevention. These high-risk settings include hereditary cancer syndromes such as hereditary breast-ovarian cancer syndrome, hereditary diffuse gastric cancer, multiple endocrine neoplasia type 2, FAP, and hereditary non-polyposis colorectal cancer, as well as some nonhereditary Tumor controlComplicationsABDosePercentFigure 10-16. The probability of tumor control and of complica-tions at different radiation doses. A. At lower doses, the probability of complications is low, with a moderate chance of tumor control. B. Increasing the dose may gain a higher chance of tumor control at the price of significantly higher complication risks. (Reproduced with permission from Eisbruch A, Lichter AS. What a surgeon needs to know about radiation, Ann Surg Oncol. 1997 Sep;4(6):516-522.)Brunicardi_Ch10_p0305-p0354.indd 34822/02/19 2:14 PM 349ONCOLOGYCHAPTER 10conditions such as chronic ulcerative colitis. Most prophy-lactic surgeries are large ablative surgeries (e.g., bilateral risk-reducing mastectomy or total proctocolectomy). There-fore, it is important that the patient be completely informed about potential surgical complications as well as long-term lifestyle consequences. Further, the conservative options of close surveillance and chemoprevention need to be discussed. The patient’s cancer risk needs to be assessed accurately and implications for survival discussed. Ultimately, the decision to proceed with surgical prevention should be individualized and made with caution.TRENDS IN ONCOLOGYCancer Screening and DiagnosisIt is clear that the practice of oncology will change dramati-cally over the next few decades because our understanding of the molecular basis of cancer and available technologies are evolving rapidly. One of the critical changes expected is earlier detection of cancers. With improvements in available imaging modalities and development of newer functional imaging tech-niques, it is likely that many tumors will be detected at earlier, more curable stages in the near future.Another area of rapid development is the identification of serum markers. High-throughput technologies such as matrix-assisted laser desorption ionization time-of-flight mass spec-troscopy and liquid chromatography ion-spray tandem mass spectroscopy have revolutionized the field of proteomics and are now being used to compare the serum protein profiles of patients with cancer with those of individuals without cancer. Identification of unique proteins as well as unique proteomic profiles for most cancer types is being pursued actively by many researchers and, if successful, could dramatically enhance our ability to detect cancers early.182DNA fragments that are derived from tumors and are circulating in the blood stream are referred to as circulating tumor DNA (ctDNA). Analysis of ctDNA can potentially pro-vide information on the entire tumor genome and has poten-tial clinical utility as a so-called “liquid biopsy” when blood samples are obtained during important junctures of a clinical scenario. ctDNA may originate directly from the tumor or from circulating tumor cells, which refers to intact tumor cells that are shed from primary tumors and enter the bloodstream. The precise mechanism of ctDNA release has not been determined; however, there is evidence to show that the length of the DNA fragments are similar to those seen during the process of apop-tosis. ctDNA can be reliably procured from peripheral blood and analyzed via a number of advanced techniques, including next generation sequencing. The main advantages of using ctDNA in genomic studies is the ability to obtain information on the entire tumor genome, thus avoiding the difficulties of tumor heteroge-neity that are encountered with needle biopsies, and the ability to obtain multiple samples with much less risk to the patient.181Surgical TherapyThe current trend in surgery is toward more conservative resec-tions. With earlier identification of tumors, more conservative operations may be possible. The goal, however, is always to remove the tumor en bloc with wide negative margins. Another interesting area being explored is the destruction of tumors by techniques such as radiofrequency ablation, cryoablation, and heat-producing technologies like lasers, microwaves, or focused ultrasound.The debate over how to manage the regional lymph node basins for certain cancer types continues. With an increasing understanding of the metastatic process, surgeons may be able to stratify patients on the basis of the likelihood that their disease will spread metastatically, based on the gene expression profile of their primary tumors, and offer regional therapy accordingly. There is also a growing interest in minimally invasive surgical treatments for a variety of cancer types.Systemic TherapyThe current trend in systemic therapy is toward individual-ized therapy. Therefore, the intent is to determine the under-lying biology of each tumor to tailor therapy accordingly. Genomic, transcriptional, and proteomic profiling approaches are being used to identify molecular signatures that correlate Table 10-13Local effects of radiationORGANACUTE CHANGESCHRONIC CHANGESSkinErythema, wet or dry desquamation, epilationTelangiectasia, subcutaneous fibrosis, ulcerationGI tractNausea, diarrhea, edema, ulceration, hepatitisStricture, ulceration, perforation, hematocheziaKidney—Nephropathy, renal insufficiencyBladderDysuriaHematuria, ulceration, perforationGonadsSterilityAtrophy, ovarian failureHematopoietic tissueLymphopenia, neutropenia, thrombocytopeniaPancytopeniaBoneEpiphyseal growth arrestNecrosisLungPneumonitisPulmonary fibrosisHeart—Pericarditis, vascular damageUpper aerodigestive tractMucositis, xerostomia, anosmiaXerostomia, dental cariesEyeConjunctivitisCataract, keratitis, optic nerve atrophyNervous systemCerebral edemaNecrosis, myelitisBrunicardi_Ch10_p0305-p0354.indd 34922/02/19 2:14 PM 350BASIC CONSIDERATIONSPART Iwith response to certain agents. It is likely that in the near future all tumors can be tested and treatments individualized. Patients who will respond to conventional therapies can be treated with these regimens, whereas patients who will not respond will not, which spares them the toxicity. Instead, the latter patients can be offered novel therapies. Furthermore, with the advent of effec-tive immune-based therapies, it is likely that patients may be given treatments that can specifically target the alterations driv-ing tumor growth in combination with drugs that can enhance the anticancer immune response. Patients can be genotyped for critical alleles that may affect drug metabolism and thus, may influence the efficacy as well as the side effects of the drugs given. 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In 2017 alone, according to the United Network for Organ Shar-ing (UNOS), about 115,000 patients in the United States were awaiting a transplant, yet the number of transplants performed approached only about 35,000 (Fig. 11-2).DEFINITIONSIn addition to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a surgical procedure in which a failing organ is replaced by a functioning one. The organ is transplanted either orthotopically (implanted in the same anatomic location in the recipient as it was in the donor) or heterotopically (implanted in TransplantationDavid L. Dunn, Angelika C. Gruessner, and Rainer W.G. Gruessner 11chapterBackground 355Definitions 355History 356Transplant Immunobiology 357Transplant Antigens 358Allorecognition and  Lymphocyte Activation 358Clinical Rejection 358Hyperacute / 358Acute / 358Chronic / 358Clinical Immunosuppression 358Induction 359Depleting Antibodies / 359Nondepleting Antibodies / 359Maintenance 359Corticosteroids / 359Azathioprine / 360Mycophenolate Mofetil / 361Sirolimus / 361Cyclosporine / 362Tacrolimus / 362Belatacept / 362Humoral Rejection 362Rituximab / 362Bortezomib / 363Eculizumab / 363Infections and Malignancies 363Infections / 363Malignancies / 364Organ Procurement  and Preservation 364Deceased Donors / 364Living Donors / 366Organ Preservation / 366Kidney Transplantation 368Introduction / 368Pretransplant Evaluation / 368Medical Evaluation / 369Surgical Evaluation / 370Recipient Operation / 370Grafts With Multiple Renal Arteries / 372En Bloc Grafts / 372Perioperative Care / 373Results / 373Pancreas Transplantation 374Donor Operation / 374Back Table Preparation of the Pancreas Graft / 375Recipient Operation / 375Complications / 377Living Donor Pancreas Transplants / 377Results / 378Islet versus Pancreas Transplants / 378Islet Transplantation 378Liver Transplantation 379History / 379Indications / 380Recipient Selection / 381Contraindications / 382Surgical Procedure / 382Pediatric Transplants / 383Deceased Donor Split-Liver Transplants / 383Living Donor Transplants / 383Postoperative Care / 383Evaluation of Graft Function / 384Complications / 385Intestine and Multivisceral  Transplantation 385Indications and Recipient Selection / 386Surgical Procedure / 386Postoperative Care / 388Heart and Lung  Transplantation 388History / 388Heart Transplants / 389Lung Transplants /390Heart-Lung Transplants / 391Xenotransplants 391BACKGROUNDOrgan transplantation is a relatively novel field of medicine that has made significant progress since the second half of the 20th century. Advances in surgical technique and a better under-standing of immunology are the two main reasons that transplants have evolved from experimental procedures, just several decades ago, to a widely accepted treatment today for patients with end-stage organ failure. Throughout the world, for a variety of indications, kidney, liver, pancreas, intestine, heart, and lung transplants are now the current standard of care.But the success of transplantation has created new chal-lenges. A better understanding of the pathophysiology of end-stage organ failure as well as advances in critical care medicine and in the treatment of various diseases led to expanding the cri-teria for, and decreasing the contraindications to, transplants. As a result, the discrepancy between the ever-growing number of 1Brunicardi_Ch11_p0355-p0396.indd 35501/03/19 6:53 PM 356Figure 11-1. Patients on the waiting list and the number of organ transplants performed, 2000 to 2009. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org)Key Points1 The field of transplantation has made tremendous advances in the last 50 years, mainly due to refinements in surgical technique and development of effective immunosuppressive medications.2 Although immunosuppressive medications are essential for transplantation, they are associated with significant shortand long-term morbidity.3 Opportunistic infections can be significantly lowered by the use of appropriate antimicrobial agents.4 Kidney transplantation represents the treatment of choice for almost all patients with end-stage renal disease. The gap between demand (patients on the waiting list) and supply (available kidneys) continues to widen.5 Pancreas transplantation represents the most reliable way to achieve euglycemia in patients with poorly controlled diabetes.6 The results of islet transplantation continue to improve but still trail those of pancreas transplantation.7 Liver transplantation has become the standard of care for many patients with end-stage liver failure and/or liver cancer.another anatomic location). Orthotopic transplants require the removal of the diseased organ (heart, lungs, liver, or intestine); in heterotopic transplants, the diseased organ is kept in place (kidney, pancreas).According to the degree of immunologic similarity between the donor and recipient, transplants are divided into three main categories: (a) an autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same person, so no immunosuppression is required; this type of transplant includes skin, artery or vein, bone, carti-lage, nerve, and islet cell transplants; (b) an allotransplant is the transfer of cells, tissue, or an organ from one person to another of the same species; with the exception of identical twins, the immune system of the recipient recognizes the donated organ as a foreign body, so immunosuppression is required in order to avoid rejection; and (c) a xenotransplant is the transfer of cells, tissue, or an organ from one organism to another of a different species. To date, animal-to-human transplants are still experi-mental procedures, given the very complex immunologic and infectious issues that have yet to be solved.HISTORYOver the centuries, many different references to transplantation can be found in the world’s literature, yet transplantation as a recognized scientific and medical field began to emerge only in 2000200120022003200420052006200720082009010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000110,000Number of patients# Waiting# Transplantedthe middle of the 20th century. Two major events led to the rise of transplantation.First, the surgical technique of the vascular anastomosis was developed by the French surgeon Alexis Carrel.1 This led to increased transplant activity, especially in animal models. Rus-sian surgeon Yu Yu Voronoy was the first to report a series of human-to-human kidney transplants in the 1940s.2 But the out-comes were dismal, mainly because of the lack of understanding of the underlying immunologic processes.Second, the findings of British scientist Sir Peter B. Medawar in the 1940s were also key.3 In his work with skin grafts in animal models and in human burn patients, he learned that the immune system plays a crucial role in the failure of skin grafts. His research led to a better understanding of the immune system and is considered to be the birth of transplant immunobiology.The first human transplant with long-term success was performed by Joseph Murray in Boston, Massachusetts, in 1954.4 Because it was a living related kidney transplant between identical twins, no immunosuppression was required; the recipi-ent lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar trans-plants and could reproduce similar good results.Ultimately, attempts were made to perform kidney trans-plants between nonidentical individuals. For immunosup-pression, total-body radiation and an anticancer agent called Brunicardi_Ch11_p0355-p0396.indd 35601/03/19 6:53 PM 357TRANSPLANTATIONCHAPTER 11Figure 11-2. Patients on the waiting list and the number of organ transplants performed, 2009. KP = kidney and pancreas. (U.S. data from the Scientific Registry of Transplant Recipients Annual Report, http://srtr.org)TotalKidneyPancreas and KPLiverIntestineHeartLungsHeart/Lung010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000110,000Number of patients# Waiting# Transplanted6-mercaptopurine were used, but given the profound toxicity of both those methods of immunosuppression, results were dis-couraging. A breakthrough was achieved in the early 1960s with the introduction of maintenance immunosuppression through a combination of corticosteroids and a less toxic derivative of 6-mercaptopurine, azathioprine.5,6Increasing experience with kidney transplants and the better results achieved with maintenance immunosuppression paved the way for the era of nonrenal transplants (Table 11-1). In 1963, the first liver transplant was performed by Thomas Starzl in Denver, Colorado, and the first lung transplant was performed by James Hardy in Jackson, Mississippi. In 1966, the first pancreas transplant was performed by William Kelly and Richard Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of trans-plantation were marked by high mortality, mainly because of irreversible rejection. However, dramatic advances occurred with the further development of new forms of immunosup-pression. The groundbreaking event was the introduction of the first anti-T lymphocyte (T cell) drug, cyclosporine, in the early 1980s.7 Since then, with an even better understanding of immunologic processes, many other drugs have been introduced that target specific pathways that lead to rejection. As a result, rejection rates have decreased substantially, allowing a 1-year graft survival rate in excess of 80% in all types of transplants.Table 11-1Transplant historyORGANYEARSURGEONLOCATIONKidney1954Joseph E. MurrayBoston, MALiver1963Thomas E. StarzlDenver, COLung1963James D. HardyJackson, MSPancreas1966Richard C. LilleheiMinneapolis, MNHeart1967Christiaan N. BarnardCape Town, South AfricaSmall intestine1967Richard C. LilleheiMinneapolis, MNHeart/lung1981Bruce ReitzStanford, CAMultivisceral1989Thomas E. StarzlPittsburgh, PAThe gradual increase in the organ shortage led to inno-vative surgical techniques. For example, deceased donor split-liver transplants and living donor liver transplants have helped expand the liver donor pool. Similarly, living donor intestine and pancreas techniques have been developed. The evolution of donor nephrectomy from an open to a minimally invasive procedure (laparoscopic or robotic) has helped increase the pool of living kidney donors.TRANSPLANT IMMUNOBIOLOGYThe outcomes of early transplants were less than satisfactory. The limiting factor was the lack of understanding of immuno-logic processes, and irreversible rejection was the reason for graft loss in the vast majority of recipients. A better understand-ing of transplant immunobiology led to significant improve-ments in patient and graft survival rates.8,9 The immune system is designed as a defense system to protect the body from foreign pathogens, such as viruses, bacteria, and fungi, but it also acts to reject transplanted cells, tissues, and organs, recognizing them as foreign. It mediates other complex processes as well, such as the body’s response to trauma or to tumor growth. No matter what type of agent, the immune system recognizes it as foreign and triggers a strong response that is designed to either to eradi-cate pathogenic organisms or reject foreign cells or tissue.Brunicardi_Ch11_p0355-p0396.indd 35701/03/19 6:53 PM 358BASIC CONSIDERATIONSPART ITRANSPLANT ANTIGENSTransplants between genetically nonidentical persons lead to recognition and rejection of the organ by the recipient’s immune system, if no intervention is undertaken. The main antigens responsible for this process are part of the major histocompat-ibility complex (MHC). In humans, these antigens make up the human leukocyte antigen (HLA) system. The antigen-encoding genes are located on chromosome 6. Two major classes of HLA antigens are recognized. They differ in their structure, function, and tissue distribution. Class I antigens (HLA-A, HLA-B, and HLA-C) are expressed by all nucleated cells. Class II antigens (HLA-DR, HLA-DP, and HLA-DQ) are expressed by antigen-presenting cells (APCs) such as B lymphocytes, dendritic cells, macrophages, and other phagocytic cells.The principal function of HLA antigens is to present the fragments of foreign proteins to T lymphocytes. This leads to recognition and elimination of the foreign antigen with great specificity. HLA molecules play a crucial role in transplant recipients as well. They can trigger rejection of a graft via two different mechanisms. The most common mechanism is cellular rejection, in which the damage is caused by acti-vated T lymphocytes. The process of activation and prolifera-tion is triggered by exposure of T lymphocytes to the donor’s HLA molecules. The other mechanism is humoral rejection, in which the damage is mediated by circulating antibodies against the donor’s HLA molecules. The donor-specific anti-bodies can be present either pretransplant, due to previous exposure (because of a previous transplant, pregnancy, blood transfusion, or immunization), or posttransplant. After anti-body binding to the donor’s HLA molecules, the complement cascade is activated, leading to cellular lysis.ALLORECOGNITION AND LYMPHOCYTE ACTIVATIONThe immune system of each person is designed to discriminate between self and nonself cells and tissues. This process is called allorecognition, with T cells playing the crucial role. The recog-nition of foreign HLA antigens by the recipient’s T cells may occur by either a direct or an indirect pathway. Direct recogni-tion occurs when the recipient’s T cells are activated by direct interaction with the donor’s HLA molecules. Indirect recogni-tion occurs when the recipient’s T cells are activated by interac-tion with APCs that have processed and presented the foreign antigen. The foreign antigen can be shed from the graft into the circulation, or it can be identified by the APCs within the graft itself.Independent of the pathway of foreign HLA antigen presentation, the ensuing activation of T cells is similar and involves complex cell surface receptors and markers, i.e., the T-cell receptor (TCR) and an array of cluster differentiation markers (CDs). A two-signal model, T-cell activation begins with the engagement of the TCR/CD3 complex with the foreign molecule. This interaction causes transmission of the signal into the cell, namely signal 1. However, this signal alone is not suf-ficient to activate the T cell. An additional costimulatory signal is required, i.e., signal 2. Two well-characterized costimula-tory interactions are the CD40/CD154 and B7/CD28 pathways. The “master switch” is turned on by the interaction of CD40 protein with APCs, along with the interaction of CD154 pro-tein with T cells; this ligation induces the upregulation of other costimulatory molecules. Transmission of signal 1 and signal 2 into the cell nucleus leads to upregulation of the transcrip-tion of genes for several cytokines, including the T-cell growth factor interleukin-2 (IL-2). In turn, IL-2 activates a number of pathways, leading to proliferation and differentiation of T cells. Rejection is the result of an attack of activated T cells on the transplanted organ.Although T-cell activation is the main culprit in rejection, B-cell activation and subsequent antibody production also play a role. After the foreign HLA antigen is processed by B cells, it interacts with activated helper T cells, leading to differentiation of B cells into plasma cells and subsequently to their prolifera-tion and antibody production.CLINICAL REJECTIONGraft rejection is due to a complex interaction of different com-ponents of the immune system, including B and T lymphocytes, APCs, and cytokines. The end result is graft damage caused by inflammatory injury. According to its onset and pathogenesis, rejection is divided into three main types: hyperacute, acute, and chronic, and each is described in the following sections.HyperacuteHyperacute rejection, a very rapid type of rejection, results in irreversible damage and graft loss within minutes to hours after organ reperfusion. It is triggered by preformed antibodies against the donor’s HLA or ABO blood group antigens. These antibodies activate a series of events that result in diffuse intra-vascular coagulation, causing ischemic necrosis of the graft. Fortunately, pretransplant blood group typing and cross-matching (in which the donor’s cells are mixed with the recipient’s serum, and then the cells are observed for any destruction) have virtu-ally eliminated the incidence of hyperacute rejection.AcuteAcute rejection, the most common type of rejection, usually occurs within a few days or weeks posttransplant. According to the mechanism involved, it is further divided into cellular (T-cell–mediated) rejection, humoral (antibody-mediated) rejection, or a combination of both. The diagnosis is based on the results of biopsies of the transplanted organ, special immu-nologic stains, and laboratory tests (such as elevated creatinine levels in kidney transplant recipients, elevated liver test values in liver transplant recipients, and elevated levels of glucose, amylase, and lipase in pancreas transplant recipients).ChronicChronic rejection occurs slowly and usually is progressive. It can manifest within the first year posttransplant but most often takes place gradually over several years. The mechanisms are not well understood, but the pathologic changes eventually lead to tissue fibrosis and loss of graft function. As advances in immunosuppression have diminished the incidence of acute rejection, this form of rejection is becoming more common.CLINICAL IMMUNOSUPPRESSIONA successful transplant hinges upon a balance between the extent of the recipient’s immune response, the health and viabil-ity of the donor allograft, and pharmacologic immunosuppres-sion. Immunosuppressive regimens are critical to graft and Brunicardi_Ch11_p0355-p0396.indd 35801/03/19 6:53 PM 359TRANSPLANTATIONCHAPTER 11patient survival posttransplant. Immunosuppression has evolved from the use of azathioprine and steroids in the 1960s and 1970s to the development in the 1980s of cyclosporine, the latter which markedly increased allograft survival.10,11 The intro-duction of tacrolimus and mycophenolate mofetil (MMF) in the 1990s further advanced the field of transplantation, enabling a variety of combinations to be used for immunosuppression often “tailored” for each recipient (Table 11-2).Presently, immunosuppressants are used in multidrug regimens aimed at increasing efficacy by targeting multiple pathways to lower the immune response and to decrease the toxicity of individual agents. Certain regimens may involve withdrawal, avoidance, or minimization of certain classes of drugs. Transplant centers generally institute their immunosup-pressive protocols based on experience, risk profiles, cost con-siderations, and outcomes. Immunosuppression is delivered in two phases: induction (starting immediately posttransplant, when the risk of rejection is highest) and maintenance (usu-ally starting within days posttransplant and usually continuing for the life of the graft and the recipient). Thus, the degree of immunosuppression is highest in the first 3 to 6 months posttransplant; during this time, prophylaxis against a number of different bacterial, viral, or even antifungal opportunistic pathogens is administered.12,13A conventional immunosuppressive protocol might include (a) induction with anti-T-lymphocyte–depleting or nondepleting antibodies and (b) maintenance with calcineurin inhibitors, antiproliferative agents, and corticosteroids. Char-acteristics of the most common immunosuppressive agents are listed in Table 11-3.2Table 11-2Immunosuppressive drugs by groupingImmunophilin binders Calcineurin inhibitors  Cyclosporine  Tacrolimus Noninhibitors of calcineurin  SirolimusAntimetabolites Inhibitors of de novo purine synthesis  Azathioprine  Mycophenolate mofetilBiologic immunosuppression Polyclonal antibodies  Atgam  Antithymocyte immunoglobulin Monoclonal antibodies  Muromonab-CD3  Basiliximab  Belatacept  Alemtuzumab  Rituximab  Bortezomib  EculizumabOther CorticosteroidsINDUCTIONInduction includes the use of depleting (polyclonal) antibodies or nondepleting antibodies within the first month posttransplant. Studies have shown that induction with antibody regimens may prevent acute rejection, potentially leading to improved graft survival and the use of less maintenance immunosuppression.Depleting AntibodiesRabbit antithymocyte globulin (Thymoglobulin) is a purified gamma globulin obtained by immunizing rabbits with human thymocytes. Atgam, which has largely been replaced by Thy-moglobulin, is a purified gamma globulin obtained by immu-nizing horses with human thymocytes. These agents contain antibodies to T cells and B lymphocytes (B cells), integrins, and other adhesion molecules, thereby resulting in rapid depletion of peripheral lymphocytes. Typically, the total dose of Thymo-globulin is roughly 6 mg/kg, a dose that has been shown to con-fer adequate lymphocyte depletion and better allograft survival. Doses of 3 mg/kg may not effectively prevent acute rejection, but more doses and prolonged administration increase the risk of infection and the potential occurrence of lymphoma. Thymo-globulin administration causes a cytokine release syndrome, so premedications (acetaminophen and diphenhydramine) are usu-ally given. The principal side effects of Thymoglobulin include fever, chills, arthralgias, thrombocytopenia, leukopenia, and an increased incidence of a variety of infections.14,15Nondepleting AntibodiesBasiliximab (Simulect) is an anti-CD25 monoclonal antibody. The alpha subunit of the IL-2 receptor, also known as Tac or CD25, is found exclusively on activated T cells. Blockade of this component by this monoclonal antibody selectively pre-vents IL-2–induced T-cell activation. No lymphocyte depletion occurs with basiliximab; thus, it is not designed to be used to treat acute rejection. Its selectivity in blocking IL-2–mediated responses makes it a powerful induction agent without the added risks of infections, malignancies, or other major side effects. Currently, basiliximab is the only available anti-CD25 mono-clonal antibody approved for clinical use. Usually, it is followed by the use of calcineurin inhibitors, corticosteroids, and MMF as maintenance immunosuppression.16Alemtuzumab (Campath, Lemtrada), another anti-CD52 monoclonal antibody, was initially used to treat chronic lym-phocytic leukemia. The use of alemtuzumab has grown in the field of transplantation, given its profound lymphocyte-depleting effects. It causes cell death by complement-mediated cytoly-sis, antibody-mediated cytotoxicity, and apoptosis. One dose alone (30 mg) depletes 99% of lymphocytes. Monocyte recov-ery can be seen at 3 months posttransplant; B-cell recovery at 12 months; and T-cell recovery, albeit only to 50% of base-line, at 36 months. Alemtuzumab causes a significant cytokine release reaction and often requires premedications (steroids and antihistamines). Because of the long-lasting T-cell depletion, the risks of infection and posttransplant lymphoproliferative dis-order remain. Initially, alemtuzumab was available only through a limited distribution program, but more recently has been stud-ied in a number of clinical trials.17,18MAINTENANCECorticosteroidsCorticosteroids have had a role in immunosuppression since the beginning of the field of transplantation. Despite numerous Brunicardi_Ch11_p0355-p0396.indd 35901/03/19 6:53 PM 360BASIC CONSIDERATIONSPART ITable 11-3Summary of the main immunosuppressive drugsDRUGMECHANISM OF ACTIONADVERSE EFFECTSCLINICAL USESDOSAGECyclosporine (CSA)Binds to cyclophilinInhibits calcineurin and IL-2 synthesisNephrotoxicityTremorHypertensionHirsutismImproved bioavailability of microemulsion formOral dose 5 mg/kg per day (given in two divided doses)Tacrolimus (FK506)Binds to FKBPInhibits calcineurin and IL-2 synthesisNephrotoxicityHypertensionNeurotoxicityGI toxicity (nausea, diarrhea)Improved patient and graft survival in (liver) primary immunosuppression and rescue therapyUsed as mainstay of maintenance protocolsIV 0.015 mg/kg per day as continuous infusionPO 0.05 mg/kg per day (given every 12 h)Mycophenolate mofetilAntimetaboliteInhibits enzyme necessary for de novo purine synthesisLeukopeniaGI toxicityEffective for primary immunosuppression in combination with tacrolimus1 g bid POSirolimusInhibits lymphocyte effects driven by IL-2 receptorThrombocytopeniaIncreased serum cholesterol/LDLPoor wound healingMay allow early withdrawal of steroids and decreased calcineurin doses2–4 mg/d, adjusted to trough drug levelsCorticosteroidsMultiple actionsAnti-inflammatoryInhibits lymphokine productionCushingoid stateGlucose intoleranceOsteoporosisUsed in induction, maintenance, and treatment of acute rejectionVaries from milligrams to several grams per dayMaintenance doses, 5–10 mg/dAzathioprineAntimetaboliteInterferes with DNA and RNA synthesisThrombocytopeniaNeutropeniaLiver dysfunctionUsed in maintenance protocols or if intolerance to mycophenolate mofetil1–3 mg/kg per day for maintenanceBelataceptT-cell blockerIncreased risk of bacterial infectionsNew drug for maintenance immunosuppression in renal transplants only5–10 mg/kg per day infusionFKBP = FK506-binding protein; GI = gastrointestinal; IL = interleukin; IV = intravenous; LDL = low-density lipoprotein; PO = oralattempts to limit or discontinue their use, they remain an inte-gral component of most immunosuppressive protocols, for both induction and maintenance. Moreover, they are often the first-line agents in the treatment of acute rejection. Steroids bind to glucocorticoid-responsive elements in DNA that prevent the transcription of cytokine genes and cytokine receptors. In addition, steroids have an impact on lymphocyte depletion, on decreases in cell-mediated immunity, and on T-cell activation of many phases of rejection.Nonetheless, the numerous adverse effects of steroid therapy contribute significantly to morbidity in transplant recipients.19 Common side effects include acne, increased appetite and asso-ciated weight gain, mood changes, diabetes, hypertension, and impaired wound healing.One of the most common maintenance immunosuppres-sive regimens consists of triple-drug therapy: prednisone, a cal-cineurin inhibitor, and an antimetabolite. Large doses of steroids are usually given perioperatively and in the immediate postop-erative period. Protocols vary by center, but the steroid dose is usually tapered to an adult dose of roughly 5 to 15 mg daily, or completely stopped at some point. Steroids are substrates for CYP3A4, CYP3A5, and P-glycoprotein pathways where drug interactions might need to be monitored.20,21AzathioprineAn antimetabolite, azathioprine (AZA) is converted to 6-mercaptopurine and inhibits both the de novo purine synthe-sis and salvage purine synthesis. AZA decreases T-lymphocyte activity and decreases antibody production. It has been used as a first-line agent in transplant recipients for more than 40 years, but it became an adjunctive agent after the introduction of cyclospo-rine. With the development of newer agents such as MMF, the use of AZA has decreased significantly. However, it is preferred in recipients who are considering conceiving a child because MMF is teratogenic and can cause birth defects. Use of AZA remains an option for recipients who cannot tolerate the gastro-intestinal (GI) side effects of MMF.The most significant side effect of AZA, often dose-related, is bone marrow suppression. Leukopenia is often reversible with dose reduction or temporary cessation of the drug. Other significant side effects include hepatotoxicity, pancreatitis, neoplasia, anemia, and pulmonary fibrosis. Its most significant drug interaction is with allopurinol, which blocks AZA metabolism, increasing the risk of pancytope-nia. Recommendations are to not use AZA and allopurinol together, or if doing so is unavoidable, to decrease the dose of AZA by 75%.22Brunicardi_Ch11_p0355-p0396.indd 36001/03/19 6:53 PM 361TRANSPLANTATIONCHAPTER 11Mycophenolate MofetilApproved in May 1995 by the U.S. Food and Drug Admin-istration (FDA) for preventing acute rejection after kidney transplants, MMF has now been incorporated into routine maintenance regimens after many solid organ transplants. Mycophenolate is the prodrug of mycophenolate acid, derived from Penicillium fungi. Mycophenolate acid is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) involved in the de novo pathway of purine synthesis.23 MMF is available in capsules (250 and 500 mg); the starting dose is 1 g twice daily. In hopes of decreasing the GI side effects, an enteric-coated formulation called Myfortic was developed; its benefits have not been clearly demonstrated in studies, but in some conversion studies patients did report less GI intolerance. The pharmacoki-netics of MMF are complex; mycophenolic acid (MPA) levels are not routinely performed at most transplant centers. Studies have shown that MPA levels and the incidence of rejection are not significantly correlated.24 The most common side effects of MMF are GI in nature, most commonly diarrhea, nausea, dys-pepsia, and bloating. Esophagitis and gastritis occur in roughly 5% of recipients and may represent a cytomegalovirus (CMV) Table 11-4Side effects and drug interactions of the main immunosuppressive drugs COMMON SIDE EFFECTSOTHER MEDICATIONS THAT INCREASE BLOOD LEVELSOTHER MEDICATIONS THAT DECREASE BLOOD LEVELSOTHER MEDICATIONS THAT POTENTIATE TOXICITYCyclosporine (CSA)Hypertension, nephrotoxicity, hirsutism, neurotoxicity, gingival hyperplasia, hypomagnesemia, hyperkalemiaVerapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juiceIsoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wortNephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBsTacrolimus (FK506)Hypertension, nephrotoxicity, alopecia, hyperglycemia, neurotoxicity, hypomagnesemia, hyperkalemiaVerapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juiceIsoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wortNephrotoxicity: ganciclovir, aminoglycosides, NSAIDs, ACE-Is, and ARBsSirolimusThrombocytopenia and neutropenia, elevated cholesterol, extremity edema, impaired wound healingVerapamil, diltiazem, clarithromycin, azithromycin, erythromycin, azole antifungals, protease inhibitors, grapefruit juiceIsoniazid, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort—Mycophenolate mofetilLeukopenia, thrombocytopenia, GI upset—Cholestyramine, antacidsBone marrow suppression: valganciclovir, ganciclovir, TMP-SMXCorticosteroidsHyperglycemia, osteoporosis, cataracts, myopathy, weight gain———AzathioprineLeukopenia, anemia, thrombocytopenia, neoplasia, hepatitis, cholestasis——Bone marrow suppression: allopurinol, sulfonamidesACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; NSAID = nonsteroidal anti-inflammatory drug; TMP-SMX = trimethoprim-sulfamethoxazoleor herpesvirus family infection. The other important side effects are leukopenia, anemia, and thrombocytopenia (Table 11-4). Leukopenia can sometimes be reversed by lowering the MMF dose and discontinuing other agents like valganciclovir. MMF does not have any significant drug interactions, but clinicians should be careful to avoid additive toxicities with other medica-tions that might lead to leukopenia and thrombocytopenia.SirolimusThe first mammalian target of rapamycin (mTOR) inhibitors to enter clinical use was sirolimus (Rapamune). A key regulatory kinase, mTOR changes cells from the G1 to S phase in the cell cycle, in response to proliferation signals provided by cytokines like IL-2. The mTOR inhibitors bind to FK506-binding pro-tein (FKBP), and the sirolimus-FKBP complex binds to mTOR. Sirolimus also inhibits proliferation of vascular smooth muscle cells, possibly easing the vasculopathy and progressive fibrosis that can affect allografts. Sirolimus is a substrate for CYP3A4/4 and has many significant drug interactions (see Table 11-4).To date, sirolimus has been used in a variety of com-binations for maintenance immunosuppression, alone or in Brunicardi_Ch11_p0355-p0396.indd 36101/03/19 6:53 PM 362BASIC CONSIDERATIONSPART ITable 11-5Drug interactions and side effects associated with calcineurin inhibitorsINTERACTIONSMEDICATIONSInhibition of metabolismClarithromycin, erythromycin, azole antifungals, diltiazem, verapamil, nicardipine, amiodarone, grapefruit juice, ritonavir, azithromycinInduction of metabolismNevirapine, rifampin, St. John’s wort, carbamazepine, phenobarbital, phenytoin, caspofunginHyperkalemiaPotassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), β-blockers, trimethoprim-sulfamethoxazoleNephrotoxicityNonsteroidal anti-inflammatory drugs, aminoglycosides, amphotericin, ACE-Is, ARBsconjunction with one of the calcineurin inhibitors. In such com-binations, sirolimus usually is used to help withdraw from, or completely avoid, the use of steroids. It also has been used as an alternative to tacrolimus or cyclosporine, in a calcineurin-sparing protocol. One of the most significant side effects of siro-limus is hypertriglyceridemia, a condition that may be resistant to statins and fibrates. Impaired wound healing (immediately posttransplant in particular), thrombocytopenia, leukopenia, and anemia also are associated with sirolimus, and these problems are exacerbated when it is used in combination with MMF.25,26CyclosporineThe introduction of cyclosporine in the early 1980s dramati-cally altered the field of transplantation by significantly improv-ing outcomes after kidney transplantation. Cyclosporine binds with its cytoplasmic receptor protein, cyclophilin, which sub-sequently inhibits the activity of calcineurin, thereby decreas-ing the expression of several critical T-cell activation genes, the most important being for IL-2. As a result, T-cell activation is suppressed.27Many formulations of cyclosporine exist, so it is important to know which one the transplant recipient is taking. Sandim-mune, an older, oil-based formulation, has poor bioavailabil-ity and variable absorption. The newer formulations, Gengraf and Neoral, are microemulsified with improved bioavailability. Cyclosporine can be given intravenously or orally to maintain trough levels of 250 to 350 ng/mL for the first 3 months post-transplant; then it can be tapered to 150 to 250 ng/mL.28The metabolism of cyclosporine is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4). Calcineurin inhibitors are nephrotoxic and constrict the afferent arteriole in a dose-dependent, reversible manner (Table 11-5). They also can cause hyperkalemia and hypomagnesemia. Several neurologic complications, including headaches, tremor, and seizures, also have been reported.29Cyclosporine has several undesirable cosmetic effects, including hirsutism and gingival hyperplasia. It is associated with a higher incidence of hypertension and hyperlipidemia than is tacrolimus.TacrolimusThe calcineurin inhibitor tacrolimus (Prograf) is now the back-bone of most immunosuppressive regimens. Tacrolimus acts by binding FKBPs, causing roughly 10 to 100 times more potent inhibition of IL-2 production than cyclosporine (which acts by binding cyclophilins). It can be given intravenously, orally, or sublingually to maintain trough levels of 8 to 12 ng/mL for the first 3 months posttransplant; then it can be tapered to 6 to 10 ng/mL. The metabolism of tacrolimus is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4).Tacrolimus causes a higher incidence of new-onset dia-betes posttransplant than does cyclosporine. Other side effects include alopecia, nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and an increased incidence of certain types of infection.30BelataceptThe best-characterized pathway of T-cell costimulation includes CD28; its homologue, the cytotoxic T-lymphocyte–associated protein 4 (CTLA4); and their ligands, CD80 and CD86. Belatacept (also known as LEA29Y) was developed through two amino acid substitutions to abatacept (also known as CTLA4-Ig), a fusion protein consisting of the extracellular domain of CTLA4 and the Fc domain of immunoglobulin G (IgG). It is a high-avidity molecule with slower dissociation rates.Clinical trials have compared the use of belatacept vs. a standard cyclosporine protocol in recipients of living donor, deceased donor, and extended-criteria donor kidneys. Belata-cept was not inferior to cyclosporine in both patient and allograft survival rates, but was associated with a higher rate of biopsy-proven acute cellular rejection.In terms of adverse effects, belatacept differs from stan-dard calcineurin-based regimens because of an increased risk of posttransplant lymphoproliferative disorder (PTLD); the greatest risk is in recipients who are Epstein-Barr virus (EBV)-seronegative pretransplant. The FDA recommends the use of belatacept only in seropositive recipients. Studies in liver trans-plant recipients were halted early because of increased mortality rates.However, belatacept does have a lower incidence of car-diovascular risk factors including metabolic lipid disorders, hypertension, neurotoxicity, glucose abnormalities, and adverse cosmetic effects. Except for the increased risk of malignancy, the more favorable adverse effect profile of belatacept and its convenient monthly dosing schedule may make it an attrac-tive option for maintenance of immunosuppression, possibly improving compliance.31,32HUMORAL REJECTIONRituximabA chimeric anti-CD20 (anti-B cell) monoclonal antibody, ritux-imab is currently FDA approved for treating several types of lymphoma. The CD20 antigen is expressed early in the B-cell cycle but is absent on mature plasma cells. The variable region binds to CD20 through three different mechanisms: (a) antibody-dependent cell cytotoxicity, (b) complement-dependent cell killing, and (c) induction of apoptotic cell death. The use of Brunicardi_Ch11_p0355-p0396.indd 36201/03/19 6:53 PM 363TRANSPLANTATIONCHAPTER 11rituximab has grown to include the treatment of antibody-mediated rejection and use in desensitization protocols. Studies so far have been small, with rituximab usually used in conjunc-tion with plasmapheresis, steroids, and intravenous immuno-globulin (IVIG).33-35BortezomibA proteasome inhibitor, bortezomib is FDA approved for treat-ing multiple myeloma. It can directly target plasma cells. Tradi-tional treatments have been successful in removing antibodies, inhibiting antibody activity, or lowering antibody production; however, targeting mature antibody production in plasma cells has not met with success. Bortezomib has been shown to cause apoptosis of normal plasma cells, thereby decreasing alloan-tibody production in sensitized patients. Several case reports and series have described the use of bortezomib for the treat-ment of antibody-mediated rejection and in desensitization protocols.34,36,37EculizumabA humanized monoclonal antibody with high affinity for C5, eculizumab is a first-in-class, FDA-approved agent for treat-ing paroxysmal nocturnal hemoglobinuria, hemolytic uremic syndrome, and generalized myasthenia gravis. It blocks the activation of the terminal complement cascade. Most antibody-mediated rejection episodes are associated with early comple-ment activation as evidenced on renal transplant biopsies by the presence of C4d+ staining of the peritubular capillaries. Given its highly selective mechanism of action, this agent is predicted to be useful to treat antibody-mediated rejection and to desensi-tize patients pretransplant. However, its serious adverse effects include an increased risk of infections, especially due to encap-sulated bacteria such as Neisseria meningitidis. Patients should be immunized with meningococcal vaccine at least 2 weeks before the administration of eculizumab.34,38,39INFECTIONS AND MALIGNANCIESAdvances in immunosuppression have led to improved graft survival rates. However, the growing population of immuno-suppressed patients, in turn, has led to an increased incidence of opportunistic infections and malignancies. Such posttransplant complications have become important barriers to long-term disease-free survival.InfectionsTransplant recipients are predisposed to a variety of infections. Immunosuppression is the obvious reason. Moreover, such patients have already endured end-stage organ disease pre-transplant and then the stress of an invasive transplant opera-tion. Posttransplant, they continue to have significant comorbid conditions.Early. Early infections (i.e., infections occurring within 1 month posttransplant) can be due to a wide spectrum of pathogens (bacterial, viral, and fungal). In the immediate postoperative period, recipients are significantly compromised from the stress of the operation, from induction immunosuppression, and often from initially impaired graft function. Infections during this period can be devastating.It is imperative to differentiate between medical and surgical infections. Surgical infections are the most common and require expedient surgical intervention. Typical examples include generalized peritonitis, intra-abdominal abscesses, and wound infections.In liver and pancreas recipients, surgical infections are most severe. The incidence of intra-abdominal infections is decreasing, but they remain a significant problem: they are the second most common reason (after vascular thrombosis) for graft loss in pancreas recipients.Lengthy operations with significant blood loss, prolonged warm and cold ischemic times, and spillage of contaminated fluid (bile, urine, or bowel contents) predispose patients to intra-abdominal infections. Other prominent risk factors are the high level of induction immunosuppression immediately post-transplant and anastomotic leaks. Furthermore, pretrans-plant infections can reemerge or worsen.The signs and symptoms of intra-abdominal infections are those of peritonitis: fever, hypotension, ileus, and abdominal pain, although the latter can be masked by immunosuppres-sion. Treatment entails a prompt return to the operating room. Intra-abdominal infections are usually polymicrobial, involving several bacterial and fungal species. Common bacterial isolates include Escherichia coli, as well as Enterococcus, Klebsiella, and Pseudomonas species. Common fungal isolates are Candida albicans, Candida krusei, and Candida glabrata. Localized infections or abscesses can be treated with percutaneous drain-age and antibiotics.Medical infections include respiratory, urinary tract, and bloodstream infections. Medical treatment should also be aggressive, often including empiric antibiotics and antifungal medications even before culture results are available. Recipients of organs from infected donors should be treated per the results of donor culture speciation and the antibiotic sensitivity profile.Late. Late infections primarily are due to chronic immunosup-pression, specifically the depression of cell-mediated immu-nity that renders recipients susceptible to viruses, fungi, and parasites.Members of the herpesvirus group are the most common etiologic agents of viral infections posttransplantation, with her-pes simplex virus (HSV), CMV, and EBV being the most prom-inent. Pretransplant exposure to viruses may confer immunity. Recipients who are seronegative for HSV, CMV, and/or EBV have a higher incidence of posttransplant infections, especially if they receive donor allografts from seropositive donors.CMV is a latent infection that can be transmitted to sero-naive recipients by donor organs from seropositive individuals, can reactivate during immunosuppression, or both. Infections usually occur 3 to 6 months posttransplant or during treatment for rejection. The incidence of CMV has been greatly reduced with 12-week acyclovir prophylaxis.40 CMV infections range from an asymptomatic or mild flu-like syndrome to tissue-invasive disease resulting in pneumonitis, hepatitis, and GI ulcerations. Symptomatic infections and all tissue-invasive CMV disease should be treated with intravenous (IV) ganciclovir, a reduction in immunosuppression, or both, although successful treatment of mild to moderate rejection and concurrent mild to moderate CMV disease has been described.EBV infections range from a mild mononucleosis syn-drome to severe hepatitis and highly morbid PTLD. PTLD ranges from a localized tumor to a progressive, diffuse infiltration of various organs including the brain. It results from the prolifera-tion of EBV-positive B cells in immunosuppressed patients. The main risk factors are a high degree of immunosuppression and 3Brunicardi_Ch11_p0355-p0396.indd 36301/03/19 6:53 PM 364BASIC CONSIDERATIONSPART Ia predisposing EBV serostatus (seronaive recipient, seroposi-tive donor). Among patients with early lesions, the first line of treatment is to reduce immunosuppression. For those with more advanced PTLD, rituximab is used.After 6 months posttransplant, the risk of invasive fungal infections is closely associated with environmental exposures. Blastomyces dermatitidis grows in moist soil in the Midwest and Southeast regions of the United States. Diagnosis is con-firmed by biopsy; the preferred treatment is IV amphotericin B.Coccidioides immitis can cause invasive coccidioidomy-cosis after inhalation of aerosolized infectious particles. It is endemic in the Southwest, Northern Mexico, and various parts of Central and South America. This infection can be resilient and difficult to treat. The first line of treatment is high-dose amphotericin B.Histoplasma capsulatum is found in chicken, pidgeon, and bat droppings in the Ohio River and Mississippi River val-leys. Dissemination is commonplace; up to a quarter of patients have central nervous system (CNS) involvement. Treatment consists of prolonged (3 to 13 months) administration of oral itraconazole.Opportunistic infections with Aspergillus, Cryptococcus, Mucor, and Rhizopus species are rare but can cause serious infections. Patients with invasive Candida or Aspergillus infec-tions exhibit a 20% mortality rate. Prophylaxis with fluconazole has been shown to reduce invasive fungal infections in liver recipients.41Pneumocystis jiroveci (also known as PCP) is ubiqui-tous and can cause pulmonary disease in immunocompromised patients. However, trimethoprim-sulfamethoxazole (TMP-SMX) is effective prophylaxis against PCP, and daily, lifelong administration has virtually eliminated this infection among transplant recipients.MalignanciesChronic immunosuppression increases the risk of develop-ing certain types of malignancies. The most extensive data, from a cohort study involving more than 175,000 solid organ transplant recipients, showed that 10,656 of them developed malignancies. The standardized incidence ratio was 2:10 (as compared with the general population). Recipients had at least a fivefold increase (as compared with the general population) in these types of malignancies: Kaposi’s sarcoma, nonmelanoma skin cancer, non-Hodgkin’s lymphoma, and cancer of the liver, anus, vulva, and lip. In addition, recipients had a statistically significant increase (as compared with the general population) in melanoma, Hodgkin’s lymphoma, and cancer of the lung, kidney, colon, rectum, and pancreas.42ORGAN PROCUREMENT AND PRESERVATIONOrgan procurement is a key element in organ transplantation. Currently, over 100 organ procurement organizations (OPOs) exist in the United States, all members of the Organ Procure-ment and Transplantation Network (OPTN), which is a feder-ally mandated network created by and overseen by UNOS. Each OPO is responsible for evaluating and procuring deceased donor organs for transplantation in a specific geographic region. Hospitals receiving any type of federal reimbursement for their services (whether transplant-related or not) are required to report all deaths to their OPO in a timely manner. Each OPO then determines the medical suitability of the deceased for organ donation; requests consent for donation from family members; if consent is given, contacts the OPTN to analyze and identify potential recipients whose HLA antigens most closely match those of the donor; and arranges for the recovery and transport of any donated organs.Strategies to increase organ donation and utilization have been successfully implemented in the last 10 to 15 years. The nationwide “Organ Donation Breakthrough Collaborative,” sponsored by the U.S. Department of Health and Human Ser-vices in 2003, brought the OPOs and transplant communities into a single concerted program to develop best practices guide-lines. However, a severe donor shortage remains. The number of living organ donors peaked in 2007 and has declined since.Alternative options include tissue engineering and stem cell research, but those fields are in their infancy in terms of producing fully functional and vascularized human organs. With the development of genetic “knockout” pigs, xenotrans-plantation still shows promise, but two problems in particular—immunologic barriers and xenosis (also known as zoonosis) of endogenous porcine retroviruses—have yet to be satisfactorily addressed.Today, the gap between patients waiting for organ trans-plants and the number of organs available continues to widen. More than 118,000 patients are on the waiting list for solid organ transplants, but only 33,611 transplants were performed in 2016.Deceased DonorsMost transplants today utilize organs from deceased donors. Formerly, death was determined by the cessation of both cardiac and respiratory function.Donation After Brain Death. In 1968, the concept of “irre-versible coma” was introduced by an ad hoc committee report at Harvard Medical School; that concept was pivotal to the final acceptance, in 1981, of “brain death” as a legal definition in the United States. The legal language states that the declara-tion of brain death should be in accordance with acceptable medical standards but does not specify clinical methodology. It is customary for hospitals to establish their own policies to declare brain death, according to their standards of care and local regulations.Typically, brain death is defined as the irreversible cessa-tion of brain function, including the brainstem. The presence of medical conditions that mimic brain death—such as drug over-dose, medication side effects, severe hypothermia, hypoglyce-mia, induced coma, and chronic vegetative state—need to be excluded. The latest evidence-based guideline on determining brain death in adults reaffirmed the validity of current clinical practice.43 Briefly, the clinical diagnosis of brain death consists of four essential steps: (a) establishment of the proximate cause of the neurologic insult; (b) clinical examinations to determine coma, absence of brainstem reflexes, and apnea; (c) utilization of ancillary tests, such as electroencephalography (EEG), cere-bral angiography, or nuclear scans, in patients who do not meet clinical criteria; and (d) appropriate documentation. A similar guideline on determining brain death in pediatric patients was recently developed.44Once the diagnosis of brain death has been established, the local OPO assumes the care of the potential donor and initiates the process of donor evaluation and organ donation, and the potential donor is screened for contraindications to donation. The medical history and social history are obtained from the available family members. A battery of tests, including serologic Brunicardi_Ch11_p0355-p0396.indd 36401/03/19 6:53 PM 365TRANSPLANTATIONCHAPTER 11or molecular detection of human immunodeficiency virus (HIV) and viral hepatitis, are performed. The exact medical conditions that preclude donation vary; nonetheless, in the United States, infections and other medical conditions that determine eligibil-ity are dictated by UNOS bylaws and routinely reviewed and updated.The OPO focuses on preserving organ function and opti-mizing peripheral oxygen delivery until organ procurement commences.45 In all deceased donors, core temperature, sys-temic arterial blood pressure, arterial oxygen saturation, and urine output must be determined routinely and frequently. Arterial blood gases, serum electrolytes, blood urea nitrogen, serum creatinine, liver enzyme, hemoglobin, and coagulation tests need to be monitored regularly. In all brain-dead donors, elevated intracranial pressure triggers a compensatory catechol-amine response to maintain cerebral profusion pressure. Isch-emic injury to the spinal cord and the sympathetic system may lead to a profound vasodilation. As a result, brain-dead donors frequently have severe hemodynamic and metabolic derange-ments, so aggressive monitoring and intervention are required to prevent loss of precious organs.Previous studies of deceased donor care focused on organ-specific resuscitation protocols that resulted in only marginal gains in the number of organs transplanted. The latest develop-ments center on multisystem protocols to increase the number of organs transplanted per donor (OTPD).46,47 The goals are to maintain a core temperature between 36.0°C and 37.5°C, a mean arterial pressure >70 mmHg or a systolic pressure >100 mmHg, and a hemoglobin level between 7 and 10 g/dL; hormonal therapy and aggressive treatment of arrhythmias and metabolic derangements are also called for.47Surgical Technique. Procurement of multiple organs (heart, lungs, kidney, liver, pancreas, and/or small bowel), or multivis-ceral procurement, was first described by the Pittsburgh group in 1987.48 Since then, most centers have incorporated changes, especially with regard to the timing and location of dissection and flushing.49,50 The basic steps involve a long incision to provide wide exposure of all thoracic and abdominal organs (Fig. 11-3). A Cattell-Braasch maneuver (complete mobiliza-tion of the distal small bowel, right colon, and duodenum) is performed to allow for identification of the distal aorta, iliac Figure 11-3. Exposure for thoracic and abdominal organ procurement.bifurcation, and distal inferior vena cava (IVC). The infrare-nal aorta is the site for inserting the cannula that will allow for flushing of the organs with cold preservation solution. Some-times, division of the inferior mesenteric artery is necessary to facilitate the exposure of the distal aorta. The third portion of the duodenum is retracted cephalad to expose the root of the supe-rior mesenteric artery (SMA). Limited dissection is performed at the root of the SMA, which is encircled with a vessel loop to enable its temporary occlusion at the time of flushing, thus reducing the incidence of overperfusion injury to the pancreas.A large anomalous or replaced right hepatic artery typi-cally rises from the SMA, and this should be identified and preserved. Lateral to the SMA is the inferior mesenteric vein (IMV), which can be cannulated for portal flushing. Dissection of the hepatic hilum and the pancreas should be limited to the common hepatic artery (CHA), and branches of the CHA (e.g., splenic, left gastric, and gastroduodenal arteries) are exposed. The gastrohepatic ligament is carefully examined to preserve a large anomalous or replaced left hepatic artery, if present. The supraceliac aorta can be exposed by dividing the left triangular ligament of the liver and the gastrohepatic ligament.The common bile duct is transected at the superior mar-gin of the head of the pancreas. The gallbladder is incised and flushed with ice-cold saline to clear the bile and sludge. If the pancreas is to be procured, the duodenum is flushed with anti-microbial solution. Before the cannulation of the distal aorta, systemic heparinization (300 units/kg) is administered. The supraceliac aorta is clamped; cold preservation fluid is infused via the aortic (systemic) and IMV (portal) cannulas. The tho-racic organs, liver, pancreas, and kidneys are then removed.Donation After Cardiac Death. Given the severe shortage of donor organs, donation after cardiac death (DCD)—also known as donation by non–heart-beating donors (NHBDs)—was rein-troduced to the transplant community in the 1990s.51 The cat-egory of DCD (Maastricht classification) was initially proposed at an international workshop and is now widely adopted for organ procurement.52 Currently, most NHBDs in the United States meet Maastricht classification III; that is, they have suffered a devastating injury with no chance of a meaningful recovery but do not meet the criteria for brain death. After consent for dona-tion is obtained from the next of kin, the donor’s life support is removed. After the cessation of cardiac and respiratory function, organ procurement commences. DCD procurement protocols vary between states; religious and cultural differences need to be taken into consideration. The surgical team must be familiar with, and respect, the local protocol.With cardiac death (as opposed to brain death), warm ischemic injury to organs can occur during the period between circulatory cessation and rapid core cooling through perfusion of preservation solution. However, the difference in long-term outcomes is negligible for recipients of organs from either type of donor. Still, a significant percentage of liver grafts procured after cardiac death, especially those with more than 25 minutes of warm ischemic time, develop devastating ischemic cholan-giopathy and fail.53A new development to minimize ischemic injury to organs procured after cardiac death has been the application of extra-corporeal membrane oxygenation (ECMO). With ECMO, DCD differs in two key ways: (a) cannulation occurs before with-drawal of life support and (b) organs are perfused via ECMO with warm oxygenated blood after declaration of cardiac death. Brunicardi_Ch11_p0355-p0396.indd 36501/03/19 6:53 PM 366BASIC CONSIDERATIONSPART IThe initial experience with organs procured using ECMO has been encouraging.Surgical Technique. Surgeons who perform multiple organ retrieval should be familiar and experienced with the super-rapid technique described by the Pittsburgh group.54 Preferably, NHBDs undergo withdrawal of life support in the operating room after the surgical site is prepped and draped, as soon as the surgical team is ready. Alternatively, the NHBD is transported to the operating room after declaration of cardiac death.A midline incision is used to rapidly gain entry into the abdominal cavity. An assistant retracts the small bowel and the sigmoid colon laterally, so that the bifurcation of the aorta can be easily identified on the left side of the vertebral column. A short segment of the distal aorta is dissected out from the retro-peritoneum. A moist umbilical tape is passed around the aorta, which is used to secure a cannula. The distal aorta is clamped. Next, a cannula is passed cephalad through an aortotomy and secured. Flushing with cold preservation solution is started at once, followed by cross-clamping the aorta proximally (thoracic aorta) and venting through the vena cava. The portal flush is then instituted.The rest of the procedure is similar to procurement after brain death, with two noticeable differences. First, to avoid injury to a large anomalous or replaced left hepatic artery, the gastrohepatic ligament and the left gastric artery are separated from the stomach at the lesser curvature. Second, to avoid injury to a large anomalous or replaced right hepatic artery, the SMA is examined before it is divided. If the pancreas is not procured, a common aortic patch encompassing both the SMA and the celiac artery can be procured with the liver.Living DonorsThe maxim of medical ethics is “primum non nocere” (first, do no harm), and for that reason, living organ donation pres-ents unique ethical and legal challenges. Performing potentially harmful operations to remove organs from healthy individuals seems, at first glance, to contradict that maxim. But in fact, the ethical framework of living organ donation rests on three guid-ing principles respected in all discussions of medical practice: beneficence to the recipient, nonmaleficence to the donor, and the donor’s right to autonomy.55 In order to achieve optimal outcomes (the common good), transplant professionals should focus on maximizing the benefits for the recipient and minimiz-ing the damage to the donor. The Uniform Anatomical Gift Act adopted by all states in the United States (with slight variations) provides the legal framework for competent adult living donors to decide whether or not to donate. It is the fiduciary duty of transplant professionals to explain the risks of organ donation. Any decision to donate should be uncoerced, and no entice-ments should be offered.The use of living donors offers numerous advantages for recipients in need. First and foremost is the availability of lifesaving organs for those who would otherwise succumb to the progression of their end-stage disease. In certain parts of the world, such as East Asia, the concept of brain death and the use of deceased donors conflict with the prevailing culture or religion. Even in countries where the use of deceased donors is accepted, the use of living donors may significantly shorten the waiting time for recipients. A shorter waiting time gener-ally implies a healthier recipient—one whose body has not been ravaged by prolonged end-stage organ failure. Moreover, with the use of living donors, transplants are planned (rather than emergency) procedures, allowing for better preoperative preparation of the recipient. Receiving an organ from a closely matched relative may also have immunologic benefits. And long-term results may be superior with the use of living donors, as is certainly the case with kidney transplants.The major disadvantage is the risk to the living donor. Medically, there is no possibility of benefit to the donor, only the potential for harm. The risk of death associated with dona-tion depends on the organ being removed. For a nephrectomy, the estimated mortality risk is less than 0.05%; for a partial hepatectomy, about 0.2%. The risk of surgical and medical complications also depends on the procedure being performed. In addition, long-term complications may be associated with a partial loss of organ function after donation. The guiding prin-ciple should be minimization of risk to the donor. All potential risks must be carefully explained to the potential donor, and written informed consent must be obtained.56Surgical Technique. The kidney, the first organ to be trans-planted from living donors, is still the most common organ donated by these individuals. The donor’s left kidney is usually preferable because of the long vascular pedicle. Use of living donor kidneys with multiple renal arteries should be avoided in order to decrease the complexity of the vascular reconstruction and to help avoid graft thrombosis. Most donor nephrectomies are now performed via minimally invasive techniques, that is, laparoscopically, whether hand-assisted or not. With laparo-scopic techniques, an intraperitoneal approach is most common: it involves mobilizing the colon, isolating the ureter and renal vessels, mobilizing the kidney, dividing the renal vessels and the distal ureter, and removing the kidney (Fig. 11-4). Extensive dissection around the ureter should be avoided, and the surgeon should strive to preserve as much length of the renal artery and vein as possible.Liver transplants with living donors are not as commonly performed, given the significantly higher rates of donor mor-tality and morbidity. Initially, only adult donors for pediatric recipients were selected, but now, living donor liver transplants also involve adult donors for adult recipients. In dual graft living donor liver transplants, segmental grafts from two living donors augment the recipient’s graft size.57 The donor hepatectomy is similar to a major lobar hepatectomy, except that it is impor-tant to preserve the integrity of the vascular structure until graft resection (Fig. 11-5).Living donor transplants of organs other than the kidney and liver are fairly uncommon, but certain centers do perform such transplants. Living donor pancreas transplants involve per-forming a distal pancreatectomy, with the graft consisting of the body and tail of the pancreas; vascular inflow and outflow are provided by the splenic artery and splenic vein. Living donor intestinal transplants usually involve removal of about 200 cm of the donor’s ileum, with inflow and outflow provided by the ileocolic vessels. Living donor lung transplants involve removal of one lobe of one lung from each of two donors; both grafts are then transplanted into the recipient.Organ PreservationThe development and continuing refinement of organ preser-vation methods have completely revolutionized the transplant field. Extending the time that organs can be safely stored after procurement has enabled better organ utilization and better recipient outcomes.58,59 Hypothermia and pharmacologic inhibi-tion are the two most frequent methods. Both slow—yet cannot Brunicardi_Ch11_p0355-p0396.indd 36601/03/19 6:53 PM 367TRANSPLANTATIONCHAPTER 11ABCDEFFigure 11-4. Laparoscopic left donor nephroureterectomy. A. Takedown of splenic flexure of colon to expose the left renal hilum. B. Dissection of left ureter off the psoas muscle. C. Dissection of left renal vein and gonadal vein. Left ureter seen lateral to the dissection. D. Dissection of left renal artery. Lumbar veins clipped and divided. E. Endo-TA stapler transection of the left renal artery. F. Placement of ports and Pfannenstiel incision for the donor kidney extraction.ABFigure 11-5. Donor hepatectomy (right hepatectomy). A. The liver parenchymal transection line (c, the Cantlie line) marked with cautery. Right portal vein (p) and right hepatic artery (a) isolated. b = bile duct. Cystic duct was cannulated for intraoperative cholangiography. B. Exposure of hepatic veins after transection of the parenchyma. IVC = inferior vena cava; L = left hepatic vein; M = middle hepatic vein; R = right hepatic vein.Brunicardi_Ch11_p0355-p0396.indd 36701/03/19 6:54 PM 368BASIC CONSIDERATIONSPART Icompletely shut down—the removed organ’s metabolic activ-ity, so both have adverse effects, such as cellular swelling and degradation. Cold storage solutions were introduced to mitigate some of the adverse effects of hypothermia or pharmacologic inhibition alone. Such solutions help prevent cellular swelling and the loss of cellular potassium.One, and perhaps the most effective, preservation solu-tion was developed at the University of Wisconsin and remains in wide use.60 Its ingredients include lactobionate (which helps prevent cellular swelling and reperfusion injury), raffinose, and hydroxyethyl starch (which helps reduce swelling of endothe-lial cells, thereby decreasing edema). Histidine-tryptophan-ketoglutarate solution is also currently in wide use.61Despite enhancements in preservation methods, the amount of time that an organ can be safely stored remains rel-atively short (hours, not days), particularly with organs from marginal donors. Among kidney recipients, delayed graft func-tion becomes significantly more frequent after cold ischemic times of more than 24 hours, necessitating temporary dialysis, which is associated with increased risks of graft loss and higher costs.62 Among liver recipients, primary nonfunction and bili-ary complications ensue after prolonged cold ischemic times. In the case of heart and lung recipients, ischemic times should be under 6 hours. All of those times assume the use of normal donors.There is revived interest in the use of the pulsatile perfu-sion pump, a kidney graft preservation method that has been available for more than 40 years.63 With the increasing shortage of available donor organs and the rise in the use of organs after cardiac death, the pulsatile perfusion pump is garnering renewed enthusiasm as an adjunct method of preservation, even for donor organs other than kidneys.64,65KIDNEY TRANSPLANTATIONIntroductionUllman reported the first attempted human kidney transplant in 1902.66 For the next 50 years, sporadic attempts all ended in either technical failure or in graft failure from rejection. Joseph Murray performed the first successful kidney transplant in 1954, an epochal event in the history of organ transplantation. In that first case, the immunologic barrier was circumvented by transplanting a kidney between identical twins.67 For his pivotal contribution, Murray shared the Nobel Prize in Physiology or Medicine in 1990 with E. Donnall Thomas for their discoveries concerning “organ and cell transplantation in the treatment of human disease.”The introduction of AZA (Imuran) in 1960 marked the beginning of a new era in kidney transplantation. With the com-bination of steroids and AZA for maintenance immunosuppres-sion, the 1-year graft survival rate with a living related donor kidney approached 80%; with a deceased donor kidney, the rate was 65%.68 In the ensuing years, major milestones included the introduction of more effective immunosuppressive medications with lower toxicity profiles, such as polyclonal antilymphocyte globulin in the 1970s, cyclosporine in the 1980s, tacrolimus in the 1990s, and biologics in the first decade of the 21st century, as previously mentioned.Parallel to the developments in medical science were the transplant community’s concerted efforts to improve use of healthcare resources. In the United States, the Social Security amendments of 1972 provided Medicare coverage for patients with end-stage renal disease (ESRD). The National Organ Transplant Act of 1984 initiated the process of creating what later became UNOS, an umbrella organization to ensure access to organs by patients in need, to enhance organ procurement and allocation, and to improve posttransplant outcomes. This infrastructure later became the blueprint for other countries to follow. As a result, organ transplantation is the most transparent field of medicine. Data such as transplant center performance are readily available on public websites; penalties for violation of regulations and for underperformance often result in trans-plant programs being shut down.Today, a kidney transplant remains the most definitive and durable renal replacement therapy for patients with ESRD. It offers better survival and improved quality of life and is considerably more cost-effective than dialysis.69,70 According to the 2016 Scientific Registry of Transplant Recipients (SRTR) annual report, nearly 100,000 adult patients were on the kidney transplant waiting list, while nearly 20,000 patients underwent renal transplantation. Trends over the past decade indicated that living related transplants remained rela-tively stable, while the number of deceased donor transplants rose. Posttransplant outcomes have continued to improve: in 2015, the 1-year graft survival rate with a living donor kidney was nearly 98%; with a deceased donor kidney, the rate was approximately 95.0%.71The advantages of a living donor kidney transplant include better posttransplant outcomes, avoidance of prolonged waiting time and dialysis, and the ability to coordinate the donor and recipient procedures in a timely fashion. Living donor kidney recipients enjoy better long-term outcomes, a low incidence of delayed graft function, and reduced risks of posttransplant complications. Furthermore, the elective nature of living donor kidney transplants provides unique opportunities for recipient desensitization treatment if the donor and recipient are ABOincompatible or if the HLA cross-match results are positive.Some of the challenges transplant professionals face today are closing the growing gap between supply and demand and thereby reducing the current prolonged waiting times; refining immunosuppressive medications to achieve better outcomes with reduced toxicity; and caring for patients who develop rejection, especially antibody-mediated rejection.Pretransplant EvaluationActive infection or the presence of a malignancy, active substance abuse, and poorly controlled psychiatric illness are the few abso-lute contraindications to a kidney transplant. Studies have demon-strated the overwhelming benefits of kidney transplants in terms of patient survival, quality of life, and cost-effectiveness, so most patients with ESRD are referred for consideration of a kidney transplant. However, to achieve optimal transplant outcomes, the many risks (such as the surgical stress to the cardiovascu-lar system, the development of infections or malignancies with long-term immunosuppression, and the psychosocial and finan-cial impacts on compliance) must be carefully balanced.Any problems detected during the evaluation of transplant candidates are communicated to their referring physician and/or to a specialist if advanced evaluation and treatment are needed, ultimately improving overall care. Essentially, the pretransplant evaluation is a multifaceted approach to patient education and disease management.Before the pretransplant medical evaluation begins, kidney transplant candidates are encouraged to attend a group meeting 4Brunicardi_Ch11_p0355-p0396.indd 36801/03/19 6:54 PM 369TRANSPLANTATIONCHAPTER 11focused on patient education. The meeting is coordinated by a transplant physician or surgeon. The intent is to familiarize patients with the pretransplant evaluation process and with per-tinent medical concepts and terms. In an open forum format, important decisions such as type of donor (living vs. deceased) are discussed. The group meeting empowers patients to fully participate in their care and serves as an impetus for a meaning-ful dialogue with healthcare professionals.Medical EvaluationCardiovascular Disease. Diabetes and hypertension are the leading causes of chronic renal disease. Concomitant cardiovas-cular disease (CVD) is a common finding in this population. An estimated 30% to 42% of deaths with a functioning kidney graft are due to CVD.72,73 Therefore, assessment of the potential kid-ney transplant candidate’s cardiovascular status is an important part of the pretransplant evaluation.In fact, the American Heart Association and the American College of Cardiology Foundation recently published their expert consensus on CVD evaluation and management for solid organ transplant candidates.74 The process should focus on care-ful screening for the presence of significant cardiac conditions (e.g., angina, valvular disease, and arrhythmias) and for a prior history of congestive heart failure, coronary interventions, or valvular surgery. The perioperative risk assessment is based on patient symptoms and exercise tolerance. For all kidney trans-plant candidates, a resting 12-lead electrocardiogram (ECG) should be obtained. In addition, in this population, the use of echocardiography to analyze left ventricular function and to assess for pulmonary hypertension is useful.Stress testing may be considered in patients with no active cardiac condition but with risk factors such as diabetes, hemo-dialysis for more than 1 year, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The utility of noninvasive stress testing (as compared with angiographic studies) for evaluating coronary artery disease is controversial; an additional prognostic marker is the troponin T (cTnT) level.Malignancies. Because of the long-term use of immunosup-pressive medications, transplant recipients are at increased risk for development of malignancies. Untreated and/or active malig-nancies are absolute contraindications to a transplant (with two exceptions: nonmelanocytic skin cancer and incidental renal cell cancer identified at the time of concurrent nephrectomy [i.e., for polycystic kidney disease] and renal transplantation). For most patients who have undergone treatment of low-grade tumors with a low risk of recurrence (e.g., completely locally excised low-grade squamous cell cancer of the skin, colon cancer in a polyp absent stalk invasion), a wait of at least 2 years after suc-cessful treatment is recommended before a kidney transplant can be considered. However, for certain types of tumors, espe-cially at advanced stages or those with a high risk of recurrence (e.g., melanoma, lymphoma, renal cell cancer, breast cancer, colon cancer), a delay of at least 5 years is advisable. Accord-ing to the Israel Penn International Transplant Tumor Registry, tumor recurrence posttransplant is not infrequent: the recurrence rate is 67% in patients with multiple myeloma, 53% in nonme-lanocytic skin cancer, 29% in bladder cancer, and 23% in breast cancer.75Infections. A thorough history of infections and immuniza-tions should be obtained from transplant candidates, who need all recommended age-appropriate vaccinations according to the Centers for Disease Control and Prevention (CDC) guidelines. Ideally, vaccinations should be completed at least 4 to 6 weeks before the kidney transplant takes place. Immunosuppressive medications blunt the immune response and reduce the effec-tiveness of vaccinations; even more important, with attenuated vaccines, vaccine-derived infections could occur. If a splenec-tomy is anticipated (e.g., in recipients whose donor is ABO-incompatible or whose HLA cross-match results are positive), then they should be immunized against encapsulated organisms (such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) well in advance of the splenectomy.Transplant candidates should undergo routine tuberculosis (TB) screening. According to the Centers for Disease Control (CDC), in 2016, 9272 TB cases were diagnosed in the United States with 68.5 percent of cases occurring in foreign-born persons.76 Serologic screening combined with a chest roentgenogram for fungal infections such as coccidioidomycosis or histoplasmosis, in patients who either have a history of those infections or are from an endemic area, are recommended. Chronic infections such as osteomyelitis or endocarditis must be fully treated; a suitable waiting period after successful treatment must occur, in order to ensure that relapse does not occur.Hepatitis can be caused by five different type of viruses, hepatitis virus A, B, C, D, and E, with the first three being the most common. Acute viral hepatitis is a contraindication to a kidney transplant; however, chronic viral hepatitis (most com-monly caused by hepatitis B [HBV] or C [HCV]) does not pre-clude a recipient from undergoing a kidney transplant. In such candidates, obtaining a liver biopsy is essential to assess the disease severity. Recipients infected with HBV should undergo antiviral treatment (e.g., lamivudine) to prevent reactivation and progression of liver disease. Note that HBV is a noncytopathic virus; the liver damage is the result of an immune-mediated process.77 Moreover, the presence of normal liver enzymes in patients with HBV antigenemia does not predict the severity of parenchymal damage.Transplant candidates with chronic HCV infection often have HCV-related glomerulonephritis. As with HBV infection, the clinical presentation and biochemical findings with HCV infection are often unreliable in predicting liver damage. In such patients who also exhibit evidence of cirrhosis, a combined liver-kidney transplant should be considered. In appropriate candidates, pretransplant antiviral treatment with interferon-α may be considered. However, after a kidney transplant, inter-feron treatment is not recommended because it is an immunos-timulant, and thus HIV may precipitate graft rejection.Thanks to the excellent outcomes of highly active anti-retroviral therapy (HAART), infection with HIV is no longer considered a contraindication to a kidney transplant. Kidney transplant candidates with HIV must have an undetectable HIV viral load and a CD4 lymphocyte count greater than 200/mm3; in addition, they must not have developed any opportunistic infection in the previous year.78Latent viral infections such as CMV and EBV are of par-ticular interest in the field of transplantation, given the risks of reactivation posttransplant and their detrimental effects on graft and patient survival. Knowing the CMV and EBV sero-logic status of the recipient and donor helps transplant pro-fessionals gauge the risk of immunosuppressive regimens in relation to potential infection, thereby guiding plans for post-transplant antiviral prophylaxis treatment or, as noted earlier, Brunicardi_Ch11_p0355-p0396.indd 36901/03/19 6:54 PM 370BASIC CONSIDERATIONSPART Iavoiding transplants between a seropositive donor and a sero-naive recipient.Kidney Disease. The third most common cause of graft loss in kidney transplant recipients is recurrence of glomerular diseases such as focal segmental glomerulosclerosis (FSGS), immunoglobulin A (IgA) nephropathy, hemolytic uremic syn-drome, systemic lupus erythematosus, and membranoprolifera-tive glomerulonephritis. FSGS deserves special mention due to its frequent occurrence and dramatic presentation of early graft loss. An estimated 30% to 40% of FSGS patients develop recur-rent disease posttransplant; of those, up to half eventually lose their graft.79 In recipients with a history of FSGS, posttrans-plant nephrotic proteinuria should be promptly investigated; if diagnosis is confirmed by transplant kidney biopsy, rescue plas-mapheresis should be instituted at once. Adjuvant therapy with rituximab has been proposed.80Hypercoagulopathy. Kidney transplant candidates with a history of thrombotic events, repeated miscarriages, or a fam-ily history of thrombophilia should be screened for the fol-lowing coagulopathic disorders: activated protein C resistance ratio, factor V Leiden mutation, factor II 20210 gene mutation, antiphospholipid antibody, lupus anticoagulant, protein C or S deficiency, antithrombin III deficiency, and hyperhomocyste-inemia. In recipients at risk for hypercoagulopathy, pediatric kidney grafts and any kidney allografts with a complex vascular anatomy should be avoided.81 A perioperative anticoagulation protocol is recommended in this population.Surgical EvaluationUrologic Evaluation. Kidney transplant candidates (pediatric patients, in particular) with chronic kidney disease as a result of congenital or genitourinary abnormalities should undergo a thorough urologic evaluation. A voiding cystourethrogram and a complete lower urinary tract evaluation to rule out out-let obstruction are essential. Indications for a native nephrec-tomy include chronic pyelonephritis, large polycystic kidneys with loss of intra-abdominal domain, significant vesicoureteral reflux, or uncontrollable renovascular hypertension.Vascular Evaluation. The potential implant sites for a kidney graft include the recipient’s iliac vessels and, less commonly, the aorta and vena cava. Careful physical examination often reveals significant central and/or peripheral vascular disease. Findings such as a pulsatile intra-abdominal mass, diminished or absent peripheral pulse, claudication, rest pain, and tissue loss in lower extremities should be further evaluated by abdomi-nal computed tomography scan or ultrasound, Doppler studies, and/or angiography. With the popularity of endovascular inter-ventions, transplant surgeons also should be familiar with such technology and obtain detailed anatomic studies of patients with vascular stents.Immunologic Evaluation. ABO blood typing and HLA typ-ing (HLA-A, -B, and -DR) are required before a kidney trans-plant. The method of screening for preformed antibodies against HLA antigens (because of prior transplants, blood transfusions, or pregnancies) continues to evolve. The panel-reactive anti-body (PRA) assay is a screening test that examines the ability of serum from a kidney transplant candidate to lyse lymphocytes from a panel of HLA-typed donors. A numeric value, expressed as a percentage, indicates the likelihood of a positive cross-match with a donor. A higher PRA level identifies patients at high risk for a positive cross-match and therefore serves as a surrogate marker to measure the difficulty of finding a suitable donor and the subsequent risk of graft rejection.An important development in anti-HLA antibody screen-ing is Luminex technology, using HLA-coated fluorescent microbeads and flow cytometry, which is considered the “gold standard.” This technology pinpoints donor-specific antibodies (DSAs) in the serum of a kidney transplant candidate with a high PRA level. Since all organ donors must undergo HLA typing, a negative cross-match for recipients with a high PRA level can be ensured by avoiding the selection of donors carrying unac-ceptable antigens (i.e., a virtual cross-match).82 Kidney trans-plant candidate data (including ABO blood types, HLA types, and DSAs) are entered into a nationwide central database to facilitate deceased donor kidney allocation, as described earlier.Psychosocial Evaluation. Psychiatric disorders have been recognized as important contributing factors to poor outcomes posttransplant. Patients with uncontrolled psychiatric disor-ders are at high risk for noncompliance with drug treatment, impaired cognitive function, and the development of substance abuse. A robust psychosocial evaluation is essential to ensure that transplant candidates understand the risks and benefits of the procedure and that they adhere to the lifetime immunosup-pressive medication regimen.Recipient OperationKidney allografts usually are transplanted heterotopically. The iliac fossa is recognized as the ideal position because of its prox-imity to the recipient’s bladder and iliac vessels.83,84Retroperitoneal allograft placement also allows easy access for percutaneous biopsies and interventions for ureteral complications. The right iliac fossa is the preferred site because of its easy access to the recipient’s iliac vessels. However, if a pancreas transplant is anticipated in the future or if now failed kidney grafts have been placed at the right iliac fossa, then the left iliac fossa is used for implantation. The current surgical technique for kidney transplants was developed and popularized in the 1950s and 1960s and has changed little since.85A large-bore three-lumen urinary catheter is inserted after the recipient is anesthetized, and it is occluded with a clamp beneath the surgical drapes. Recipients whose native kidneys produce urine will naturally fill up the urinary bladder; those individuals whose kidneys do not will require insufflation of saline prior to creation of the ureteral anastomosis.Exposure of the operative field starts with a curvilinear skin incision, one to two finger widths above the midline pubic bone and the lateral edge of the rectus sheath. Superiorly, the extension of the incision depends on the recipient’s body habitus and the size of the donor kidney. The anterior rectus sheath is incised, medially to laterally, until the lateral edge of the rectus sheath is exposed. The posterior rectus sheath is missing below the arcuate line, thus providing direct access to the extraperito-neal space. The rectus muscle can be easily mobilized medially without being divided. The remainder of the fascial incision is along the lateral edge of the rectus sheath until the desired expo-sure is achieved (Fig. 11-6).The retroperitoneal space of the iliac fossa is entered by mobilizing the peritoneum medially. The inferior epigastric ves-sels, the round ligament (in females), and the spermatic cord and its vasculature (in males) are encountered in this space; the former two structures are divided, while the latter is retracted with a vascular loop. A self-retained retractor is used to expose Brunicardi_Ch11_p0355-p0396.indd 37001/03/19 6:54 PM 371TRANSPLANTATIONCHAPTER 11ABCABFigure 11-6. Incision and exposure for kidney transplant. A. Mark for the skin incision. B. Anterior rectus sheath incised obliquely. The abdominal muscle transected lateral to the rectus muscle. C. External iliac artery and vein dissected.Figure 11-7. Vascular anastomoses of kidney transplant. A. Arterial anastomosis: donor renal artery with Carrel patch to recipient external iliac artery, end-to-side. B. Venous anastomosis: donor renal vein with caval extension conduit to recipient external iliac vein, end-to-side.the surgical field. The iliac vessels should be dissected with great care. To minimize the risk of lymphocele development postoperatively, dissection of the iliac artery should be limited; the intertwining lymphatics around the iliac vessels should be ligated. In general, the donor’s renal artery and vein are anasto-mosed to the recipient’s external iliac vessels in an end-to-side fashion (Fig. 11-7). In recipients with a severely calcified iliac artery, the internal iliac artery can be used as an alternative, and in select cases, an endarterectomy must be performed.After restoring the circulation to the donor’s kidney, urinary continuity can be established via several approaches. The approach chosen depends on such factors as the length of the donor ureter and a recipient history of bladder surgery, native nephrectomy, or pelvic radiation. The two most com-mon procedures to restore urinary continuity are the Leadbetter-Politano and a modification of the Lich (e.g., extravesical) ureteroneocystostomy.During the former procedure, a large cystotomy is cre-ated in the dome of the bladder, and the donor ureter is brought through a lateral and somewhat inferior 1-cm submucosal tunnel into the bladder, the end of which is spatulated and then sewn in place without tension with interrupted absorbable sutures placed through the mucosa and submucosa on the inside of the bladder.An extravesical ureteroneocystostomy is performed by careful dissection of a 1-cm portion of the muscular layers on the anterolateral portion of the bladder until a “bubble” of mucosa is exposed. The donor ureter is spatulated in a diamond-shaped fashion, the bladder mucosa is incised, absorbable interrupted sutures are placed in four quadrants, and a mucosa-to-mucosa anastomosis is created using running absorbable sutures with a temporary ureteral stent in place of the first three-quarters of the anastomosis. The muscular lay-ers of the bladder are then carefully approximated over the anastomosis to prevent reflux.The decision to place a ureteral stent depends on the sur-geon, who must try to balance the risk of infectious compli-cations with the possible technical complications of a ureteral anastomosis, but in general, this is not required except during the rarely performed donor ureter to recipient ureter anastomo-sis or in the case of a pediatric kidney transplant. Fixation of the donor’s kidneys is not necessary, except in the case of small kidneys (usually from a pediatric donor) or en bloc kidneys.Brunicardi_Ch11_p0355-p0396.indd 37101/03/19 6:54 PM 372BASIC CONSIDERATIONSPART IFigure 11-8. Arterial and venous reconstruction. A. Two renal arteries combined into a single Carrel patch (arrow). Right renal vein exten-sion conduit constructed with stapled caval patch. IVC = inferior vena cava; R = right renal vein. B. Three renal arteries anastomosed to external iliac artery separately.ABABFigure 11-9. En bloc kidney transplant (3-month-old donor kidneys). A. En bloc kidneys benched. Vascular integrity tested with methylene blue (blue hue look of the kidneys). B. En bloc kidneys transplanted into a 62-year-old woman. Donor aorta anastomosed to recipient’s exter-nal iliac artery; donor cava, to recipient’s external iliac vein.Grafts With Multiple Renal ArteriesIn 10% to 30% of donor kidneys, multiple renal arteries are encountered. Unless kidney transplant candidates have hyper-coagulopathy, grafts with multiple renal arteries fare as well as those with single vessels.86 Vascular reconstruction options include implanting the donor’s arteries separately, reconstruct-ing the multiple arteries into a common channel, or combining multiple arteries into a common Carrel patch (Fig. 11-8).En Bloc GraftsDebate persists about whether to implant kidneys obtained from young donors (<5 years or whose body weight is under 20 kg) as a single en bloc unit into one recipient or separately into two recipients. The underlying issues are the shortage of donor organs, the complexity of the surgical procedure, the risks of graft thrombosis, ureteral complications, and long-term outcomes.In en bloc kidney transplants, the donor aorta and vena cava are used as the vascular inflow and outflow conduits. Therefore, reconstruction of the en bloc graft pretransplant is key to a successful transplant. The donor’s suprarenal vena cava and aorta are oversewn. The lumbar branches of the cava and aorta are ligated. Dissection around the renal hilum should be avoided. The orientation of the cava and aorta should be clearly marked, in order to avoid torsion of the anastomosis. If the color of the two kidneys looks different after reperfusion, repositioning should be attempted to rule out vascular torsion; fixation of the en bloc kidneys to the retroperitoneum is often necessary. The donor’s ureters are implanted to the recipient’s bladder, either as two separate anastomoses or as a common patch (Fig. 11-9). Only a handful of centers have performed en bloc kidney transplants, but the long-term outcomes are encouraging.87,88Brunicardi_Ch11_p0355-p0396.indd 37201/03/19 6:54 PM 373TRANSPLANTATIONCHAPTER 11Perioperative CarePreoperatively, a thorough history and physical examination should be performed. Any changes in transplant candidates’ recent medical history should be investigated in great detail. In those recipients with a historically negative PRA level who have recently undergone blood transfusions, a prospective tis-sue cross-match is necessary to avoid graft rejection. Electrolyte panels should be checked. Emergency dialysis may be neces-sary for transplant candidates experiencing hyperkalemia or fluid overload.For dialysis-dependent transplant candidates, the catheter sites should be examined preoperatively to rule out infections. Vascular access for hemodialysis is essential to avoid compli-cations related to posttransplant acute tubular necrosis (ATN). Vascular evaluation is mandatory; any changes in results should be investigated by appropriate imaging studies.As is routine for other major surgical procedures, trans-plant candidates should preoperatively undergo a chest X-ray, a 12-lead ECG, blood typing, cross-match tests, and prophylaxis against surgical site infection (by administration of a nonneph-rotoxic antibiotic with activity against both common skin micro-flora and gram-negative pathogens); candidates should receive nothing to eat or drink.Intraoperatively, transplant recipients should be kept well hydrated to avoid ATN and should receive heparin prior to vas-cular occlusion. Before reperfusion of the transplanted kidney, the desired central venous pressure should be maintained at around 10 mmHg, and the systolic blood pressure should be above 120 mmHg. In pediatric recipients of an adult graft, a superphysiologic condition may be necessary to avoid ATN or graft thrombosis. Mannitol often is administered before reper-fusion as a radical scavenger and diuretic agent, and a diuretic such as furosemide is administered as well.Postoperatively, the guiding principles for the care of kidney transplant recipients are the same as for other surgical patients. The crucial elements include hemodynamic stability and fluid and electrolyte balance. To achieve a euvolemic state, the recipient’s urine output is replaced with either an equal or a reduced volume of IV fluid on an hourly basis, depending on the medical status. In recipients undergoing brisk dieresis, aggressive replacement of electrolytes (including calcium, mag-nesium, and potassium) may be necessary. In recipients expe-riencing ATN, fluid overload, or hyperkalemia, however, fluid restriction, treatment for hyperkalemia, and even hemodialysis may be necessary.Hypotension is an unusual event immediately posttrans-plant. The differential diagnoses include hypovolemia, vasodila-tion, and myocardial infarction with cardiac failure. Immediate action should be taken to avoid life-threatening complications. Posttransplant hypertension can be mediated by catecholamines, fluid overload, or immunosuppressive agents.Postoperatively, urine output is used as a surrogate marker to monitor graft function. Among recipients whose native kid-neys produce significant amounts of urine, normal or increased urine output can be misleading; for them, serum blood urea nitrogen and creatinine levels are more reliable indicators of kidney graft function.Suddenly decreased or minimal urine output requires immediate attention. A change in volume status is the most common cause, but other culprits include blockage of the uri-nary catheter, urinary leak, vascular thrombosis, hypotension, drug-related nephrotoxicity, ATN, and rejection (all of which must be thoroughly investigated). Diagnostic studies such as Doppler ultrasound, nuclear renograms, or biopsies should be considered.Postoperative bleeding is an uncommon event after a kid-ney transplant. Recipients on anticoagulation or antiplatelet treatments are at increased risk. Signs and symptoms (such as an expanding hematoma over the surgical site, increased pain over the graft, a falling hemoglobin level, hypotension, and tachycardia) should arouse suspicion of hemorrhage. Doppler ultrasound is useful to establish the underlying cause. Surgical exploration seldom is required because the accumulated hema-toma tamponades the bleed. Indications for surgical explora-tion include ongoing transfusion requirement, hemodynamic instability, and graft dysfunction from hematoma compression. For recipients on anticoagulation or antiplatelet treatments, the threshold for surgical exploration is lower. Small unligated ves-sels at the donor’s renal hilum or recipient’s retroperitoneum are likely sources of bleeding.One of the most devastating postoperative complications in kidney recipients is graft thrombosis. It is rare, occurring in fewer than 1% of recipients. The recipient risk factors include a history of recipient hypercoagulopathy and severe peripheral vascular disease; donor-related risk factors include the use of en bloc or pediatric donor kidneys, procurement damage, techni-cal factors such as intimal dissection or torsion of vessels, and hyperacute rejection. Graft thrombosis usually occurs within the first several days posttransplant. Acute cessation of urine output in recipients with brittle posttransplant diuresis and the sudden onset of hematuria or graft pain should arouse suspicion of graft thrombosis. Doppler ultrasound may help confirm the diagnosis. In cases of graft thrombosis, an urgent thrombectomy is indi-cated; however, it rarely results in graft salvage.Urologic complications are seen in up to 5% of recipi-ents. The cause is often related to ureteral ischemia, damage during procurement of the donor’s distal ureter, or technical errors. Symptoms of urine leak include fever, pain, swelling at the graft site, increased creatinine level, decreased urine output, and cutaneous urinary drainage. Diagnosis can be confirmed by a combination of ultrasound, nuclear renography, drainage of perinephric fluid collection, and comparison of serum and fluid creatinine levels. Depending on the location and volume of the urine leak, satisfactory results can be achieved by surgi-cal exploration and repair or by percutaneous placement of a nephrostomy and ureteral stenting.Early urinary obstruction can be due to edema, blood clots, torsion of the ureter, or compression from a hematoma. Late urinary obstruction is often related to ischemia. The appear-ance of hydronephrosis on ultrasound is a good initial indicator. Treatment includes percutaneous placement of a nephrostomy and ureteral stenting. If transluminal intervention fails, surgical intervention (such as ureteral reimplantation or a ureteropyelos-tomy) can be undertaken.ResultsA kidney transplant remains the most common solid organ transplant in the world today. With the introduction of induc-tion immunosuppressive therapy and ever-improving, less toxic immunosuppressive medications, posttransplant outcomes have become better and better. And, as noted above, posttransplant outcomes have continued to improve: in 2014 allograft and patient survival rates were well over 90%, and in 2015, the 1-year graft survival rate with a living donor kidney was nearly Brunicardi_Ch11_p0355-p0396.indd 37301/03/19 6:54 PM 374BASIC CONSIDERATIONSPART I98%; with a deceased donor kidney, the rate was approximately 95%.71,89The biggest improvements have been in the reduction of 1-year graft failure. With a deceased donor kidney, the 1-year graft failure rate dropped from approximately 20% in 1989 to less than 7% in 2009 to 4.8% in 2015; with a living donor kidney, the rate dropped from 8.5% in 1989 to less than 3% in 2015.89 Furthermore, steroid-free protocols90 and calcineurin-free protocols91 have been validated and implemented in the last several decades, further reducing medication-related side effects and vastly improving the quality of life for tens of thousands of recipients.Currently, the most common cause of graft loss is recipi-ent death (usually from cardiovascular causes) with a function-ing graft. The second most common cause is chronic allograft nephropathy; characterized by a slow, unrelenting deterioration of graft function, it likely has multiple causes (both immuno-logic and nonimmunologic).92,93 The graft failure rate due to complications related to surgical technique has remained at about 1% to 2%.PANCREAS TRANSPLANTATIONA successful pancreas transplant currently is the only definitive long-term treatment for patients with insulin-dependent diabetes mellitus (IDDM) that (a) restores normal glucose hemostasis without exposing patients to the risk of severe hypoglycemia and (b) prevents, halts, or, in some cases, reverses the development or progression of secondary complications of diabetes.94Given its vast medical, social, and financial implications, diabetes mellitus is a huge burden to patients and to society as a whole. An estimated 10% to 15% of the U.S. population is affected by it; of all diabetic patients, 10% have early-onset dis-ease. In the United States, diabetes mellitus is the most common cause of end-stage kidney disease, blindness, impotence, major limb amputations, and coronary or peripheral vascular bypass procedures. It is one of the most common causes of death, along with myocardial infarction and stroke. Diabetes significantly decreases not only the quality of life but also life expectancy.Despite improvements in exogenous insulin administra-tion (including the use of devices such as insulin pumps), wide fluctuations in glucose levels and the risk of hypoglycemic epi-sodes are common. The Diabetes Control and Complications Trial (DCCT) demonstrated in the late 1990s that intensive insulin therapy may slow the rate of secondary complications of diabetes—yet at the expense of (life-threatening) iatrogenic hypoglycemia. The annual mortality rate of patients with insu-lin-induced inadvertent hypoglycemia is estimated to be as high as 2% to 3%.Since the first pancreas transplant in December 1966, per-formed by William Kelly and Richard Lillehei at the Univer-sity of Minnesota, more than 25,000 pancreas transplants in the United States and more than 10,000 pancreas transplants from all over the world have been reported to the International Pan-creas Transplant Registry (IPTR).94,95Pancreas transplants are performed in three recipient categories:• Simultaneous pancreas and kidney (SPK) transplant in diabetic and uremic patients. Almost 80% of pancreas trans-plants are performed in this category. The recipient is already 5obligated to lifelong immunosuppressive therapy, due to the need for a kidney transplant, so only the surgical risk of a pancreas transplant is added. A successful SPK transplant renders the recipient dialysis-free and insulin-independent.• Pancreas after kidney (PAK) transplant in diabetic and posturemic patients. Approximately 15% of all pancreas trans-plants fall into this category. These patients previously under-went a kidney transplant with either a living or deceased donor, but are candidates for a subsequent pancreas transplant because of poor glucose control or because of progression of secondary diabetic complications (which may include the development of diabetic nephropathy in the transplanted kidney).• Pancreas transplant alone (PTA) in nonuremic patients with brittle diabetes mellitus. Only about 5% of all pancreas trans-plants are in this category. These patients have not yet devel-oped advanced diabetic nephropathy, but their glucose levels are extremely labile despite best efforts of control. Because of the lifelong need for immunosuppressive therapy, the sur-gical risk has to be balanced with the medical risks of brittle diabetes (e.g., frequent episodes of hypoglycemia and hypo-glycemic unawareness).In SPK recipients, a plethora of literature exists that demonstrates significant improvements in secondary dia-betic complications (across all organ systems) posttransplant. Improvements have been reported in diabetic nephropathy, neu-ropathy (autonomic and peripheral), microand macrovascular disease, retinopathy, gastroparesis, and other secondary com-plications.96 Currently, more than 1000 pancreas transplants are performed annually in the United States, with the goal of confer-ring the following benefits: excellent glucose control (similar to that of a functioning native pancreas), prevention or improve-ment of secondary diabetic complications, and increased quality of life and life expectancy. In addition, pancreas transplants can be successfully performed in patients who have undergone a total pancreatectomy for benign disease (such as chronic pan-creatitis) to treat both endocrine and exocrine deficiency after surgery.97Donor OperationThe general criteria for selecting deceased donors for pancreas procurement are similar to those for other solid organs; a history of type 1 diabetes mellitus obviously is a contraindication. Rela-tive contraindications include previous pancreatic procedure(s), as well as pancreatic disorders, such as chronic pancreatitis and intraductal papillary mucinous neoplasm. Hyperglycemia in itself is not a contraindication to pancreas procurement because its cause in brain-dead donors usually is severe insulin resis-tance, which is rarely observed in recipients.In light of better anatomic understanding and improved surgical skills, all three abdominal organs that share a common blood supply (pancreas, liver, and intestine) can be procured at the same time and transplanted into three different recipi-ents (Fig. 11-10). During pancreas procurement, a “no-touch” technique of the gland is preferred; dissection of the pancreas is carried out in a way that avoids direct manipulation of the organ such that simultaneous procurement of the spleen, duodenum, and surrounding connective tissues occurs.In contrast to the liver and kidneys, the pancreas should not be extensively flushed at the end of the procurement. To minimize the amount of preservation fluid that reaches the pan-creas, the splenic artery and SMA can be temporarily clamped Brunicardi_Ch11_p0355-p0396.indd 37401/03/19 6:54 PM 375TRANSPLANTATIONCHAPTER 11MHVLHVRHVIPDAMCARCAFigure 11-10. Simultaneous pancreas, in situ split-liver, and intestine procurement. IPDA = inferior pancreaticoduodenal artery; LHV = left hepatic vein; MCA = middle cerebral artery; MHV = middle hepatic vein; RCA = right coro-nary artery; RHV= right hepatic vein. (Repro-duced from Gruessner RWG, Sutherland DER: Transplantation of the Pancreas. New York, NY: Springer, 2004.)at their origin from the aorta. Usually, the celiac axis with an aortic Carrel patch is retained with the liver. The splenic artery is divided close to its origin and is retained with the pancreas. The SMA is also procured with an aortic Carrel patch and is retained with the pancreas.In case of a replaced or aberrant right hepatic artery, this first branch off of the SMA is carefully dissected out from the posterior surface of the pancreas. A replaced or aberrant right hepatic artery does not transverse the pancreas and is not a con-traindication to combined pancreas and liver procurement. But with this anatomic variant, an aortic Carrel patch with the proxi-mal SMA and replaced or aberrant right hepatic artery remains with the liver; the distal SMA with the inferior pancreaticoduo-denal artery remains with the pancreas.In the relatively rare event that the liver is not procured, then neither the splenic nor the gastroduodenal arteries need to be divided at their respective takeoff; the donor’s celiac axis and the SMA are included on a common Carrel patch. This tech-nique allows a single arterial anastomosis to be performed in the recipient without reconstruction. At the end of the procurement, the pancreas is attached to the spleen, duodenum, and proximal jejunum, which is stapled at both ends.98Back Table Preparation of the Pancreas GraftBack table preparation of the pancreas graft consists of four steps: (a) removal of the spleen; (b) shortening, restapling, and/or suture reinforcement of the mesenteric root; (c) trimming of any excess distal and proximal duodenum, along with reinforce-ment of the proximal staple line; and (d) arterial reconstruction.Back table preparation is carried out in a basin filled with chilled preservation solution. The most common tech-nique to create a single arterial inflow to the pancreas graft is the “Y-graft” reconstruction, using a resected segment of the donor iliac artery bifurcation. In this technique, the donor exter-nal iliac artery is anastomosed end-to-end to the donor SMA, and the donor internal iliac artery is anastomosed end-to-end to the splenic artery (Fig. 11-11). This procedure allows the donor common iliac artery to be anastomosed as a single vessel to the recipient’s common iliac artery. For venous outflow, the portal vein is kept relatively short, in order to avoid the risk of venous thrombosis by kinking or impingement.98Recipient OperationOver the years, different surgical techniques have been described for (a) the management of exocrine pancreatic secretions and (b) the type of venous drainage. For the secretions, the two most common techniques are drainage of the duodenal segment to the bladder (bladder drainage) or to the small bowel (enteric drain-age) (Figs. 11-12 and 11-13). For venous drainage, systemic venous drainage is preferred over portal venous drainage.The pancreas graft is usually placed intra-abdominally and preferably on the right side because the iliac vessels are Brunicardi_Ch11_p0355-p0396.indd 37501/03/19 6:54 PM 376BASIC CONSIDERATIONSPART IFigure 11-11. Posterior view of the pancreas graft with Y-graft reconstruction. EIA = external iliac artery; IIA = internal iliac artery; SA = splenic artery; SMA = superior mesenteric artery. (Reproduced from Gruessner RWG, Sutherland DER: Transplanta-tion of the Pancreas. New York, NY: Springer, 2004.)Figure 11-12. Whole-organ transplant with systemic vein and bladder exocrine drainage. (Reproduced from Gruessner RWG, Sutherland DER: Transplantation of the Pancreas. New York, NY: Springer, 2004.)SAIIAEIASMASMAin a more shallow position on the right than on the left side; moreover, the vessels are already appropriately aligned for the vascular anastomoses (i.e., a lateral position for the com-mon iliac vein, a medial position for the common iliac artery). Venous and arterial anastomoses are performed end-to-side. After restoration of blood flow to the graft, hemostasis must be meticulously maintained. Because the donor portal vein pur-posely is kept short, ligation and transection of all of the recipi-ent’s internal iliac vein branches are frequently performed in order to prevent tension on the venous anastomosis. The pan-creas usually is placed with the pancreatic head and duodenum pointing caudally.Bladder drainage is performed using either a hand-sewn or a stapled anastomosis in which the antimesenteric side of the donor duodenum is sewn to the superior portion of the dome of the bladder. The stapled technique requires that a circular cut-ting stapler be inserted through the open distal end of the donor duodenum, which is subsequently closed. Bladder drainage has two main advantages. First, rejection of the exocrine pancreas precedes rejection of the endocrine pancreas by 5 to 7 days. Amylase levels are measured routinely in the recipient’s urine. With bladder drainage, antirejection treatment can successfully be implemented when the recipient is still normoglycemic and only hypoamylasuric. In the absence of hyperglycemia, more than 90% of pancreas rejection episodes are reversible. Second, bladder drainage avoids the bacterial contamination that occurs with enteric drainage. If an anastomotic leak occurs, it is easier to treat because the infection usually remains localized to the right lower quadrant.Enteric drainage is more physiologic and has advantages as well. The antimesenteric side of the donor’s duodenum is anastomosed to the antimesenteric portion of the recipient’s jejunum in a side-to-side fashion. The enteric anastomosis can also involve a defunctionalized Roux-en-Y loop, which mini-mizes the potential complications if an enteric leak occurs.98 Currently, in the United States, more than 80% of all pancreas transplants are performed with enteric drainage for the exocrine pancreatic secretions, and more than 90% employ systemic venous drainage.95Brunicardi_Ch11_p0355-p0396.indd 37601/03/19 6:54 PM 377TRANSPLANTATIONCHAPTER 11Figure 11-13. Whole-organ transplant with systemic vein and enteric exocrine drainage. (Reproduced from Gruessner RWG, Sutherland DER: Transplantation of the Pancreas. New York, NY: Springer, 2004.)ComplicationsThe technical complication rate for pancreas transplants is higher than for any other solid organ transplant. Four fac-tors contribute to the high surgical complication rate99: (a) the nature of the organ itself with inherent organ-specific surgical complications (e.g., pancreatitis, abscesses, necrosis, fistulas, and pseudocysts) and its low blood flow (which significantly increases the risk of thrombosis, as compared with a kidney or liver transplant); (b) the risk of a leak or infection after con-necting two hollow viscera (the duodenum and either the blad-der or small intestine); (c) the increased incidence of rejection episodes because the pancreas is one of the most immunogenic solid organs; and (d) the underlying disease of diabetes mellitus, predisposing patients not only to infections but also to cardio-vascular and other complications.The most common surgical complications are throm-bosis (an incidence of 5%–15%), intra-abdominal abscesses (5%–10%), and bleeding (6%–8%). Other pancreas-specific complications include graft pancreatitis (frequently due to pro-curement or reperfusion injury), pancreatic fistulas, and pan-creatic pseudocysts. Anastomotic leaks do not always require a graft pancreatectomy, but arterial pseudoaneurysms, arteriove-nous fistulas, and wound dehiscence may. Bleeding frequently requires relaparotomy.Thrombosis usually occurs within the first week posttrans-plant. It manifests as a sudden increase in insulin requirements or as a sharp drop in urinary amylase levels. Venous thrombosis, which is more common than arterial thrombosis, is associated with distinct clinical symptoms, including a swollen and tender graft, hematuria, lower extremity edema, and deep vein throm-bosis, the latter two occurring ipsilaterally. Arterial thrombosis is less symptomatic and may not initially cause pain; its diag-nosis is usually confirmed by Doppler ultrasonography. Surgi-cal exploration in recipients with thrombosis usually requires a graft pancreatectomy.With the advent of advanced interventional radiologic procedures to drain intra-abdominal abscesses, the reoperation rate has markedly decreased. Pancreas transplant recipients are usually kept on broad-spectrum antimicrobial agents for the first 7 days posttransplant.The most common nonsurgical complication posttrans-plant is rejection. The incidence of rejection is about 30% within the first year. The diagnosis is usually based on an increase in serum amylase and lipase levels and, in bladder-drained recipi-ents, a decrease in urinary amylase levels. A sustained drop in urinary amylase levels greater than 25% from baseline should prompt a pancreas graft biopsy to rule out rejection. In enteric-drained recipients, one must rely on serum amylase and lipase levels only. Other signs and symptoms of rejection include tenderness over the graft, unexplained fever, and hyperglyce-mia, which usually is a late finding; fewer than 5% of all rejec-tion episodes can be reversed in its presence. The diagnosis of rejection should be confirmed by a percutaneous pancreas graft biopsy.Other nonsurgical complications include infections with CMV, HCV, or extra-abdominal bacteria or fungi; malignan-cies, such as PTLD; and, rarely, graft-versus-host disease. For such complications, the diagnosis and treatment are similar to what is recommended after other solid organ transplants.Bladder-drained pancreas recipients may experience an array of unique urologic complications. Usually the result of the irritating nature of pancreatic enzymes on the urothelium in the bladder and urethra, these urologic complications can lead to cystitis, hematuria, and dysuria. With the loss of bicarbonate from pancreatic secretions, dehydration and metabolic acidosis are not uncommon. Many of these complications are chronic, such that approximately 20% to 30% of all bladder-drained recipients require conversion to enteric drainage within the first 5 years posttransplant.100Living Donor Pancreas TransplantsPancreas transplants using living donors also can be performed safely and successfully in select donors and recipients. Since 1979, about 150 such transplants have been performed world-wide, with 1-year graft survival rates in excess of 85% over the last decade. A meticulous donor evaluation using standard criteria remains key to a low donor metabolic and surgical com-plication rate. The concept of procuring the distal pancreas from a living donor is based on the observation that patients with benign or malignant pancreatic disorders can undergo a distal hemipancreatectomy without any serious change in endocrine function.Living donor pancreas transplants are ideal for patients with an identical twin, but other relatives can be suitable donors as well. In particular, patients with high PRA levels should be considered for a living donor transplant.Living donor pancreas transplants decrease the number of deaths of diabetic patients on the waiting list, help overcome the organ shortage, reduce mortality and morbidity, and improve the quality of life for patients with debilitating side effects of diabetes. The use of living donors also reduces the risk of graft rejection, as compared with the use of deceased donors. Yet living donor pancreas transplants remain relatively rare, per-formed under very selective circumstances. In terms of surgical technique, the donor splenic artery and vein are anastomosed to the recipient’s external iliac artery and vein in an end-to-side fashion, and exocrine drainage can occur via an anastomosis Brunicardi_Ch11_p0355-p0396.indd 37701/03/19 6:54 PM 378BASIC CONSIDERATIONSPART IFigure 11-14. Segmental transplant with systemic vein and blad-der exocrine drainage. The donor splenic artery and splenic vein are anastomosed end-to-side to the recipient’s external iliac artery and vein. The splenic artery anastomosis is lateral and proximal to the splenic vein anastomosis. A two-layer ductocystostomy is constructed. (Reproduced from Gruessner RWG, Sutherland DER: Transplantation of the Pancreas. New York, NY: Springer, 2004.)of the pancreatic duct and transected end of the pancreas to the bladder or bowel101 (Fig. 11-14).ResultsAs of December 2010, more than 35,000 pancreas transplants had been reported to the IPTR: more than 25,000 transplants in the United States and more than 10,000 in other countries. According to IPTR data, recipient age at the time of the trans-plant has increased significantly, and so has the number of trans-plants for patients with type 2 diabetes. The trend over time has been toward stricter donor criteria, with a concentration on younger donors, preferably trauma victims, and on short pan-creas graft preservation time.Drainage techniques have changed over time, too: enteric drainage of exocrine pancreatic secretions is now predominant, in combination with systemic drainage of the venous effluent of the pancreas graft. Immunosuppressive protocols have devel-oped toward antibody induction therapy, followed by administra-tion of tacrolimus and MMF for maintenance. Steroid avoidance has increased over time in all three recipient categories.Between 2005 and 2009 and 2010 and 2014, the num-ber of U.S. pancreas transplants declined by over 20%, while the overall number of pancreas transplants performed outside the United States has increased. The decline in U.S. numbers is predominantly due to the decline in primary and secondary pancreas after kidney transplants (PAK). During the time period studied, the number of PAK transplants dropped by 50%. In contrast, the number of simultaneous pancreas/kidney trans-plants (SPK) declined by only 10%, and the number of pan-creas transplants alone (PTA) by 20%. Over 90% of pancreas transplants worldwide were performed, with a simultaneous kidney transplant and excellent results. Transplant outcomes in SPK improved significantly because of a decrease in the rates of technical and immunologic graft loss. In 2010 to 2014 vs. 2005 to 2009, U.S. SPK transplant patient survival at 1 year posttransplant increased from 95.7% to 97.4%, pancreas graft function increased from 88.3% to 91.3%, and kidney func-tion increased from 93.6% to 95.5%. A significant improve-ment was also noted in PAK transplants. One-year patient survival increased from 96.4% to 97.9%, and pancreas graft function increased from 81.0% to 86.0%. PTA 1-year patient survival remained constant at 97%, and pancreas 1-year graft survival improved from 81.0% to 85.7%. IPTR data show sig-nificant improvements in patient survival and pancreas graft function rates since the inception of UNOS, over a course of 24 years.92,95,99,102 Clearly, pancreas transplants now offer excel-lent outcomes for patients with IDDM.Islet versus Pancreas TransplantsPancreas transplants are frequently compared with islet trans-plants (vide infra), which are less invasive and, therefore, more appealing. It is important to emphasize that these two types of transplants are not mutually exclusive but rather complementary. The results of islet transplants have improved over the past decade, but overall islet graft function, specifically long-term function, still significantly trails overall pancreas graft function.103 Islet transplants involve pancreas procurement (as described earlier) and then separation of islets from the exocrine pan-creatic tissues using proteolytic enzymes (as described later). The human pancreas contains about one million islets, of which half are lost during the isolation process. About 10,000 islets per kilo-gram of body weight are needed to achieve insulin independence when transplanted into the liver. Frequently, one donor pancreas does not suffice; in fact, up to four donor pancreases have been used for one islet recipient.Because of the relatively disappointing long-term out-comes, insurance providers in the United States do not provide reimbursement for islet transplants. Transplant centers with both pancreas and islet transplant programs follow an algorithm that favors islet transplants in patients with a high surgical risk and pancreas transplants in patients with a low surgical risk. Although solitary donor pancreases are not in short supply, only one donor pancreas is required for a successful pancreas transplant; in con-trast, two to four donor pancreases are commonly used for one islet recipient with less favorable long-term outcomes.Of note, the primary goal of current islet transplant trials is not insulin independence but rather a reduction in the inci-dence and severity of hypoglycemic events, a reduction in exog-enous insulin requirements, and an amelioration of hemoglobin A1c levels. Islet transplants rarely maintain long-term insulin independence. A recent study showed a higher rate of insulin independence in PTA recipients than in recipients of an islet transplant alone, despite the use of up to three donor pancreases in each of the islet recipients.104 Until islet transplant results sig-nificantly improve and include long-term insulin independence, a pancreas transplant remains the treatment of choice for β-cell replacement therapy in patients with IDDM.ISLET TRANSPLANTATIONTransplanting islets of Langerhans isolated from deceased donor pancreases is an appealing option for patients with type 1 diabetes. An islet transplant involves the procurement of a 6Brunicardi_Ch11_p0355-p0396.indd 37801/03/19 6:54 PM 379TRANSPLANTATIONCHAPTER 11donor pancreas and its transportation to a specialized islet iso-lation facility, where the pancreas is enzymatically digested; then, the islets are purified from the rest of the digested pan-creas using density gradients. The purified islets are then cul-tured and evaluated for their identity, viability, and potency, before being infused into the portal vein of a diabetic recipient. When the procedure is successful, these islet cells engraft into the recipient and secrete insulin, providing excellent moment-to-moment control of blood glucose, as is seen with a whole-pancreas transplant.A successful islet transplant offers advantages over exog-enous insulin injections—advantages that are similar to those of a whole-pancreas transplant. These advantages include restor-ing β-cell secretory capacity, improving glucose counterregula-tion, restoring hypoglycemia awareness, providing perfect or near-perfect glucose homeostasis, and, potentially, preventing secondary diabetic complications.Unlike a whole-pancreas transplant, an islet transplant does not involve a major surgical procedure with its associated mortality and morbidity. Instead, it can generally be performed as an outpatient procedure using percutaneous catheter-based therapy to cannulate a branch of the portal vein, with minimal recovery time for the recipient. Potential complications associ-ated with islet injection include portal hypertension, portal vein thrombosis, hepatic abscesses, and bacteremia. Theoretically, islet transplants could have wider application (as compared with current practice and with whole-pancreas transplants), given the significantly lower surgical risk, the relatively small tissue vol-ume transplanted, and the potential for islet immunomodula-tion or immunoisolation, which could minimize or eliminate the need for immunosuppression.The first reported attempt at an islet transplant was in 1893 by Watson-Williams and Harsant: they transplanted a sheep’s minced pancreas into the subcutaneous tissue of a young boy with ketoacidosis.105 The discovery of insulin may have reduced interest in islet transplants as a treatment for diabetes, at least until the realization that insulin could not provide perfect glyce-mic control and that, therefore, patients ultimately suffered dev-astating secondary complications. Several milestones ensued: the first whole-pancreas transplants,106 early success with rodent islet transplants,107 and then, in the 1970s, human islet autotrans-plants after pancreatectomy, in order to address the intractable pain associated with chronic pancreatitis, by Sutherland, Najarian, and colleagues in Minnesota.108Until recently, attempts to extend those trailblazing find-ings of clinical islet autotransplants to clinical islet allotrans-plants in patients with type 1 diabetes met with generally very poor success. For example, in 1995, a report of the International Islet Transplant Registry indicated that of 270 recipients, only 5% were insulin-independent at 1 year posttransplant.In 2000, Shapiro and colleagues reported the results of the Edmonton protocol, which enabled consistent diabetes rever-sal and short-term (<1 year) insulin independence.109-111 The Edmonton protocol prescribed transplanting a large number of freshly isolated islets (>10,000 islet equivalents per kilogram body weight, typically requiring the use of two to four pan-creases) with a specialized “islet-sparing,” steroid-free immu-nosuppressive protocol consisting of low-dose tacrolimus, sirolimus, and IL-2 receptor antibody induction. Those results were replicated at other experienced transplant centers,112,113 but the rates of long-term (>5 year) insulin independence remained poor, well below those of whole-pancreas transplants.114 Still, despite the low rates of long-term insulin independence, most islet recipients were C-peptide positive and retained hypoglycemia awareness, indicating residual islet function and benefit. In fact, at 9 years posttransplant, 15% remained insulin-independent, and 73% had hypoglycemia awareness and corrected hemoglo-bin A1c levels.115In the mid-2000s, new trials began with the goal of estab-lishing protocols that enable insulin independence, using islets from a single donor pancreas; the results were good, especially with strict donor and recipient selection.116,117 In the most expe-rienced centers, long-term rates of diabetes reversal are now about 50% at 5 years posttransplant. The reasons include refine-ments in pancreas preservation, islet isolation, and culture pro-tocols, as well as the use of newer induction immunosuppressive agent combinations, such as a T-cell–depleting antibody (anti-CD3 antibody, alemtuzumab, or antithymocyte globulin) and a tumor necrosis factor-alpha (TNF-α) inhibitor (etanercept or infliximab). Presumably, viable β-cell mass is now preserved, both preand posttransplant.116-120 Thus, islet transplant results are approaching those of whole-pancreas transplants; however, because islets from more than one pancreas are typically needed, those results cannot be directly compared with the results of whole-pancreas transplants.121,122In the United States, an islet transplant is still officially deemed an experimental procedure. In contrast, since 2001, it has been considered a standard of care and is fully reimbursed in Canada and, more recently, in the United Kingdom, Sweden, Switzerland, France, and Italy as well.118 The full potential of islet transplants remains to be realized, but the future is excit-ing. As the latest improvements in pancreas preservation, islet isolation and purification, islet culture, and islet immunoiso-lation are implemented clinically, the hope is that sustained insulin independence may become consistently possible with a single pancreas donor and without the need for systemic immunosuppression.LIVER TRANSPLANTATIONThe first attempts at liver transplants in the late 1960s through the 1980s were largely experimental endeavors, with a 1-year survival rate of only 30%. But breakthroughs in immunosup-pression, surgical technique, organ preservation, anesthesia, and critical care have improved that rate to approximately 85% today. Liver transplants remain daunting, especially in the face of an organ shortage that results in sicker potential candidates. Unfortunately, the perioperative mortality rate and the 1-year mortality rate are among the highest of any surgical operation currently performed.HistoryThe first experimental liver transplants in dogs are often attrib-uted to C. Stuart Welch in 1955 and then Jack Cannon in 1956. However, current scholarship reveals that Vittorio Staudacher first described the technique in 1952.123 A series of canine experiments followed, which refined the surgical technique to ensure perioperative survival.The next obstacle—immunologic rejection—was addressed by drug immunosuppression with AZA and predni-sone. The first human liver transplant trials started in 1963 with Thomas Starzl, but a series of deaths led to a voluntary morato-rium for 3.5 years. With the resumption of clinical transplants in 1967, Starzl performed the first successful liver transplant. Brunicardi_Ch11_p0355-p0396.indd 37901/03/19 6:54 PM 380BASIC CONSIDERATIONSPART IStill, for the next decade, survival rates were dismal: only 20% of the 170 liver transplant recipients in Starzl’s program at the University of Colorado survived more than 5 years.124Several innovations dramatically improved outcomes. The advent of better immunosuppressive drugs was instrumental. In 1978, cyclosporine was introduced clinically in England. It was soon combined with prednisone to great effect. The arrival of tacrolimus in the 1990s further improved graft survival.Technical advances were also significant. Donor procure-ment techniques and cold organ preservation protocols were standardized, and the recipient operation was also refined. Choledochocholedochostomy or choledochojejunostomy to a Roux-en-Y limb became standard and significantly decreased the frequency of biliary complications. Innovations, including living donor liver transplants and deceased donor split-liver transplants, enabled more pediatric recipients to be transplanted. Improvements in portosystemic shunting and perioperative criti-cal care also were contributory.IndicationsIn general, any form of irreversible liver disease is an indication for a liver transplant. Chronic alcoholic disease and HCV are the most common indications in the United States. An extensive list of acute and chronic diseases of the liver that are treatable by a liver transplant is provided in Table 11-6.Offering transplants to alcoholic patients has always drawn some opposition because of the perception of it being a self-inflicted illness, as well as concerns about recidivism and the recipient’s possible inability to maintain postoperative immunosuppression and care. Yet studies have shown that such patients have excellent outcomes and that liver transplants for Table 11-6Diseases amenable to treatment by a liver transplantAutoimmune liver diseases Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitisCongenital Biliary atresiaViral hepatitis Hepatitis B Hepatitis CAlcoholic liver diseaseMetabolic diseases α1-Antitrypsin deficiency Cystic fibrosis Hemochromatosis Tyrosinemia Wilson’s diseaseHepatic malignancy Hepatocellular carcinoma Neuroendocrine tumor metastatic to liverFulminant hepatic failureOther Alagille syndrome Cryptogenic cirrhosis Budd-Chiari syndrome Polycystic liver disease Amyloidosisthem are cost-effective.125-127 Because patients who drink 4 to 8 ounces of liquor daily for 10 to 15 years have an increased risk of developing cirrhosis, the general requirement for accep-tance as a transplant candidate is 6 months of abstinence. Fur-thermore, most transplant centers recommend rehabilitation and Alcoholics Anonymous programs.Transplants for HCV have yielded worse outcomes than transplants for other diseases.128 The reason is the universal recurrence of the virus posttransplant. Viral levels reach pre-transplant levels as early as 72 hours posttransplant.129 The course of the viral infection is often accelerated posttransplant: 10% to 20% of recipients develop cirrhosis after just 5 years.130 Studies have suggested that use of older donors may increase the chance of aggressive recurrence.131 The best method to prevent recurrence would be to eradicate the infection pretransplant, but doing so is not always possible because patients with decom-pensated cirrhosis often cannot tolerate treatment. Once recur-rence occurs, treatment methods are limited. One study found that pegylated interferon and ribavirin therapy achieved a sus-tained viral response in 44% of patients.132A substantial number of patients undergo liver transplants for cholestatic disorders. Primary biliary cirrhosis, an autoim-mune disease, is characterized by damage to the intralobular bile ducts that progresses to liver cirrhosis. Trends toward earlier treatment may explain the slight decrease in liver transplants for this disorder.133 Posttransplant outcomes in patients with this disorder have been excellent, with many centers achieving 1-year survival rates of 90% to 95%. Recurrence is relatively uncommon: a large series reported a 30% recurrence rate at 10 years posttransplant.134The second most common cholestatic disorder among liver transplant candidates is primary sclerosing cholangitis. It is characterized by inflammation and fibrosis of large intraand extrahepatic biliary ducts; 70% of such patients also have inflammatory bowel disease. Recurrent cholangitis is common and increases mortality rates beyond what would be expected on the basis of laboratory values. On behalf of such patients, appeals can often be made for priority in allocation to the UNOS regional review boards. Posttransplant outcomes for such patients have been excellent. Primary sclerosing cholangitis is a significant risk factor for cholangiocarcinoma, so annual screen-ings (including imaging and measurement of serum CA 19-9 levels) should be carried out. Recurrence is fairly uncommon: studies have reported a recurrence rate of up to 20% at 10 years posttransplant.135Progressive metabolic disorders also are treatable with liver transplants. Hemochromatosis, an inherited disorder, results in excessive intestinal iron absorption. Iron deposition can cause cirrhosis and severe cardiomyopathy. Careful cardiac evaluation is necessary pretransplant.Another metabolic disorder, α1-antitrypsin deficiency, is characterized by insufficient levels of a protease inhibitor, resulting in early-onset emphysema and cirrhosis. Careful pul-monary evaluation is necessary pretransplant.Wilson’s disease, an autosomal recessive disorder char-acterized by impaired cellular copper transport, leads to cop-per accumulation in the liver, brain, and cornea. Patients can develop significant neurologic complications and cirrhosis. Several reports suggest improvement of neurologic deficiencies posttransplant.136,137Transplants can also be performed in patients with hepatic malignancies, but only in accordance with strict criteria. Brunicardi_Ch11_p0355-p0396.indd 38001/03/19 6:54 PM 381TRANSPLANTATIONCHAPTER 11Hepatocellular carcinoma (HCC), a complication of cirrhosis, is the most common type of hepatic malignancy. Resection is the first line of treatment if possible, but often, cirrhosis is too advanced. If the tumor meets the Milan criteria, a liver trans-plant can be performed. These criteria were established by a landmark paper in 1996 showing that patients with a single tumor under 5 cm in diameter, or with three tumors under 3 cm in diameter, in the absence of vascular invasion, had a 4-year survival rate of 85%.138 Patients with such tumors receive excep-tion points, based on their UNOS region, allowing for a timely transplant before their tumors spread.Transplants for cholangiocarcinoma remains controver-sial but may be performed if the center has an experimental protocol in place that entails strict recipient selection. The use of a multimodality oncologic approach including neoadjuvant chemo radiotherapy with subsequent OLT achieves excellent results for patients with localized, regional lymph node-negative phCCA. Patient survival after OLT is comparable to the results of OLT for other causes.139Acute fulminant hepatic failure also is an indication for a liver transplant; in fact, such patients are the highest priority for the next available liver in their UNOS region. This devas-tating illness is defined by acute and severe liver injury with impaired synthetic function and encephalopathy in a person who had normal liver function. It is often caused by acetaminophen overdose; acute fulminant viral hepatitis A, B, and E; other viral infections; drug toxicity; ingestion of Amanita mushrooms; acute fatty liver of pregnancy; or Wilson’s disease. A significant number of patients will recover with supportive care. The diffi-culty lies in predicting who will not recover and therefore would benefit from a liver transplant. The King’s College criteria were developed for this purpose: patients with acetaminophen-induced disease, a pH <7.3 or grade III/IV encephalopathy, a pro-thrombin time >100 seconds, and serum creatinine >3.4 mg/dL meet those criteria.140 Management of acute liver failure is very intensive. Such patients suffer from severe coagulopathy, hypoglycemia, lactic acidosis, and renal dysfunction. They are susceptible to infections, which are frequently overwhelming. Cerebral edema, a serious complication of acute liver failure, is a leading cause of death from brain herniation. Intracranial pressure monitoring and serial imaging are often necessary; if a patient develops irreversible brain damage, a transplant is not performed.Recipient SelectionThe diagnosis of cirrhosis itself is not an indication for a trans-plant. Patients may have compensated cirrhosis for years such that the traditional indication for a transplant is decompensated cirrhosis, manifested by hepatic encephalopathy, ascites, spon-taneous bacterial peritonitis, portal hypertensive bleeding, and hepatorenal syndrome (each described below).Hepatic encephalopathy is an altered neuropsychiatric state caused by metabolic abnormalities resulting from liver failure. The early stages result in sleep disturbances and depression. As the liver disease progresses, patients can become somnolent and confused and, in the end stages, comatose. Ammonia is pro-duced by enterocytes from glutamine and from colonic bacterial catabolism, and the use of serum ammonia levels as a marker of encephalopathy is controversial because a variety of factors can influence levels. Hyperammonemia suggests worsening liver function and bypass of portal blood flow around the liver. GI bleeding and infection can exacerbate hepatic encephalopathy.Ascites (the accumulation of fluid in the abdominal cavity) that is caused by cirrhosis is a transudate with a high serum-ascites gradient (>1.1 g/dL). Associated with portal hypertension, it is treated initially with sodium restriction and diuretics. Refractory ascites necessitates large-volume paracentesis and eventually a transjugular intrahepatic portosystemic shunt (TIPS). Contrain-dications to TIPS placement include significant hepatic enceph-alopathy, advanced liver disease, congestive heart failure, renal insufficiency, and severe pulmonary hypertension.141Spontaneous bacterial peritonitis, an infection of the ascitic fluid without an evident intra-abdominal source, is char-acterized by fever, abdominal pain, and an ascitic fluid poly-morphonuclear count ≥250 cell/mm3 on paracentesis. The first line of empiric treatment is with a third-generation cephalospo-rin because the majority of cases are caused by aerobic gram-negative microbes such as E. coli, although Gram stain and culture results should be used to guide therapy.Portal hypertensive bleeding can be a devastating event for patients with cirrhosis. Each bleeding event carries a 30% mortality rate and accounts for a third of all deaths related to cirrhosis. Only 50% of bleeding events cease spontaneously, so treatment must be expedient. The initial medical treatment is with vasopressin and octreotide. The initial intervention is endoscopy with sclerotherapy and band ligation of bleeding varices. If those initial attempts fail, more aggressive treatment is necessary with a balloon tamponade (using a Sengstaken-Blakemore tube) and with emergent TIPS placement. The last line of treatment is emergency surgery to place a portosystemic shunt, transect the esophagus, or devascularize the gastroesoph-ageal junction (Sugiura procedure). Preventing variceal bleed-ing is essential and can be achieved, with some success, using β-blockers.Hepatorenal syndrome is a form of acute renal failure that develops as liver disease worsens. The etiology is unclear, but splanchnic vasodilation from portal hypertension and increased production of circulating vasodilators result in a decline in renal perfusion. Characterized by oliguria (<500 mL of urine/day) and low urine sodium levels (<10 mEq/L), hepatorenal syndrome is often reversed by a liver transplant, even after dialysis depen-dence. Pretransplant, other causes of renal failure need to be excluded, including ATN, drug nephrotoxicity, and chronic renal disease. The initial medical therapy includes octreotide, midodrine, and vasopressin analogs, but the syndrome often progresses to dialysis dependence.The Model for End-Stage Liver Disease (MELD) was originally developed to assess risk for TIPS placement.142 Later analysis revealed it to be an excellent model to predict survival among patients with cirrhosis, especially those on the waiting list for a liver transplant.143 In 2002, liver graft allocation was restructured to be based on the MELD score.Although the historic indication for a liver transplant is decompensated cirrhosis, a landmark analysis comparing wait-ing list mortality with posttransplant mortality established that a minimum MELD score of 18 is necessary to have a survival benefit posttransplant. A MELD score between 15 and 18 does not confer a survival advantage, but a transplant may be justified if the patient has significant morbidity from cirrhosis.144Acute liver failure itself is an indication for a liver trans-plant. To qualify for Status 1 (first priority for a donor liver within the UNOS region), the transplant candidate must meet the following criteria: (a) onset of hepatic encephalopa-thy within 8 weeks after the first symptoms of liver disease; Brunicardi_Ch11_p0355-p0396.indd 38101/03/19 6:54 PM 382BASIC CONSIDERATIONSPART I(b) absence of preexisting liver disease; and (c) ventilator depen-dence, dialysis, or an international normalized ratio (INR) >2.0.ContraindicationsIn general terms, contraindications to a liver transplant include insufficient cardiopulmonary reserve, uncontrolled malignancy or infection, and refractory noncompliance. Older age is only a relative contraindication: carefully selected recipients over the age of 70 years can achieve satisfactory outcomes.145Patients with reduced cardiopulmonary reserve are unlikely to survive a liver transplant. Candidates should have a normal ejection fraction. If coronary arterial disease is pres-ent, they should undergo revascularization pretransplant. Severe chronic obstructive pulmonary disease (COPD) with oxygen dependence is a contraindication. Severe pulmonary hyper-tension with a mean pulmonary artery pressure greater than 35 mmHg that is refractory to medical therapy is also a contra-indication. Candidates with pulmonary hypertension should be evaluated with a right heart catheterization.For candidates with alcoholic liver disease, few reliable predictors of posttransplant relapse exist.146 Most centers require 6 months of abstinence from drugs and alcohol. Insurance com-panies often make more stringent demands, including random drug screening and 1 year of abstinence.Uncontrolled infections pretransplant are a substantial risk posttransplant when the patient becomes significantly immuno-suppressed. Fungal and multidrug-resistant bacterial infections are relative contraindications. Some centers require an extended period of treatment and documented eradication pretransplant. HIV infection is a relative contraindication; some centers have strict protocols that exclude patients with a history of acquired immunodeficiency syndrome (AIDS)-related illnesses as well as those who are coinfected with HCV.Ideally, patients with a history of malignancy (with the exception of HCC) should be cured of the cancer pretransplant. In most cases, this means eradication, completion of curative therapy, and absence of recurrence over a certain period of time, which varies by the tumor type, but can be up to 5 years or lon-ger for aggressive tumors (see “Malignancies”).Surgical ProcedureA liver transplant is among the most extensive operations per-formed, and it can be associated with considerable blood loss. A bilateral subcostal incision with midline extension is used. Mechanical retraction spreads the rib cage to allow access. The ligamentous attachments of the liver are dissected free. The vascular structures are isolated, including the suprahepatic and infrahepatic vena cava, the portal vein, and hepatic artery (Fig. 11-15). The bile duct, portal structures, and vena cava are divided, completing the hepatectomy (Fig. 11-16)—often the bloodiest and most difficult part of the operation, particularly in the presence of extensive varices and severe coagulopathy.After the liver is removed, the anhepatic phase begins. This phase is characterized by the absence of inferior vena caval return to the heart and by portal congestion due to clamp-ing of the portal vein. Significant hemodynamic instability and increased variceal bleeding can occur. Patients who are unable to tolerate this phase can be placed on venovenous bypass, with cannulas drawing blood from the IVC via the femoral vein and via the portal vein, returning it to the systemic circulation via the subclavian vein. Venovenous bypass itself can cause complica-tions, including air embolism, thromboembolism, and trauma to the cannulated vessels.Figure 11-15. Cirrhotic liver immobilized in preparation for com-plete hepatectomy.Figure 11-16. Isolation and division of the hilar structures to dis-eased liver-hepatic artery, portal vein, and common bile duct.The donor liver is placed in the orthotopic position. The suprahepatic vena caval anastomosis is performed first in an end-to-end fashion, followed by the infrahepatic vena caval and portal anastomosis, both also end-to-end. The liver is then reper-fused, often leading to a period of hemodynamic instability and cardiac arrhythmias due to the release of byproducts of ischemia from the donor liver. Coagulopathy also can worsen because of these byproducts as well as fibrinolysis.The arterial anastomosis between the donor common hepatic or celiac trunk is most often performed with the recipi-ent CHA in an end-to-end fashion. Of course, many variations are possible. After arterial reperfusion, the bile duct anastomosis is performed between the donor and recipient common ducts, also in an end-to-end fashion. If necessary for technical reasons, the recipient common duct can be joined to a Roux-en-Y limb. Some surgeons choose to insert a T-tube or place internal stents in the common bile duct to protect the anastomosis.The piggyback technique is a common variation of the standard technique. The recipient’s IVC is preserved by care-fully dissecting off the posterior aspect of the liver. This added dissection is a disadvantage of this variation, often increas-ing hepatectomy time and blood loss. The recipient’s liver is Brunicardi_Ch11_p0355-p0396.indd 38201/03/19 6:55 PM 383TRANSPLANTATIONCHAPTER 11removed by dividing it at the confluence of the hepatic veins. The preserved IVC is an advantage of this variation, allow-ing venous return from the lower body to the heart during the anhepatic phase and improving renal perfusion. No randomized studies, however, have demonstrated the superiority of the pig-gyback technique over the standard technique.Pediatric TransplantsOutcomes after pediatric liver transplants are among the best after any type of transplant, with a 1-year survival rate of 90%. The most common indication is biliary atresia. After diagno-sis is confirmed, a Kasai procedure is promptly carried out: a Roux-en-Y loop of bowel is directly anastomosed to the hilum of the liver. The Kasai procedure often allows time for the chil-dren to grow in size, reducing the risk of a transplant when it is required, as it eventually is in 75% of such children.The other common indication for a pediatric liver trans-plant is a metabolic disorder, such as α1-antitrypsin deficiency, tyrosine metabolism deficiencies, and primary oxalosis. Since the MELD score was developed for adults, pediatric liver allo-cation is based on an analogous model, the Pediatric End-Stage Liver Disease (PELD) score, which incorporates bilirubin lev-els, INR, albumin levels, age, and growth failure.The surgical procedure is similar to the adult procedure. Graft implantation is more challenging, given the pediatric recipient’s smaller vascular structures. As a result, surgical complications are much more common in pediatric recipients. Hepatic artery thrombosis is about three times more common. Donor size matching is very important in the pediatric popula-tion and often limits the donor pool for pediatric recipients. To address this issue, deceased donor split-liver transplants and liv-ing donor transplants (both described in the following sections) have been developed.Deceased Donor Split-Liver TransplantsA deceased donor allograft can be split into two grafts, most frequently into a left lateral segment for a child and an extended right segment for an adult (Fig. 11-17). It can be done in vivo (during the donor operation) or ex vivo (on the back table after the donor liver is removed). Both techniques have simi-lar outcomes. Increased morbidity is associated with splitting allografts, whether for adult or pediatric recipients; however, the technique is justified given the donor shortage and has been important for improving access to transplants for pediatric recipients.147Living Donor TransplantsDonation by an adult living donor to an adult recipient requires either the right or left lobe of the liver (Fig. 11-18). Donation by an adult living donor to a pediatric recipient requires the left lateral lobe (Fig. 11-19). Donor safety is paramount. The over-all donor mortality rate after donation was 0.4%, and the over-all complication rate was 40%, with multiple complications occurring in 19% of the patients. The rate of serious complica-tions resulting in lasting disability was 1.1%, with liver failure or death in 0.4%148 Careful donor selection is vital. Potential donors should be medically and psychologically healthy, their hepatic anatomy should be amenable to donation, and absolutely no coercion can occur. A separate donor team should serve as the donor advocate and thoroughly explain all risks.Careful recipient selection is essential. Transplant can-didates also must qualify for a deceased donor liver trans-plant because a significant number of living donor transplant DonorLeft hepatic veinLeft portal veinLeft hepatic arteryRecipientHepatic arteryPortal veinRoux limbFigure 11-17. Donor and recipient procedure for living donor liver transplant into a pediatric recipient.recipients will eventually require a retransplant. Transplant can-didates should be medically fit enough to withstand the rigors of the operation and of the postoperative course with a partial graft. An absolute contraindication is a critical illness: the limited suc-cess of such transplants does not justify the risks to the living donor. The obvious advantages of a living donor transplant are that it can be done expediently (avoiding the waiting list mortal-ity associated with candidates for a deceased donor transplant) and that it can be planned.Postoperative CareA liver transplant imposes significant trauma on the major organ systems. Immediately posttransplant, the first goal is to stabi-lize those systems. Acid-base equilibrium and hemodynamic stability are often difficult to maintain but are essential. Periods of hypotension can increase the risk of hepatic artery throm-bosis. Careful attention needs to be paid to ongoing bleeding. Appropriate hemoglobin levels should be maintained. Ongoing bleeding mandates a return trip to the operating room; the rate of reoperation can be as high as 25% among high-risk patients. Transfusion of platelets and fresh frozen plaza must be done prudently because theoretically their administration can increase the risk of hepatic artery thrombosis. Graft function should be evaluated frequently; if it is impaired, an ultrasound is urgently required to assess for the presence of vascular complications.Brunicardi_Ch11_p0355-p0396.indd 38301/03/19 6:55 PM 384BASIC CONSIDERATIONSPART ICHARHVMPVMHVLHVLHVS4S2FLS3IVCIVCLHVRHVMHVLHDLHALPVMPVPHACBDR.P.V.R.P.A.RHDC.A.C.D.ABFigure 11-18. A. Hepatic transection completed for right lobe removal. CA = cystic artery; CBD = common bile duct; CD = cystic duct; FL = falciform ligament; IVC = inferior vena cava; LHD = left hepatic duct; LHV= left hepatic vein; MHV = middle hepatic vein; MPV = main portal vein; PHA = proper hepatic artery; RHA = right hepatic artery; RHV = right hepatic vein; RPV = right portal vein; S2, S3, S4 = segments 2, 3, and 4. B. Implantation of the donor right lobe with the MHV. CHA = common hepatic artery. (Reproduced with permission from Gruessner RWG, Benedetti E: Living Donor Organ Transplantation. New York, NY: McGraw-Hill Education; 2008.)Evaluation of Graft FunctionEvaluation of the graft begins in the operating room. Its appearance overall, any swelling, and the quantity and quality of bile production after reperfusion can help assess function. In the intensive care unit, hemodynamic stability, correc-tion of coagulopathy, euglycemia, successful temperature regulation, clearance of lactic acid, and restoration of neuro-logic status are all signs of a functioning graft, even before the first set of liver function test results are obtained. Trans-aminases usually peak by postoperative day 2. An aspartate transaminase (AST) level greater than 2500 IU/L is sugges-tive of significant injury. Cholestasis usually peaks from Brunicardi_Ch11_p0355-p0396.indd 38401/03/19 6:55 PM 385TRANSPLANTATIONCHAPTER 11Figure 11-19. A. Hepatic transection completed for removal of left lateral segments (S2 and S3). Bile ducts to segments 2 and 3 divided; vascular structures still intact. B. Implantation of the donor left lobe. (Reproduced with permission from Gruessner RWG, Benedetti E: Living Donor Organ Transplantation. New York, NY: McGraw-Hill Education; 2008.)S2 + 3ABpostoperative day 7 to 12. The INR should improve shortly after reperfusion.In 3% to 4% of patients undergoing a liver transplant, the graft does not function for any identifiable reason, a condition termed primary nonfunction; in such cases, a retransplant is the only option. Some studies suggest that a peak AST level of 5000 IU/L may be predictive of primary nonfunction.149-151 Factors associated with primary nonfunction include donor macroste-atosis, prolonged cold and warm ischemic times, and prolonged donor hospital stay.151ComplicationsVascular complications occur in about 8% to 12% of recipi-ents and include thrombosis, stenosis, and pseudoaneurysm formation.The most common vascular complication is hepatic artery thrombosis. Initial reviews suggest that its incidence is between 1.6% and 4%152; the mortality rate is 50%, even after defini-tive therapy.153 Early presentation can be quite dramatic, with fulminant hepatic necrosis, primary nonfunction, transamini-tis, or fever. Late presentation, however, can be asymptom-atic or subtle, with cholangitis, bile leak, mild transaminitis, hepatic abscesses, or failure to thrive. Diagnostic imaging with ultrasound has more than 90% sensitivity and specificity. If hepatic artery thrombosis is identified, urgent reexploration is needed. A thrombectomy or revision of an anastomosis may be successful, but with significant hepatic necrosis, a retransplant is necessary.Thrombosis of the portal vein is very uncommon. Signs of early thrombosis include liver dysfunction, ascites, and variceal bleeding. Upon diagnosis, an operative thrombectomy should be attempted.Biliary complications remain the “Achilles’ heel” of liver transplantation, affecting 10% to 35% of these organ recipients. Signs include fever and abdominal pain, with bilious drainage from surgical drains. Diagnosis is made with cholangiography.Complications manifest themselves as leaks or strictures. Leaks require a reoperation and surgical correction, whereas strictures can most often be managed with radiologic or endo-scopic interventions. Two common reconstructions are cho-ledochostomy and choledochojejunostomy. Some centers also routinely use T-tube stents or internal stents. Consensus has not been reached as to which reconstruction technique is superior. Early infectious complications are often associated with initial graft function and pretransplant risk factors. Intra-abdominal infections should raise concerns of a possible bile leak. Fungal infections are often associated with poor graft function. Given the immunosuppressed and compromised state of liver recipi-ents, early infectious complications can be devastating.The types of opportunistic infections that occur in liver transplant recipients are similar to those that occur in other types of solid organ transplant recipients and are due to suppression of cell-mediated immunity by chronic immunosuppressive drug administration.Acute rejection occurs in approximately 20% of liver recipients. The first line of treatment is with a high dose of a corticosteroid, which is usually effective; if not, antilympho-cyte therapy is initiated. Rejection of the liver (unlike other transplanted organs) does not adversely affect patient or graft survival rates. Maintenance immunosuppression consists of a corticosteroid, tacrolimus, and mycophenolate.INTESTINE AND MULTIVISCERAL TRANSPLANTATIONAfter the introduction of long-term total parenteral nutrition (TPN) in the late 1970s and the early success of liver, kidney, and heart transplants, the first attempts at intestine transplants were made. Over the first two decades, the results were dismal. But the introduction of the immunosuppressive drug tacrolimus in the late 1980s led to significant improvement in graft and patient survival rates. Nonetheless, intestine transplants remain the least frequently performed of all transplants, with the lowest graft survival rates.The main obstacle is the high immunogenicity of the intestine, caused by its abundant lymphoid tissue. High lev-els of immunosuppression are needed, yet the rejection rate is still high. The microbial colonization of the intestine confers the risk of translocation of pathogenic microorganisms into the recipient’s circulation, causing severe systemic infections. Through the first decade of the 21st century, the survival of patients on long-term TPN was superior to the survival of intes-tine transplant recipients, so a transplant was considered only as rescue therapy for patients with life-threatening TPN-related complications.Brunicardi_Ch11_p0355-p0396.indd 38501/03/19 6:55 PM 386BASIC CONSIDERATIONSPART IOver the last several years, improvements in surgical tech-niques, in perioperative and postoperative care, and particularly in immunosuppressive protocols have led to significantly bet-ter patient and graft survival rates posttransplant.154 Recent data indicate that survival rates after an intestine transplant often are better than, or at least similar to, survival rates among patients receiving chronic TPN in the home setting with improved qual-ity of life in selected patients.155 Today, an intestine or multivis-ceral transplant is recognized as a feasible treatment.Indications and Recipient SelectionAn intestine transplant is indicated for patients with irreversible intestine failure in combination with TPN failure. The defini-tion of intestine failure does not specify the exact length of the remaining intestine. Intestine failure is typically multifactorial. Variables include what part of the small intestine is absent, whether or not the ileocecal valve is present, whether or not the patient underwent an ostomy, and how long the remaining colon is. TPN failure is defined as significant biochemical or pathologic evidence of liver injury, loss of central vein access with thrombosis of at least two central veins, frequent indwell-ing catheter infection or a single episode of fungal infection, and recurrent episodes of severe dehydration despite IV fluid supplementation.Indications for a transplant differ between the adult and pediatric population. The leading causes of intestine failure are summarized in Table 11-7. The disease involvement of organs other than the intestine dictates the extent of the operation required. Liver failure is often seen in patients on long-term TPN. If pathologic or biochemical evidence of severe liver damage is combined with signs of portal hypertension, then a combined liver-intestine transplant is the treatment of choice. However, a multivisceral transplant (liver, pancreas, stomach, duodenum, and/or small intestine) might be necessary among children who suffer diffuse intestinal dysmotility syndromes and adults who develop diffuse portomesenteric thrombosis, extensive intra-abdominal desmoid disease encasing the main visceral vascular structures with concurrent short gut syndrome, or massive abdominal trauma.Table 11-7Leading causes of intestine failureCHILDRENADULTSGastroschisisVisceral ischemia secondary to SMA/SMV thrombosisMidgut volvulusCrohn’s diseaseIntestinal atresiaTraumaNecrotizing enterocolitisMesenteric desmoid tumorsMicrovillus involution diseaseRadiation enteritisHirschsprung’s diseaseMassive resection secondary to tumorsCrohn’s diseaseChronic intestinal pseudo-obstructionPseudo-obstructionAutoimmune enteropathySMA = superior mesenteric artery; SMV = superior mesenteric veinSurgical ProcedureFor both the donor and recipient surgery, the key decision is which organs will be transplanted.156 For an isolated intestine transplant, the blood supply is based on the arterial inflow from the SMA and on the venous outflow from the superior mesen-teric vein (SMV). Both vessels are isolated at the root of the mesentery.For a combined liver-intestine transplant, the blood supply is based on the arterial inflow from the celiac axis and SMA, which are procured en bloc with an aortic patch. The liver, duo-denum, pancreas, and small intestine—because of their close anatomic relationship—are procured en bloc. If the hepatoduo-denal ligament is left intact, no biliary reconstruction is neces-sary, which virtually eliminates the risk of postoperative biliary complications.157 Because the entire splanchnic system drains into the liver, venous drainage is achieved by anastomosis of the hepatic veins to the recipient’s vena cava.For both an isolated intestine transplant and a combined liver-intestine transplant, the proximal transection of the GI tract occurs at the first portion of the duodenum. For a multivisceral transplant, the stomach is part of the graft; hence, the transection of the GI tract occurs at the distal esophagus. Figures 11-20 to 11-22 show these three main types of transplants.The vast majority of intestine transplants use a deceased donor organ. However, advances in surgical techniques have made the use of living donors a feasible alternative for either an isolated intestine transplant or a combined liver-intestine transplant. With a living donor, the donor operation is slightly different: for an isolated intestine transplant, 150 to 200 cm of the donor’s ileum, on a vascular pedicle comprising the ileocolic artery and vein, are used158 (Fig. 11-23); for a combined liver-intestine transplant, performed almost exclusively for pediatric recipients, segments II and III of the donor’s liver are used, in addition to the intestine (Fig. 11-24).Figure 11-20. Isolated intestine transplant.Brunicardi_Ch11_p0355-p0396.indd 38601/03/19 6:55 PM 387TRANSPLANTATIONCHAPTER 11Figure 11-21. Combined liver-intestine transplant.Figure 11-22. Multivisceral transplant.ABFigure 11-23. A. Donor operation. About 180 to 200 cm of distal ileum on a vascular pedicle comprising the ileocolic artery and vein are removed. B. Recipient operation. The donor’s ileocolic artery and vein (or the terminal branches of the donor’s superior mesenteric artery and vein) are anastomosed end-to-side to the recipient’s infrarenal aorta and vena cava. (Reproduced with permission from Gruessner RWG, Benedetti E: Living Donor Organ Transplantation. New York, NY: McGraw-Hill Education; 2008.)Brunicardi_Ch11_p0355-p0396.indd 38701/03/19 6:55 PM 388BASIC CONSIDERATIONSPART IFigure 11-24. Recipient operation. For a combined living donor liver-intestine transplant in a pediatric recipient, liver segments 2 and 3 are implanted in standard fashion (the donor’s left hepatic vein to the recipient’s vena cava, the donor’s left hepatic artery to the recipient’s proper or common hepatic artery, the donor’s left portal vein branch to the recipient’s portal vein trunk). The donor’s ileocolic artery and vein are anastomosed to the recipient’s infra-renal aorta and cava. In the recipient, a duodenum-to-donor ileum anastomosis and a distal Bishop-Coop ileostomy are constructed to reestablish bowel continuity. A very short Roux-en-Y loop (10 to 20 cm) is anastomosed to the donor’s bile duct(s). (Reproduced with permission from Gruessner RWG, Benedetti E: Living Donor Organ Transplantation. New York, NY: McGraw-Hill Education; 2008.)Similarly, the recipient operation also varies by the organs transplanted. Generally, the recipient’s infrarenal aorta is used to achieve the arterial inflow to the graft. For an isolated intestine transplant, venous drainage is achieved via systemic or portomesenteric drainage; for a combined liver-intestine trans-plant or a multivisceral transplant, venous drainage is achieved via the hepatic veins. Systemic venous drainage, given its lesser technical difficulty, is preferred over portomesenteric drainage. The diversion of splanchnic flow into the systemic venous cir-culation can cause several metabolic abnormalities, but no hard evidence shows any negative impact clinically on the recipient.After the organs are perfused, the continuity of the recipi-ent’s GI tract is restored, which includes the placement of a gastrostomy or jejunostomy feeding tube and an ileostomy. In the early postoperative period, the ileostomy enables regular endoscopic surveillance and biopsy of the intestinal mucosa. Once the recipient recovers, the ileostomy can be taken down.The last, but often the most difficult, part of the recipi-ent operation is abdominal wall closure. It is especially challenging in intestine transplant recipients because they have usually undergone multiple previous procedures, resulting in many scars, ostomies, feeding tubes, and the loss of abdomi-nal domain. To provide sufficient coverage of the transplanted organs, the use of prosthetic mesh often is necessary.Postoperative CareInitial postoperative care for intestine transplant recipients does not significantly differ from that for other organ transplant recipients. In the intensive care unit, each recipient’s cardio-vascular, pulmonary, and renal function is closely monitored; aggressive resuscitation with fluid, electrolytes, and blood prod-ucts is performed. Broad-spectrum antibiotics are an integral component of care.Of all solid organ transplants, intestine transplants have the highest rate of rejection. With intestine transplants, no sero-logic marker of rejection is available, so frequent biopsies and histologic evaluation of the intestinal mucosa are of utmost importance. Rejection leads to structural damage of the intes-tinal mucosa. Translocation of endoluminal pathogens into the circulation can cause systemic infections.Thanks to the introduction of new immunosuppressive protocols, the rejection rates and the overall patient and graft survival rates have improved significantly. Variations between the protocols exist, but the general concept is to induce immu-nosuppression with polyclonal T-cell antibody and high doses of a corticosteroid, followed by maintenance doses of cortico-steroids and the calcineurin inhibitor tacrolimus.Immediately, posttransplant, recipients are maintained on TPN. Enteral nutrition is initiated as early as possible, but it is advanced very cautiously. It can take several weeks for the transplanted intestine to achieve structural integrity and func-tionality and for the recipient to tolerate the full strength of tube feeds.Despite all the recent advances, the complication rate posttransplant remains high. The most common complica-tions include intra-abdominal abscesses, enteric leaks, intra-abdominal sepsis, the need for a reoperation, graft thrombosis, life-threatening bleeding, and central line problems. Immuno-suppression-specific complications include rejection, PTLD, graft-versus-host disease (GVHD), infections, and malignan-cies. Tailoring the recipient’s immunosuppression plays a critical role in preventing these complications: a low level of immunosuppression leads to graft rejection, but too much con-fers a high risk of infectious complications, PTLD, and, less commonly, GVHD—all of which are associated with a signifi-cantly increased risk of graft failure and mortality.The long-term results of intestine transplants have improved significantly, even though they still remain inferior to the results of other abdominal organ transplants.159,160HEART AND LUNG TRANSPLANTATIONHistoryThe first successful heterotopic heart transplant, in an animal model, was performed by Carrel and Guthrie in 1905.161 Subse-quent progress with cardiopulmonary bypass and immunologic modulation facilitated the first successful adult human heart transplant, performed by Christiaan Barnard in 1967 in Cape Town, South Africa.162 However, it was Norman Shumway at Stanford who persisted with heart transplants, in the face of disappointing patient outcomes at a number of early centers. Brunicardi_Ch11_p0355-p0396.indd 38801/03/19 6:55 PM 389TRANSPLANTATIONCHAPTER 11Thanks to the diligence of Shumway and colleagues in perfect-ing heart transplant techniques, along with the development, by Caves, of endomyocardial biopsy as a method of allograft rejection surveillance, human heart transplants began to reap-pear in the 1980s as a viable solution to end-stage heart failure. By 1981, the introduction of cyclosporin A finally created the necessary clinical immunologic modulation necessary to make long-term survival of heart recipients a reality.161Lung transplants have a similar history. In the 1950s, Metras in France and Hardin and Kittle in the United States performed canine lung transplants, demonstrating that meticu-lous anastomotic technique could produce normal pulmonary pressures. Hardy performed the first human lung transplant in 1963, although the patient lived only 18 days. The first suc-cessful long-term lung transplant was performed in 1983 in Toronto. These early lung recipients, however, were plagued by infection, rejection, and, most significantly, bronchial anas-tomotic dehiscence. Cooper and colleagues soon determined that the high-dose corticosteroids used for immunosuppression were responsible for the frequent occurrence of dehiscence. The combination of high-dose corticosteroids and ischemic donor bronchi was deadly to lung recipients. Cooper, Morgan, and colleagues showed that the bronchial anastomosis could be pro-tected by wrapping it with a vascular omental pedicle, which not only provided neovascularity but also offered a buttress against any partial dehiscence.163Once cyclosporine became available for lung recipients, corticosteroid doses could be quickly tapered and stopped; cyclosporine poses no danger to the integrity of the bronchial anastomosis. In fact, the introduction of cyclosporine allowed the success of the first combined heart-lung transplant at Stanford in 1981 (after unsuccessful attempts by Cooley in 1969, Lillehei in 1970, and Barnard in 1981, all of whom used only high-dose corticosteroids for immunosuppression). The 1980s marked the start of the modern age of thoracic transplants.Heart TransplantsIndications. The most common diagnosis leading to a heart transplant is ischemic dilated cardiomyopathy, which stems from coronary artery disease, followed by idiopathic dilated myopathy and congenital heart disease. About 3000 patients are added to the waiting list each year.Evaluation. Pretransplant, both candidates and potential donors are evaluated to ensure their suitability for the procedure. Transplant candidates undergo echocardiography, right and left heart catheterization, evaluation for any undiagnosed malignan-cies, laboratory testing to assess the function of other organs (such as the liver, kidneys, and endocrine system), a dental examination, psychosocial evaluation, and appropriate screen-ing (such as mammography, colonoscopy, and prostate-specific antigen testing). Once the evaluation is complete, the selec-tion committee determines, at a multidisciplinary conference, whether or not a heart transplant is needed and is likely to be successful. Transplant candidates who meet all of the center’s criteria are added to the waiting list, according to the UNOS criteria, which are based on health status.Once a potential deceased donor is identified, the surgeon reviews the status report and screening examination results. The donor is initially matched to the recipient per the recipient’s status on the UNOS waiting list, the size match, and the blood type. Results of the donor’s serologic testing, echocardiography, chest X-ray, hemodynamic testing, and possibly coronary artery evaluation are assessed, in order to determine whether or not the donor’s heart can withstand up to 4 hours of cold ischemic time during procurement, transport, and surgery.Procedure. Heart transplants are most often performed ortho-topically (Fig. 11-25). The recipient’s native heart is removed, leaving the superior vena cava, the IVC, the left atrial cuff, the aorta, and the pulmonary artery in situ, in order to allow for anastomosis of the donor’s heart. Usually the left atrial cuff is anastomosed first, providing left heart inflow. Right heart inflow is achieved using a bicaval technique, by directly sew-ing the donor’s superior vena cava and IVC to the recipient’s venae cavae or by creating an anastomosis of the right atrium to a right atrial cuff. The donor’s main pulmonary artery is con-nected to the recipient’s pulmonary artery, and finally, the aortic anastomosis is completed (Fig. 11-26).Once the cross-clamp is removed, the heart is allowed to receive circulation from the recipient and begins to function normally. Inotropic support with isoproterenol, dobutamine, or epinephrine is often required for 3 to 5 days, in order to support recovery from the cold ischemia.164On rare occasions, a heterotopic or “piggyback” heart can be transplanted, leaving the native heart in place. But this sce-nario is becoming very uncommon with the increasing use of mechanical circulatory support for single-ventricle failure.Posttransplant Care. Patient survival rates for heart recipients differ slightly after primary transplants vs. retransplants. In 2016, 3209 heart transplants were performed in the United States. New, active listings increased 57% since 2005. Overall 1-year survival for patients who underwent heart transplant in 2009 to 2011 was 90.1%, 3-year survival was 83.5%, and 5-year Figure 11-25. A donor’s heart brought forward for anastomosis.Brunicardi_Ch11_p0355-p0396.indd 38901/03/19 6:55 PM 390BASIC CONSIDERATIONSPART IFigure 11-26. Suture lines for bicaval anastomosis (a), biatrial anastomosis (b), aortic anastomosis (c), and pulmonary artery anas-tomosis (d).aacbdsurvival was 78.3%, and the most common cause of death within the first year after transplant was infection.165 An increasing number of heart recipients have now survived more than 15 to 20 years with their first graft, especially those with no significant history of either cellular or antibody-mediated rejection.Heart recipients must be monitored for both early and late complications. Early complications include primary graft dys-function, acute cellular or antibody-mediated rejection, right heart failure secondary to pulmonary hypertension, and infec-tion. Hemodynamic values are monitored to assess early graft function; pharmacologic and sometimes mechanical support is instituted if needed.The goal of immunosuppression is to prevent rejection, which is assessed by immunosuppressive levels and, early on, by endomyocardial biopsy. Both T-cell–mediated (cellular) and B-cell–mediated (antibody-mediated) rejection are moni-tored. Most of the immunosuppression used is aimed at T cells; however, if the recipient has many preformed antibodies or develops donor-specific antibodies, other strategies (such as plasmapheresis or rituximab) are used to reduce the antibody load. Immunosuppressive regimens can vary by center, but most often consist of three categories of medications: a calcineurin inhibitor (usually tacrolimus or cyclosporine), an antiprolifera-tive agent (MMF or AZA), and a corticosteroid (prednisone). Other immunosuppressive agents can be used, depending on the needs of individual recipients.Recipients are also assessed for any infections, with visual inspection of wound healing and with monitoring of the com-plete blood count and cultures as needed. Other common early sequelae include drug-induced nephrotoxicity, glucose intoler-ance, hypertension, hyperlipidemia, osteoporosis, malignancies, and biliary disease.Late complications include acquired transplant vasculopa-thy, progressive renal failure, and, most commonly, malignan-cies, especially skin cancer and PTLD. Accelerated coronary artery disease is the third most common cause of death posttrans-plant (after infections and acute rejection) and the most common cause after the first year. Coronary artery disease can begin to develop as early as 1 year posttransplant. Its pathogenesis is unknown, but it is believed to be immunologic. Because of these late complications, most transplant centers continue to perform screening tests and recipient examinations at least annually after the first year.Lung TransplantsIndications. The indications for a lung transplant include congenital disease, emphysema, COPD, cystic fibrosis, idio-pathic pulmonary fibrosis, primary pulmonary hypertension, α1-antitrypsin deficiency, and the need for a retransplant after primary graft failure. Each year in the United States, about 1600 patients are added to the waiting list; nearly a third of them have COPD and/or emphysema. The next most common diagnosis among patients on the waiting list is cystic fibrosis. A lung allo-cation score (LAS) was instituted in 2005. The average lung transplant candidate requires oxygen (often 4 L/min or more at rest) and has an extensively compromised quality of life, as documented by the results of pulmonary function and 6-minute walk tests.Evaluation. Evaluation for a lung transplant is very similar to evaluation for a heart transplant, except that lung transplant candidates undergo more extensive pulmonary function testing, a 6-minute walk test, chest computed tomography, ventilation-perfusion (V-Q) scanning, and arterial blood gas assessment. In addition, all lung transplant candidates must have adequate cardiac function and must meet psychosocial requirements.Potential lung donors are also screened for blood type and size match. Larger lungs are accepted for COPD patients; smaller lungs are chosen for the restricted chest cavity of fibrotic patients. Donors should have a partial pressure of oxygen in arterial blood (Pao2) value >300 mmHg on a fraction of inspired oxygen (Fio2) of 100% and a positive end-expiratory pressure (PEEP) value of 5. Ideally, donors will have normal chest X-ray results, but exceptions for isolated abnormalities that will not affect subsequent graft function can be made. Living donors can donate a single lobe to a smaller recipient, such as a child. Single-lung transplants are common in many centers and can serve to increase the availability of lungs for multiple recipients. Newer concepts, such as “lung in the box” extracorporeal lung perfusion and stem cell technologies, may further improve the availability of donor lungs by optimizing the use of otherwise marginal grafts.Procedure. Lung transplants can be done either as (a) single-lung transplants (to either side via thoracotomy) or as (b) sequential bilateral-lung transplants (via bilateral thoracotomies or via a single clamshell incision that divides the sternum; Fig. 11-27). They can be done absent extracorporeal mechanical cardiopul-monary perfusion (bypass), with the lung with the worst func-tion (as predicted by preoperative ventilation and perfusion scanning) transplanted first. Despite careful surgical technique and excellent anesthesia, the poor pulmonary reserve of some lung recipients may require the institution of cardiopulmonary bypass to complete the transplant. Bypass is initiated through the chest by direct cardiac cannulation or peripherally via the femoral vessels.Once the thoracotomy is made, a recipient pneumonec-tomy is performed with care, in order to avoid injury to the phrenic or recurrent laryngeal nerves. The pulmonary veins and main pulmonary artery are encircled outside the peri-cardium. At this point, once the main pulmonary vessels are occluded, the need for cardiopulmonary bypass can be assessed. Brunicardi_Ch11_p0355-p0396.indd 39001/03/19 6:55 PM 391TRANSPLANTATIONCHAPTER 11Figure 11-27. Clamshell incision. Bronchial anastomosis with ligated pulmonary arteries and veins.Figure 11-28. Bronchial anastomosis.The vessels and bronchus are ligated; the donor’s lung is pre-pared and brought to the table wrapped in cold iced gauze, in order to extend the cold preservation time. The bronchial anas-tomosis (Fig. 11-28) is performed first and then covered with peribronchial tissue or pericardium. The pulmonary artery and, finally, the vein are anastomosed. The lung is then de-aired before the final anastomotic suture is tightened, with gentle lung insufflation. All clamps are removed, and the lung is aerated. At least two chest tubes are left in place. After the transplant is complete, a bronchoscopy is performed to clear the airway of blood and secretions.Posttransplant Care. Patient survival rates for lung recipients vary significantly after primary vs. redo transplants. After pri-mary transplants, the patient survival rates at 1, 3, and 5 years are 83%, 62%, and 46%, respectively; after retransplants, the rates are 64%, 38%, and 28%.Postoperative care of lung recipients can be very labor-intensive. These patients require meticulous ventilator manage-ment, in order to maintain Fio2 at a minimum and to keep Pao2 at 70 mmHg. Most patients are extubated within the first 24 to 48 hours. Recipients can require multiple bronchoscopies for both airway management and surveillance biopsies. Diuretics are used generously to counteract any positive fluid balance from the operation and to help with pulmonary recovery.Early complications include technical complications, graft dysfunction, infections, and rejection. Technical complications often involve stenosis of one or more anastomoses leading to graft dysfunction. Bronchoscopy, V-Q scanning, echocardiogra-phy, and radiologic imaging are useful in identifying the causes of graft dysfunction. In up to 20% of recipients, primary early graft dysfunction can occur with no obvious cause. Such dys-function may be due to some pathology from the donor, perhaps an unknown aspiration, infection, or contusion; or it could result from poor graft preservation at the time of organ procurement. In the intensive care unit, aggressive ventilator and pharmaco-logic management can help, but recipients can nonetheless prog-ress to the need for mechanical support in the form of ECMO. Infections are treated with appropriate antibiotics, which can be challenging in patients with cystic fibrosis and a history of multidrug-resistant organisms. Rejection is monitored by biop-sies and treated as needed.Late complications include airway complications, such as strictures and, rarely, dehiscence, bronchiolitis obliterans, and malignancies. Strictures are treated with bronchoscopic dilation and intervention. Bronchiolitis obliterans often is a sequela of chronic rejection, but can be due to aspiration, chronic infec-tions, or various other causes. In recipients with a progressive fall in their forced expiratory volume in 1 second (FEV1), bron-chiolitis obliterans is suspected. All recipients should be taught to perform microspirometry at home as a screening tool post-transplant. Biopsies are performed to confirm the diagnosis of any complication and, if possible, the cause. Despite aggres-sive screening and treatment, more than 50% of recipients will develop graft dysfunction. Most if not all of the sequelae of chronic immunosuppression that occur in lung transplant recipi-ents are similar to those occurring in other groups of solid organ transplants.Heart-Lung TransplantsEvery year in the United States, 30 to 50 patients are added to the list of patients waiting to receive a simultaneous heart-lung transplant. The most common diagnosis is idiopathic pulmo-nary fibrosis, followed by primary pulmonary hypertension. Heart-lung candidates are often younger than their single-organ counterparts. The patient survival rates at 1, 3, and 5 years are 66%, 48%, and 39%, respectively. Often, lung complications ultimately lead to graft failure. The immunosuppression is the same as that for single thoracic organ recipients, with emphasis on weaning the patient off corticosteroids as early as possible.XENOTRANSPLANTSXenotransplants (i.e., cross-species transplants of organs, tis-sues, or cells) have immense, yet untapped, potential to solve the critical shortage of available grafts. A primary hurdle is the formidable immunologic barrier between species, especially Brunicardi_Ch11_p0355-p0396.indd 39101/03/19 6:55 PM 392BASIC CONSIDERATIONSPART Iwith vascularized whole organs.161-170 Other problems include the potential risk of transmitting infections (known as zoono-ses or xenoses) and the ethical problems of using animals for widespread human transplants, even though great progress has been made in the past few years in efforts to overcome these problems.166-172Pigs are generally accepted as the most likely donor spe-cies for xenotransplants into human beings.173 Pigs would also be easier to raise on a large-scale basis. Guidelines for raising pigs in specialized facilities designated as pathogen-free have been established; in anticipation of clinical trials, such facilities have already been created and populated.171,172The immunologic barrier in pig-to-human xenotrans-plants is highly complex, but generally involves four subtypes of rejection.166 The first is hyperacute rejection (HAR), which is mediated by the presence of natural (preformed) xenoantibod-ies in humans. These antibodies bind to antigens found mainly on the vascular endothelial cells of porcine donor organs, lead-ing to complement activation, intravascular coagulation, and rapid graft ischemia soon after the transplant. The second sub-type is acute humoral xenograft rejection (AHXR), a delayed form of antibody-mediated rejection seen in pig-to-nonhuman-primate transplants after steps to prevent HAR—steps such as depletion of antipig antibodies or complement from nonhu-man primates’ serum. Alternative names for AHXR include acute vascular rejection or delayed xenograft rejection. The third subtype is an acute cellular rejection process (similar to the classic T-cell–mediated acute rejection seen in allograft recipients). The fourth subtype is chronic rejection in grafts that survive for more than a few weeks (similar to the chronic rejection seen in long-surviving allograft recipients, with fea-tures of chronic vasculopathy).Many different options are being tested to overcome this immunologic barrier, including the genetic engineering of pigs, the use of agents to inhibit platelet aggregation and complement activation, and the administration of powerful immunosuppres-sive drugs.166-173During the first decade of the 21st century, the field of whole-organ xenotransplantation progressed significantly, thanks to the increasing availability of genetically engineered pigs and new immunosuppressive protocols. At a recent sympo-sium organized by the International Xenotransplantation Asso-ciation, data presented demonstrated extended survival time of porcine solid organs in nonhuman primates: from about 30 days to an average of 60 days and even up to 250 days (depending on the model).166,169,174,175 However, clinical application is still limited by thrombotic microangiopathy and consumptive coagu-lopathy; novel methods to prevent those complications will be required for further progress.Cellular xenotransplants have made great strides and are currently in the early stages of clinical trials. Porcine islet xenotransplants are the most advanced form; five independent groups have now demonstrated survival and function of porcine islets in nonhuman primates for more than 100 days.166,175-181 For the clinical trials, cost-benefit models have been developed, and the regulatory framework has been established.170-172,178 One trial of particular interest involves transplanting encapsulated porcine islets without immunosuppression.179 Early results are encouraging. But the efficacy of that approach may be limited until further genetic engineering enables proper oxygenation and nourishment of islet grafts, thereby supporting their viabil-ity and function.The future of xenotransplantation is exciting. Continued active research will focus on further genetic engineering of pigs, newer immunosuppressive drugs, and tissue engineering approaches that will minimize or eliminate the need for immu-nosuppression. 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Shapiro AM, Ricordi C, Hering B. Edmonton’s islet suc-cess has indeed been replicated elsewhere. Lancet. 2003; 362(9391):1242. 113. Shapiro AM, Ricordi C, Hering Bj, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318-1330. 114. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005;54(7): 2060-2069. 115. McCall M, James Shapiro AM. Update on islet transplanta-tion. Cold Spring Harb Perspect Med. 2012;2(7):1-16. 116. Markmann JF, Deng S, Huang X, et al. Insulin independence following isolated islet transplantation and single islet infu-sions. Ann Surg. 2003;237(6):741-749. 117. Hering BJ, Kandaswamy R, Ansite JD, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 dia-betes. JAMA. 2005;293(7):830-835. 118. Shapiro AM. Strategies toward single-donor islets of Lang-erhans transplantation. Curr Opin Organ Transplant. 2011; 16(6):627-631. 119. Bellin MD, Kandaswamy R, Parkey J, et al. Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant. 2008;8(11):2463-2470. 120. Bellin MD, Barton FB, Heitman A, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant. 2012;12(6):1576-1583. 121. Rickels MR. Recovery of endocrine function after islet and pancreas transplantation. Curr Diabet Rep. 2012;12:587-596. 122. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35(7):1436-1445. 123. Busuttil RW, De Carlis LG, Mihaylov PV, Gridelli B, Fassati LR, Starzl TE. The first report of orthotopic liver trans-plantation in the Western world. Am J Transplant. 2012;12(6): 1385-1387. 124. Starzl TE, Demetris AJ, Trucco M, et al. Cell migra-tion and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology. 1993;17(6): 1127-1152. 125. Cohen C, Benjamin M. Alcoholics and liver transplantation. The Ethics and Social Impact Committee of the Transplant and Health Policy Center. JAMA. 1991;265(10):1299-1301. 126. Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transplant. 2011;17(7):751-759. 127. Longworth L, Young T, Buxton MJ, et al. Midterm cost-effectiveness of the liver transplantation program of England and Wales for three disease groups. Liver Transplant. 2003; 9(12):1295-1307. 128. Charlton M, Ruppert K, Belle SH, et al. Long-term results and modeling to predict outcomes in recipients with HCV infec-tion: results of the NIDDK liver transplantation database. Liver Transplant. 2004;10(9):1120-1130. 129. Garcia-Retortillo M, Forns X, Feliu A, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology. 2002;35(3):680-687. 130. Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrho-sis after liver transplantation. Hepatology. 2000;32(4 Pt 1): 852-858. 131. Lake JR, Shorr JS, Steffen BJ, Chu AH, Gordon RD, Wiesner RH. Differential effects of donor age in liver trans-plant recipients infected with hepatitis B, hepatitis C, and without viral hepatitis. Am J Transplant. 2005;5(3):549-557. 132. Neff GW, Montalbano M, O’Brien CB, et al. Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy. Transplantation. 2004;78(9):1303-1307. 133. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in primary biliary cirrhosis. Clin Gas-troenterol Hepatol. 2007;5(11):1313-1315. 134. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: ret-rospective analysis of 400 patients in a single center. Hepatol-ogy. 2001;33(1):22-27. 135. Campsen J, Zimmerman MA, Trotter JF, et al. Clinically recur-rent primary sclerosing cholangitis following liver transplanta-tion: a time course. Liver Transplant. 2008;14(2):181-185. 136. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson’s disease: indications and outcome. Hepatology. 1994;19(3):583-587. 137. Medici V, Mirante VG, Fassati LR, et al. Liver transplantation for Wilson’s disease: the burden of neurological and psychiat-ric disorders. Liver Transplant. 2005;11(9):1056-1063. 138. Mazzaferro V, Regalia E, Doci R, et al. Liver transplanta-tion for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-699. 139. Sapisochín G, Fernández de Sevilla E, Echeverri J, et al. Liver transplantation for cholangiocarcinoma: Current status and new insights. World J Hepatol. 2015;7(22):2396-2403. 140. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445. 141. Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology. 2010;51(1):306. 142. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470. 143. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124(1):91-96. 144. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transplant. 2005;5(2):307-313. 145. Safdar K, Neff GW, Montalbano M, et al. Liver transplant for the septuagenarians: importance of patient selection. Transplant Proc. 2004;36(5):1445-1448.Brunicardi_Ch11_p0355-p0396.indd 39501/03/19 6:55 PM 396BASIC CONSIDERATIONSPART I 146. Bellamy CO, DiMartini AM, Ruppert K, et al. Liver transplan-tation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence. Transplantation. 2001;72(4):619-626. 147. Vagefi PA, Parekh J, Ascher NL, Roberts JP, Freise CE. Out-comes with split liver transplantation in 106 recipients: the University of California, San Francisco, experience from 1993 to 2010. Arch Surg. 2011;146(9):1052-1059. 148. Abecassis MM, Fisher RA, Olthoff KM, et al. Complications of living donor hepatic lobectomy—a comprehensive report. Am J Transplant 2012;12:1208-1217. 149. Bilzer M, Gerbes AL. Preservation injury of the liver: mech-anisms and novel therapeutic strategies. J Hepatol. 2000; 32(3):508-515. 150. Jaeschke H. Preservation injury: mechanisms, prevention, and consequences. J Hepatol. 1996;25(5):774-780. 151. Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg. 2001;181(2):160-166. 152. Drazan K, Shaked A, Olthoff KM, et al. Etiology and man-agement of symptomatic adult hepatic artery thrombo-sis after orthotopic liver transplantation (OLT). Am Surg. 1996;62(3):237-240. 153. Tzakis AG, Gordon RD, Shaw BW, Jr., Iwatsuki S, Starzl TE. Clinical presentation of hepatic artery thrombosis after liver transplantation in the cyclosporine era. Transplantation. 1985;40(6):667-671. 154. Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the intestine transplant registry: a new era has dawned. Ann Surg. 2005;241(4):607-613. 155. Bharadwaj S, Tandon P, Gohel TD, et al. Current status of intestinal and multivisceral transplantation. Gastroenterol Rep. 2017;5(1):20-28. 156. Yersiz H, Renz JF, Hisatake GM, et al. Multivisceral and iso-lated intestinal procurement techniques. Liver Transplant. 2003;9(8):881-886. 157. Bueno J, Abu-Elmagd K, Mazariegos G, Madariaga J, Fung J, Reyes J. Composite liver–small bowel allografts with preser-vation of donor duodenum and hepatic biliary system in chil-dren. J Pediatr Surg. 2000;35(2):291-295; discussion 95-96. 158. Farmer DG, McDiarmid SV, Edelstein S, et al. Improved out-come after intestinal transplantation at a single institution over 12 years. Transplant Proc. 2004;36(2):303-304. 159. Tzakis AG, Kato T, Levi DM, et al. 100 multivisceral trans-plants at a single center. Ann Surg. 2005;242(4):480-490; dis-cussion 91-93. 160. Gruessner RWG, Sharp HL. Living related intestinal trans-plantation: first report of a standardized surgical tech-nique. Transplant. 1997;64:1605-1607. 161. Kouchoukos NT, Blackstone EH, Doty DB. Heart failure. In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds. Cardiac Surgery. 3rd ed. New York: Kirklin/Barratt-Boyes; 2003:1725. 162. First human heart transplant. The History Channel website. Available at: https://www.history.com/this-day-in-history/first-human-heart-transplant. Accessed May 8, 2018. 163. Meyers BF, Patterson GA, Haverich A, Harringer W. Lung transplantation, heart-lung transplantation. In: Pearson FG, Cooper JD, Deslauriers J, et al, eds. Thoracic Surgery. 2nd ed. New York: Churchill-Livingston; 2002:1085-1131. 164. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation guidelines for care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914-956. 165. Colvin M, Smith JM, Hadley N, et al. OPTN/SRTR 2016 annual data report: heart. Amer J Transplant. 2018;18(S1):291-362. 166. Esker B, Cooper DKC. Overcoming the barriers to xenotrans-plantation: prospects for the future. Exp Rev Clin Immunol. 2010;6(2):219-230. 167. Schuurman HJ. Xenotransplantation: from the lab to the clinic: Sunrise Symposium at the XXIII International Congress of the Transplantation Society, Vancouver, Canada, August 2010. Clin Transplant. 2011;25(4):E415-E421. 168. Dooldeniya MD, Warrens AN. Xenotransplantation: where are we today? J R Soc Med. 2003;96:111. 169. Thompson P, Badell IR, Lowe M, et al. Alternative immu-nomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am J Transplant. 2012;12(7):1765-1775. 170. Hering BJ, Cooper DKC, Cozzi E, et al. The International Xenotransplantation Association consensus statement on con-ditions for undertaking clinical trials of porcine islet products in type I diabetes: executive summary. Xenotransplantation. 2009;16:196-202. 171. Schuurman HJ. Regulatory aspects of pig-to-human islet transplantation. Xenotransplantation. 2008;15(2):116-120. 172. Schuurman HJ. The International Xenotransplantation Associ-ation consensus statement on conditions for undertaking clini-cal trials of porcine islet products in type 1 diabetes—chapter 2: Source pigs. Xenotransplantation. 2009;16(4):215-222. 173. Meier RPH, Muller YD, Balaphas A, et al. Xenotransplanta-tion: back to the future? Transplant Int. 2017; doi: 10.1111/tri.13104. 174. Greenstein JL, Schuurman H-J. Solid organ xenotransplantation: progress, promise, and regulatory issues. J Comm Biotech. 2001;8:15-29. 175. Thompson P, Badell IR, Lowe M, et al. Islet xenotransplanta-tion using gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011;11:2593-2602. 176. Rood PPM, Cooper DKC. Islet xenotransplantation: are we really ready for clinical trials? Am J Transplant. 2006; 6(6):1269-1274. 177. Mihalicz D, Rajotte R, Rayat G. Porcine islet xenotransplan-tation for the treatment of type I diabetes. In: Type I Diabetes: Pathogenesis, Genetics and Immunotherapy. New York: InTech; 2011:479-502. 178. Beckwith J, Nyman JA, Flanagan B, et al. A health-economic anal-ysis of porcine islet xenotransplantation. Xenotransplantation. 2010;17:233-242. 179. Elliot RB, Living Cell Technologies, Ltd. Towards xeno-transplantation of pig islets in the clinic. Curr Opin Organ Transplant. 2011;16(2):195-200. 180. Marigliano M, Bertera S, Grupillo M, et al. Pig-to-nonhuman primate pancreatic islet xenotransplantation: an overview. Curr Diab Rep. 2011;11(5):402-412. 181. Dufrane D, Gianello P. Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application. Transplant Rev (Orlando). 2012;26:183-188.Brunicardi_Ch11_p0355-p0396.indd 39601/03/19 6:55 PM errors, observing that 34% of patients with health problems in the United States report experiencing medical, medication, or test errors—the highest rate of any nation, and an analysis sug-gests that the problem of medical care gone wrong, i.e., medical errors including systems errors, may rank as the third leading cause of death in the United States.1Medical error is defined as an unintended act (either of omission or commission) or one that does not achieve its intended outcome, the failure of a planned action to be com-pleted as intended (an error of execution) or the use of a wrong plan to achieve an aim (an error of planning), and a deviation from the process of care, which may or may not cause harm to the patient. Medical error can occur at the individual provider level or at the system level. An expanding taxonomy is matur-ing to better categorize the types of factors and events that are avoidable. The role of error may be complex; error can some-times tragically end the life of a thriving person with a long life expectancy, or it can also accelerate an imminent death.The most commonly cited report on the incidence of deaths due to medical error, the 1999 Institute of Medicine (IOM) report, describes an incidence of 44,000 to 98,000 deaths annually.2 However, this estimate by the IOM was not based on primary research conducted by the IOM; rather, it was based on two older studies conducted in 1984 and 1992. Both studies were small and limited. In 2013, after compiling more recent evidence from multiple sources, James estimated an incidence range of 210,000 to 400,000 deaths a year associated with Quality, Patient Safety, Assessments of Care, and ComplicationsMartin A. Makary, Peter B. Angood, and Mark L. Shapiro 12chapterBackground 397Medical Care Gone Wrong / 397Unnecessary Medical Care / 398The Science of Patient Safety 399High Reliability Organizations / 399The Conceptual Model / 399Creating a Culture of Safety 400Assessing an Organization’s Safety Culture / 401Teamwork and Communication 402Measuring Teamwork / 402Communication Tools 402Operating Room Briefings (A Surgical Checklist) / 402Operating Room Debriefings / 403Sign Outs / 403Implementation / 403Comprehensive Unit-Based  Safety Program 404Measuring Quality in Surgery 405Practice Pattern Measures / 405Agency for Healthcare Research and Quality Patient Safety Indicators / 406The Surgical Care Improvement Project Measures / 406National Surgical Quality Improvement Program / 407The Leapfrog Group / 408World Health Organization “Safe Surgery Saves Lives” Initiative / 408National Quality Forum / 408“Never Events” in Surgery 409Retained Surgical Items / 409Surgical Counts / 410Wrong-Site Surgery / 411The Joint Commission Universal Protocol to Ensure Correct Surgery / 411Transparency in Healthcare 412Public Reporting and Patient Assessment of Care / 412Risk Management 413The Importance of Communication in Managing Risk / 413Complications 415Robotic Surgery / 415Complications in Minor Procedures / 415Organ System Complications / 418Wounds, Drains, and Infection / 424Nutritional and Metabolic Support Complications / 426Problems with Thermoregulation / 427BACKGROUNDPatient harm due to medical mistakes can be catastrophic, result-ing in high-profile consequences for the patient, surgeon, and institution. A single error can even destroy a surgeon’s career. While mistakes are inherent to human nature, it is becoming more recognized that many mistakes are preventable.Patient safety is a science that promotes the use of evi-dence-based medicine and local wisdom to minimize the impact of human error on quality patient care. Wrong-site/wrong-procedure surgeries, retained sponges, unchecked blood transfusions, mismatched organ transplants, and overlooked allergies are all examples of potentially catastrophic events that can be prevented by implementing safer hospital systems. This chapter provides an overview of the modern-day field of patient safety by reviewing key measures of safety and quality, compo-nents of culture, interventions and tools, assessment methods, risk management strategies, and a selected review of common complications in surgery.Medical Care Gone WrongToday, there are more medications, diagnoses, procedures, and handoffs performed than ever in the history of medicine. More-over, overtreatment is now an endemic problem in some areas of healthcare. With more medical care being delivered, there are naturally more opportunities for things to go wrong. In fact, harm may be associated with complexity. The Commonwealth Fund reported that the United States leads the world in medical 12Brunicardi_Ch12_p0397-p0432.indd 39720/02/19 3:57 PM 398Figure 12-1. Causes of death in the United States 2013. (Reproduced with permission from Makary MA, Daniel M. Medical error–the third leading cause of death in the US, BMJ. 2016 May 3;353:i2139.)Key Points1 Medical error ranks as the third leading cause of death in the United States when defined to include system errors.2 One form of medical error is unnecessary or excessive medi-cal care, which represents 21% of medical care administered in the United States.3 New peer-comparison metrics evaluate appropriateness of surgical care by measuring a physician’s practice pattern among all the physician’s patients benchmarked to the phy-sician’s peers.4 Judicious opioid prescribing upon discharge after surgery is critical given the magnitude of the opioid crisis.5 The structure-process-outcome framework within the context of an organization’s culture helps to clarify how risks and hazards embedded within the organization’s structure may potentially lead to error and injure or harm patients.6 Poor communication contributes to approximately 60% of the sentinel events reported to The Joint Commission.7 Operating room briefings are team discussions of critical issues and potential hazards that can improve the safety of the operation and have been shown to improve operating room culture and decrease operating room delays.8 National Quality Forum surgical “never events” include retained surgical items, wrong-site surgery, and death on the day of surgery of a normal healthy patient (American Soci-ety of Anesthesiologists Class 1).9 The most important determinant of malpractice claims against a surgeon is patient rapport, not undertesting.medical errors among hospital patients.3 Any point estimate in this range would rank the problem of dying from “medical care gone wrong” as the third leading cause of death in the United States. In caring for patients and considering the risks of tests and procedures done for borderline indications, it is important to consider the magnitude of the problem of patients dying from the care they receive rather than from the disease or injury that brought them to care.Human error is inevitable. But while we cannot eliminate human error, we can better measure the problem to design safer systems mitigating its frequency, visibility, and consequences. Hospitals should consider the magnitude of the problem of med-ical error as a barrier to achieving safe, highly-reliable medical care. Investigating errors to learn from them can guide local changes to prevent future events. The strategy to rein in the endemic problem of death from medical care should include three areas: (a) make errors less frequent (by following prin-ciples that take human limitations into account); (b) make errors more visible when they occur so that their effects can be intercepted; and (c) have remedies at hand when errors affect a patient. This multitier approach necessitates guidance from reliable data.Unnecessary Medical CareIncreasingly preventable complications and complications from unnecessary procedures are considered to be forms of medical error. Unnecessary medical care accounts for an estimated $210 billion in excess spending each year, according to the National Academy of Medicine. The issue represents a significant oppor-tunity to make improve patient safety and lower healthcare Causes of death, US, 2013Based on our estimate,medical error is the3rd most commoncause of death in the USMedicalerror251 kCancer585 kHeartdisease611 kCOPD149 kAll causes2,597 kMotorvehicles34 kFirearms34 kSuicide41 kBrunicardi_Ch12_p0397-p0432.indd 39820/02/19 3:57 PM 399QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12costs. In a Johns Hopkins study, surveying over 2000 physicians in the United States, unnecessary medical care was reported to be common.4 On average, these authors reported that 21% of medical care is unnecessary. Breaking the problem down by type of medical care, the doctors reported that 22% of prescription medications, 25% of medical tests, and 11% of procedures are unnecessary. These perceptions by U.S. physi-cians validate previous estimates of the National Academy of Medicine that suggest that one-third of healthcare spending is wasteful and does not result in better health. Addressing avoid-able medical and surgical care is a topic gaining increasing recog-nition in healthcare.One example of overtreatment in surgical care is opioid over-prescribing.5 In the United States in 2015 alone, clini-cians handed out 249 million opioid prescriptions, almost one for every American adult. And in 2016, the United States produced 14 billion opioid pills (40 for every American citizen). With the exception of pain specialists treating patients with pain syndromes, surgeons are the most common prescribers of opi-oids. Judicious opioid prescribing is important because of the addictive potential of these medications. Moreover, many patients can recover comfortably after hospital discharge with nonopioid or nonaddictive pain regimens.THE SCIENCE OF PATIENT SAFETYMedicine is considered a high-risk system with a high error rate, but these two characteristics are not always correlated. Other high-risk industries have managed to maintain an impeccably low error rate. For example, one of the highest risk systems in existence today, the U.S. Navy’s nuclear submarine program, has an unmatched safety record.Much of the credit for their safety record is due to the culture of the nuclear submarine program, with its insistence on individual ownership, responsibility, attention to detail, professionalism, moral integrity, and mutual respect.6 These characteristics have created the cultural context necessary for high-quality communications under high-risk, high-stress con-ditions. Each reactor operator is aware of what is going on at all times and is responsible for understanding the implications and possible consequences of any action. Communication flows freely between crewmen and officers, and information about any mistakes that occur are dispersed rapidly through the entire system so that other workers can learn how to prevent similar mistakes in the future.High Reliability OrganizationsThe nuclear submarine program is an example of an organi-zation that has achieved the distinction of being considered a “high reliability organization.” High reliability organization theory recognizes that there are certain high-risk industries and organizations that have achieved very low accident and error rates compared to what would be expected given the inherent risks involved in their daily operations. Other high reliability industries and organizations include aircraft carrier flight decks, nuclear power plants, and the Federal Aviation Administration’s air traffic control system. In fact, one reason why nuclear power plants have such an excellent reliability record may be that their operators are often former naval submarine officers whose pre-vious experience and training within one highly reliable organi-zation are easily transferable to other organizations.7One of the assumptions underlying the science of high reliability organizations is that humans who operate and manage 34complex systems are themselves not sufficiently complex to sense and anticipate the problems generated by the system.7 This introduces another important idea undergirding the sci-ence of patient safety: the concept of normal accident theory. Instead of attributing accidents to individual error, this theory states that accidents are intrinsic to high-volume activities and even inevitable in some settings. Accidents should not be used merely to identify and punish the person at fault, but should be seen as a systems problem and addressed at a broader level. As Ruchlin states, even the “best people can make the worst errors as a result of latent conditions.”7High-risk systems, as defined by Perrow in 19848:• Have the potential to create a catastrophe, loosely defined as an event leading to loss of human or animal life, despoiling of the environment, or some other situation that gives rise to the sense of “dread.”• Are complex, in that they have large numbers of highly inter-dependent subsystems with many possible combinations that are nonlinear and poorly understood.• Are tightly coupled, so that any perturbation in the sys-tem is transmitted rapidly between subsystems with little attenuation.However, high reliability organization theory suggests that proper oversight of people, processes, and technology can handle complex and hazardous activities and keep error rates acceptably low.7 Studies of multiple high reliability organiza-tions show that they share the following common characteristics:• People are supportive of one another.• People trust one another.• People have friendly, open relationships emphasizing cred-ibility and attentiveness.• The work environment is resilient and emphasizes creativity and goal achievement, providing strong feelings of credibility and personal trust.Developing these characteristics is an important step toward achieving a low error rate in any organization. For this reason, safety culture is a measure used by hospitals nationwide to improve outcomes and is increasingly recognized as a metric of hospital quality.The Conceptual ModelThe Donabedian model of measuring quality identifies three main types of improvements: changes to organizational struc-ture, changes in organizational processes, and changes in outcomes.9 Structure refers to the physical and organiza-tional tools, equipment, and policies that improve safety. Struc-tural measures ask, “Do the right tools, equipment, and policies exist?” Process is the application of these tools, equipment, and policies/procedures to patients (good practices and evidence-based medicine). Process measures ask, “Are the right tools, policies, and equipment being used?” Outcome is the result on patients. Outcome measures ask, “How often are patients harmed?” In this model, structure (how care is organized) plus process (what we do) influences patient outcomes (the results achieved).10The structure, process, and outcome components of qual-ity measurement all occur within the context of an organiza-tion’s overall culture. The local culture impacts all aspects of the delivery of care because it affects how front-line personnel 5Brunicardi_Ch12_p0397-p0432.indd 39920/02/19 3:57 PM 400BASIC CONSIDERATIONSPART ITable 12-1Types of medical errorAdverse event• Injury caused by medical management rather than the underlying condition of the patient• Prolongs hospitalization, produces a disability at discharge, or both• Classified as preventable or unpreventableNegligence• Care that falls below a recognized standard of care• Standard of care is considered to be care a reasonable physician of similar knowledge, training, and experience would use in similar circumstancesNear miss• An error that does not result in patient harm• Analysis of near misses provides the opportunity to identify and remedy system failures before the occurrence of harmSentinel event• An unexpected occurrence involving death or serious physical or psychological injury• The injury involves loss of limb or function• This type of event requires immediate investigation and response• Other examples• Hemolytic transfusion reaction involving administration of blood or blood products having major blood group incompatibilities• Wrong-site, wrong-procedure, or wrong-patient surgery• A medication error or other treatment-related error resulting in death• Unintentional retention of a foreign body in a patient after surgeryReproduced with permission from Makary M: General Surgery Review. Washington, DC: Ladner-Drysdale; 2008.Case 12-1 Systems change resulting from medical errorLibby Zion was an 18-year-old woman who died after being admitted to the New York Hospital with fever and agitation on the evening of October 4, 1984. Her father, Sidney Zion, a lawyer and columnist for the N.Y. Daily News, was convinced that his daughter’s death was due to inadequate staffing and overworked physicians at the hospital and was determined to bring about changes to prevent other patients from suffering as a result of the teaching hospital system. Due to his efforts to publicize the circumstances surrounding his daughter’s death, Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges. Although the hospital was not indicted, in May 1986, a grand jury issued a report strongly criticizing “the supervision of interns and junior resi-dents at a hospital in NY County.”As a result, New York State Health Commissioner David Axelrod convened a panel of experts headed by Bertrand M. Bell, a primary care physician at Albert Einstein College of Medicine who had long been critical of the lack of supervision of physicians-in-training, to evaluate the training and supervision of doctors in New York State. The Bell Commission recom-mended that residents work no more than 80 hours per week and no more than 24 consecutive hours per shift, and that a senior physician needed to be physically present in the hospital at all times. These recommendations were adopted by New York State in 1989. In 2003, the Accreditation Council on Graduate Medi-cal Education followed by mandating that all residency training programs adhere to the reduced work hour schedule.understand and deliver safe patient care. In fact, culture (col-lective attitudes and beliefs of caregivers) is increasingly being recognized to be the fourth measurable component to the structure-process-outcome model. This recognition is based on growing evidence that local culture is linked to a variety of important clinical outcomes.10 For any new patient safety initiative to be deemed successful, any change in structure or process must lead to a corresponding positive change in patient outcomes.11CREATING A CULTURE OF SAFETYCulture is to an organization what personality is to the individual—a hidden, yet unifying theme that provides meaning, direction, and mobilization.7 Organizations with effective safety cultures share a constant commitment to safety as a top-level priority that permeates the entire organization. These organizations fre-quently share the following characteristics12:• An acknowledgment of the high-risk, error-prone nature of an organization’s activities• A nonpunitive environment where individuals are able to report errors or close calls without fear of punishment or retaliation• An expectation of collaboration across ranks to seek solutions to vulnerabilities• A willingness on the part of the organization to direct resources to address safety concernsTraditional surgical culture stands almost in direct oppo-sition to the values upheld by organizations with effective safety cultures for several reasons. Surgeons are less likely to acknowledge their propensity to make mistakes or to admit these mistakes to others.13 Surgeons tend to minimize the effect of stress on their ability to make decisions.14 The surgical cul-ture, especially in the operating room (OR), is traditionally rife with hierarchy. Intimidation of other OR personnel by sur-geons was historically accepted as the norm. This can prevent nurses and other OR staff from pointing out potential errors or Brunicardi_Ch12_p0397-p0432.indd 40020/02/19 3:57 PM 401QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12• I know the proper channels to direct questions regarding patient safety in this clinical area.• I receive appropriate feedback about my performance.• I would feel safe being treated here as a patient.• In this clinical area, it is not difficult to discuss mistakes.Although perceptions of teamwork climate can differ as a function of one’s role in the OR, perceptions of safety climate are relatively consistent across OR providers in a given hospital. Validated in over 500 hospitals, the SAQ is used to establish benchmark safety culture scores by healthcare worker type, department, and hospital. Using this survey, hospitals can com-pare culture between different types of healthcare workers within a department as well as culture between departments throughout the institution. Scores can be compared to those of other par-ticipating institutions to compare safety climates. This allows hospitals to participate with one another to implement programs to improve safety culture. In addition, scores are used to evaluate the effectiveness of safety interventions by comparing the SAQ safety climate scores after implementation to baseline scores.Strong teamwork is at the core of any effective organiza-tion and is a key element to ensuring patient safety in the OR. Teamwork is dependent on the underlying culture and patterns of communication. The ability for all team members, to “speak up” about patient safety concerns is one of the most important elements of creating a culture of patient safety.TEAMWORK AND COMMUNICATIONAccording to The Joint Commission, communication breakdown is one of the top three root causes of sentinel events such as wrong-site surgery (Fig. 12-2). Poor communication contributed to over 60% of sentinel events reported to The Joint Commission in 2011.17 Good communication is an essential component of teamwork and is especially important in the OR, one of the most complex work environments in healthcare.Within the realm of patient care, there are enormous amounts of information being exchanged between healthcare pro-viders on a daily basis. Much of this information, if prioritized correctly, has the potential to prevent unintended medical errors and serious harm to patients. The importance of good communi-cation in preventing medical errors is undeniable; however, it is difficult to achieve. The traditional surgical hierarchy can prevent OR personnel from sharing important patient data and expressing safety concerns. One perioperative field study showed a 30% rate of communication failure in the OR, with 36% of these break-downs having a substantial impact on patient safety.18In addition to overcoming the cultural barrier to better teamwork and communication, the prospective study by Chris-tian and associates of patient safety in the OR demonstrated that the standard workflow of the OR itself presents many opportunities for the loss or degradation of critical informa-tion.19 Hand-offs of patient care from the OR to other locations or providers are particularly prone to information loss, which has been demonstrated in other clinical settings. Hand-offs and auxiliary tasks, such as surgical sponge and instrument counts, frequently take place during critical portions of the case and place competing demands on provider attention from primary patient-centered activities. Communication between the surgeon and pathologist also is vulnerable because the communication often occurs through secondary messengers such as nurses or technicians. This information loss can lead to delays, overuse of 6Case 12-2 High-profile sentinel eventOn December 3, 1994, Betsy Lehman, a Boston Globe health columnist, died as a result of receiving four times the intended dose of chemotherapy for breast cancer. Remarkably, 2 days later, Maureen Bateman, a teacher being treated for cancer, also received a chemotherapy overdose and suffered irrevers-ible heart damage. After investigating the medication errors, the prescribing doctor, three druggists, and 15 nurses were disciplined by state regulators. The hospital was sued by the two women’s families and by one of the doctors disciplined.As a result of this widely publicized event, the Dana-Farber Cancer Institute invested more than $11 million to overhaul their safety programs, including providing new training for their employees and giving doctors more time to meet with patients. The hospital adopted a full disclosure policy so that patients would be informed anytime a mistake had affected their care. Dana-Farber also started a patient com-mittee providing advice and feedback on ways to improve care at the hospital.mistakes. Moreover, this culture is not limited to the OR. In the intensive care unit (ICU), when compared to physicians, nurses reported more difficulty speaking up, disagreements were not appropriately resolved, and decisions were made without ade-quate input.15 In addition, the field of medicine strongly values professional autonomy, which frequently promotes individual-ism over cooperation, often to the detriment of patient care.16 Finally, patient safety, although often viewed as important, is seldom promoted from an organizational priority to an organiza-tional value. Organizations often do not feel the need to devote resources to overhauling their patient safety systems as long as they perceive their existing processes to be adequate. It often takes a high-profile sentinel event to motivate leaders to com-mit the necessary time and resources to improving patient safety within their organization, as exemplified by the Dana-Farber Institute in the aftermath of Betsy Lehman’s death (Case 12-2).Assessing an Organization’s Safety CultureEfforts to foster cultural change within an organization with regard to patient safety have been limited in the past by the inability to measure the impact of any given intervention. How-ever, studies have shown that employee attitudes about culture are associated with error reduction behaviors in aviation and with patient outcomes in ICUs. The Safety Attitudes Question-naire (SAQ) is a validated survey instrument that can be used to measure culture in a healthcare setting.9 Adapted from two safety tools used in aviation, the Flight Management Attitudes Questionnaire and its predecessor, the Cockpit Management Attitudes Questionnaire, the SAQ consists of a series of ques-tions measuring six domains: teamwork climate, safety climate, job satisfaction, perception of management, stress recognition, and working conditions.The safety climate scale portion of the questionnaire con-sists of the following seven items:• I am encouraged by my colleagues to report any patient safety concerns I may have.• The culture in this clinical area makes it easy to learn from the mistakes of others.• Medical errors are handled appropriately in this clinical area.Brunicardi_Ch12_p0397-p0432.indd 40120/02/19 3:57 PM 402BASIC CONSIDERATIONSPART I0 20 40 60 80 Medication UseContinuum of CareCare PlanningOperative CareInformation ManagementPhysical EnvironmentAssessmentCommunicationLeadershipHuman FactorsPercent of Events (%)Figure 12-2. Root causes of sentinel events 2004 to 2012. (Data from The Joint Commission, 2012.)staff and resources, uncertainty in clinical decision making and planning, and oversights in patient preparation.Measuring TeamworkResearch in commercial aviation has demonstrated a strong correlation between better teamwork and improved safety per-formance. Cockpit crew members’ reluctance to question a cap-tain’s judgment has been identified as a root cause of aviation accidents. Good attitudes about teamwork are associated with error-reduction behaviors in aviation, improved patient out-comes in ICUs, and decreased nurse turnover in the OR. It is also associated with higher job satisfaction ratings and less sick time taken from work.The SAQ can be used to measure teamwork and provide benchmarks for departments or hospitals seeking to measure and improve their teamwork climate.20 The SAQ teamwork scores are responsive to interventions that aim to improve team-work among operating teams, such as the implementation of ICU checklists, executive walk rounds, and preoperative brief-ing team discussions. The communication and collaboration sections of the SAQ reflect OR caregiver views on teamwork and can be used to distinguish meaningful interventions from impractical and ineffective programs.In a survey of OR personnel across 60 hospitals, the SAQ identified substantial differences in the perception of team-work in the OR depending on one’s role. Physicians frequently rated the teamwork of others as good, while nurses at the same institutions perceived teamwork as poor (Fig. 12-3). Similar 100%87%Surgeon rates OR nurseOR nurse rates surgeon48%90%80%70%60%Percent rating quality of collaborationand communication as high or very high50%40%30%20%10%0%Figure 12-3. Differences in teamwork perceptions between sur-geons and operating room (OR) nurses. (Reproduced with permis-sion from Makary MA, Sexton JB, Freischlag JA, et al. Operating room teamwork among physicians and nurses: teamwork in the eye of the beholder, J Am Coll Surg. 2006 May;202(5):746-752.)discrepancies have been found in ICUs. These discrepancies can be attributed to differences in the communication skills that are valued by surgeons and nurses. For example, nurses describe good collaboration as having their input respected, while physicians describe good collaboration as having nurses who can anticipate their needs and follow instructions. Efforts to improve the communication that takes place between physicians and nurses can directly improve the perception of teamwork and collaboration by the OR team (Table 12-2). Empowering well-respected surgeons to promote principles of teamwork and communication can go a long way toward transforming attitu-dinal and behavioral changes in fellow physicians as well as other members of the surgical team. Surgeons are increasingly encouraging the respectful and timely voicing of concerns of OR personnel.COMMUNICATION TOOLSHigh reliability organizations such as aviation frequently use tools such as prompts, checks, standard operating protocols, and communication interventions such as team briefings and debriefings. These tools identify and mitigate hazards and allow an organization to complete tasks more efficiently. They also foster a culture of open communication and speaking up if a team member senses a safety concern. Safety checks and standardized team discussions serve as prompts to help “engineer out” human error, providing quality assurance and improving information flow. They also can prevent errors related to omissions, which are more likely to occur when there is information overload, multiple steps in a process, repetitions in steps, and planned departures from routine processes, and when there are other interruptions and distractions present while the process is being executed. These same interventions have been shown to improve patient safety in ORs and ICUs.21,22Operating Room Briefings (A Surgical Checklist)Preoperative briefings and checklists, when used appropriately, help to facilitate transfer of information between team members (Table 12-3). A briefing, or checklist, is any preprocedure dis-cussion of requirements, needs, and special issues of the proce-dure. Briefings often are locally adapted to the specific needs of the specialty. They have been associated with an improved safety culture, including increased awareness of wrong-site/wrong-procedure errors, early reporting of equipment prob-lems, reduced operational costs and fewer unexpected delays. In one study, 30.9% of OR personnel reported a delay before the 7Brunicardi_Ch12_p0397-p0432.indd 40220/02/19 3:57 PM 403QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12Table 12-2Percentage of operating room caregivers reporting a high or very high level of collaboration with other members of the operating room teamCAREGIVER POSITION PERFORMING RATING CAREGIVER POSITION BEING RATEDSURGEONANESTHESIOLOGISTNURSECRNASurgeon85848887Anesthesiologist70968992Nurse48638168CRNA58757693The best teamwork scores were recorded by anesthesiologists when they rated their teamwork with other anesthesiologists (“high” or “very high” 96% of the time). The lowest teamwork ratings were recorded by nurses when they rated their teamwork with surgeons (“high” or “very high” 48% of the time).CRNA = certified registered nurse anesthetist.Reproduced with permission from Makary MA, Sexton JB, Freischlag JA, et al. Operating room teamwork among physicians and nurses: teamwork in the eye of the beholder, J Am Coll Surg. 2006 May;202(5):746-752.Table 12-3Five-point operating room briefingWhat are the names and roles of the team members?Is the correct patient/procedure confirmed? (The Joint Commission Universal Protocol [TIME-OUT])Have antibiotics been given? (if appropriate)What are the critical steps of the procedure?What are the potential problems for the case?Data from Makary MA, Mukherjee A, Sexton JB, et al. Operating room briefings and wrong-site surgery, J Am Coll Surg. 2007 Feb; 204(2):236-243.institution of OR briefings, and only 23.3% reported delays after briefings were instituted.23 OR briefings are increasingly being used to ensure evidence-based measures are used, such as the appropriate administration of preoperative antibiotics and deep vein thrombosis (DVT) prophylaxis. Briefings allow personnel to discuss potential problems, before they become a “near miss” or cause actual harm.Operating Room DebriefingsPostprocedural debriefings improve patient safety by allowing for discussion and reflection on causes for errors and critical incidents that occurred during the case. Errors or critical inci-dents are regarded as learning opportunities rather than cause for punishment. During the debriefing, the team also can discuss what went well during the case and designate a point person to follow up on any proposed actions that result from the discus-sion. In addition, most debriefings include a verification of the sponge, needle, and instrument counts and confirmation of the correct labeling of the surgical specimen.Errors in surgical specimen labeling have not received as much attention as incorrect sponge or instrument counts as an indicator of the quality of communication in the OR. How-ever, an error in communication or during the hand-off process increases the risk of mislabeling a surgical specimen before its arrival in a pathology laboratory. In one study, this type of identification error occurred in 4.3 per 1000 surgical specimens, which implies an annualized rate of occurrence of 182 misla-beled specimens per year (Fig. 12-5).24 Errors involving speci-men identification can result in delays in care, the need for an additional biopsy or therapy, failure to use appropriate therapy, or therapy administered to the wrong body site, side, or patient. These system failures can lead to significant harm to the patient, costs to the institution, and distrust by a community. Given the frequency of occurrence and the feasibility and validity of mea-suring them, mislabeled surgical specimens may serve as a use-ful indicator of patient safety and should be included in any postprocedural debriefing checklist.Sign OutsIn healthcare, information frequently passes to covering provid-ers without prioritizing potential concerns. This makes sign outs a very vulnerable process of care, which can lead to catastrophic events.The term sign out can refer to either the verbal or written communication of patient information to familiarize oncoming physicians about patients who will be under their care. Sign outs should occur whenever a patient’s care setting or provider is changing. When performed well, sign outs help to ensure the transfer of pertinent information. However, previous studies have shown the hand-off process to be variable, unstructured, and prone to error. Common categories of communication fail-ure during sign outs include content omissions, such as failure to mention active medical problems, and failures in the actual communication process, such as leaving illegible or unclear notes (Case 12-3).25 These failures lead to confusion and uncer-tainty by the covering physician during patient care decisions, resulting in the delivery of inefficient and suboptimal care.The use of more structured verbal communication such as the Situational Debriefing Model, otherwise known as SBAR (situation, background, assessment, and recommendation), used by the U.S. Navy, can be applied to healthcare to improve the communication of critical information in a timely and orderly fashion.25 In addition, all sign outs should begin with the state-ment, “In this patient, I am most concerned about . . .” to signal to the healthcare provider on the receiving end the most impor-tant safety concerns regarding that specific patient.ImplementationTools such as checklists, sign outs, briefings, and debrief-ings improve communication between healthcare providers and create a safer patient environment (Fig. 12-6). Although their use in healthcare is still highly variable, specialties that Brunicardi_Ch12_p0397-p0432.indd 40320/02/19 3:57 PM 404BASIC CONSIDERATIONSPART ISurgical Safety ChecklistHas the patient conÿrmed his/her identity, site, procedure, and consent?YesIs the site marked?YesNot applicableYesYesNoYesDifÿcult airway or aspiration risk?NoYes, and equipment/assistance availableRisk of >500ml blood loss (7ml/kg in children)?NoYes, and two IVs/central access and ˜uids plannedConÿrm all team members have introduced themselves by name and role.Conÿrm the patient’s name, procedure, and where the incision will be made.Has antibiotic prophylaxis been given within the last 60 minutes?YesNot applicableAnticipated Critical EventsTo Surgeon:What are the critical or non-routine steps?How long will the case take?What is the anticipated blood loss?To Anaesthetist:Are there any patient-speciÿc concerns?To Nursing Team:Has sterility (including indicator results) been conÿrmed?Are there equipment issues or any concerns?YesNurse Verbally Conÿrms:The name of the procedureCompletion of instrument, sponge andneedle countsSpecimen labelling (read specimen labelsaloud, including patient name)Whether there are any equipment problemsto be addressedWhat are the key concerns for recovery andmanagement of this patient? This checklist is not intended to be comprehensive. Additions and modiÿcations to ÿt local practice are encouraged.(with at least nurse and anaesthetist)(with nurse, anaesthetist and surgeon)(with nurse, anaesthetist and surgeon)© WHO, 2009Before induction of anaesthesiaBefore skin incisionBefore patient leaves operating roomRevised 1 / 2009To Surgeon, Anaesthetist and Nurse:Is essential imaging displayed?Not applicableIs the anaesthesia machine and medicationcheck complete? Is the pulse oximeter on the patient andfunctioning?Known allergy? Does the patient have a: Figure 12-4. World Health Organization’s surgical safety checklist. (Reproduced with permission from World Health Organization Safe Surgery Saves Lives. Available at: http://www.who.int/patientsafety/safesurgery/en/. Accessed November 8, 2012.)Specimennot labeledEmptycontainerIncorrectlateralityIncorrecttissue siteIncorrectpatientnameNo patientnameNo tissuesite0.90.80.70.60.50.40.30.20.10Incidence (per 1000 specimens)Error typeFigure 12-5. Incidence of identification errors observed per 1000 specimens (n = 21,351). (Reproduced with permission from Makary MA, Epstein J, Pronovost PJ, et al. Surgical specimen identification errors: a new mea-sure of quality in surgical care, Surgery. 2007 Apr;141(4):450-455.)have incorporated them, such as intensive care and anesthesia, have made impressive strides in patient safety. Currently, com-munication breakdowns, information loss, hand off, multiple competing tasks, and high workload are considered “annoy-ing but accepted features” of the perioperative environment.20 As physician attitudes toward errors, stress, and teamwork in medicine become more favorable toward the common goals of reducing error and improving teamwork and communication, medicine will likely achieve many of the milestones in safety that high-reliability industries such as aviation have already accomplished.COMPREHENSIVE UNIT-BASED SAFETY PROGRAMAs medical care and hospitals continue to expand, the care that is provided to patients is becoming more fragmented. This frag-mentation makes communication more difficult and opportuni-ties for medical errors more common. These problems require common sense solutions, often necessitating a change in the way that care is delivered on the local level. Unit-based meetings to discuss processes that are potentially dangerous for patients can quickly bring danger areas out into the open. These meetings Brunicardi_Ch12_p0397-p0432.indd 40420/02/19 3:57 PM 405QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12Case 12-3 Inadequate sign out leading to medical errorJosie King was an 18-month-old child who was admitted to Johns Hopkins Hospital in January of 2001 for firstand second-degree burns. She spent 10 days in the pediatric intensive care unit and was well on her way to recovery. She was transferred to an intermediate care floor with the expectation that she would be sent home in a few days.The following week, her central line was removed, but nurses would not allow Josie to drink anything by mouth. Around 1 pm the next day, a nurse came to Josie’s bedside with a syringe of methadone. Although Josie’s mother told the nurse that there was no order for narcotics, the nurse insisted that the orders had been changed and administered the drug. Josie’s heart stopped, and her eyes became fixed. She was moved to the pediatric intensive care unit and placed on life support. Two days later, on February 22, 2001, she died from severe dehydration.After her death, Josie’s parents, Sorrel and Jay King, were motivated to work with leaders at Johns Hopkins to ensure that no other family would have to endure the death of a child due to medical error. They later funded the Josie King Patient Safety Program and an academic scholarship in the field of safety.A preoperativediscussionincreased myawareness of thesurgical site andside beingoperated on.01020304050Percent of respondents who agreed60708090100The surgical siteof the operationwas clear to mebefore theincision.Decision makingutilized inputfrom relevantpersonnel.Surgery andanesthesiaworked togetheras a well-coordinatedteam.Postbriefing PrebriefingFigure 12-6. Impact of operating room briefings on team-work and communication.should be held on a regular basis and bring together a multidisci-plinary team of physicians, nurses, technicians, social workers, and other staff who can each voice their concerns about safety hazards in their area. This enables all aspects of patient care to be addressed and improved continuously, thereby streamlining and improving patient care.26The implementation of the Comprehensive Unit-based Safety Program (CUSP) involves measurement of a unit’s safety culture prior to starting the program and inclusion of hospital management from the start. Having management involved allows for more efficient allocation of resources and allows them to better understand the problems faced by front-line pro-viders. Once CUSP is in place, changes can be made using local wisdom to advance patient care.26 The impact of changes made using CUSP can be measured using both patient outcomes and safety culture data.Implementation of CUSP has been associated with improved patient outcomes, including decreased surgical site infections. In a 2-year study of colorectal patients, where the first year was pre-CUSP implementation and the second year was post-CUSP implementation, there was a 33% decrease in the surgical site infection rate after CUSP.27 In this study, the CUSP group met monthly and came up with a list of interven-tions based on their experience with these cases, including stan-dardization of skin preparation and warming of patients in the preanesthesia area. This study showed that CUSP can be highly effective in ameliorating patient harm and improving patient care.MEASURING QUALITY IN SURGERYDespite the newfound focus on patient safety in surgery and the number of initiatives being undertaken by many organizations to improve their safety culture, there are few tools to actually measure whether these efforts are effective in reducing the num-ber of errors. Several agencies and private groups have devel-oped criteria to evaluate quality and safety within hospitals.Practice Pattern MeasuresNew quality measures in healthcare focus on the appropriate-ness of medical care.28 These appropriateness indicators are doctor-defined and specialty-specific so they are smart and fair. One of the first of these new appropriateness metrics is the aver-age number of tissue blocks a skin cancer (Mohs) surgeon will use to surgically remove a skin cancer. The American College of Mohs Surgeons formalized and endorsed the surgeon metric: average number of blocks a surgeon requires to remove a stan-dardized skin cancer. In a report describing the national distri-bution of surgeons by their mean number of blocks per case, the national average was found to be 1.7 blocks per surgeon. Statistical outlier surgeons had an average four or more blocks per patient. Boundaries of normal variation was determined by expert physician leaders to define an acceptable range and an Brunicardi_Ch12_p0397-p0432.indd 40520/02/19 3:57 PM 406BASIC CONSIDERATIONSPART Iunacceptable range (greater than two standard deviations from the national norm). The American College of Mohs Surgeons sent letters to outliers, letting them know where they stand, and offered coaching and retraining help. The new Mohs surgery metric demonstrates the opportunity to reduce unwarranted clinical variation and lower healthcare costs by simply using clinical wisdom and the power of peer-comparison.Appropriateness measures approach quality differently than traditional quality measures and rely on expert physicians to define the metric and set boundaries of reasonable versus unsafe variation in an individual physician’s practice pattern rel-ative to his or her peers nationally. This concept is being applied to utilization rates of minimally invasive surgery in candidate patients as well as rates of physical therapy utilization before elective spine surgery for chronic pain.Agency for Healthcare Research and Quality Patient Safety IndicatorsThe Agency for Healthcare Research and Quality (AHRQ) was created in 1989 as a Public Health Service agency in the Depart-ment of Health and Human Services. Its mission is to improve the quality, safety, efficiency, and effectiveness of healthcare for all Americans. Nearly 80% of the AHRQ’s budget is awarded as grants and contracts to researchers at universities and other research institutions across the country. The AHRQ sponsors and conducts research that provides evidence-based information on healthcare outcomes, quality, cost, use, and access. It has advocated the use of readily available hospital inpatient admin-istrative data to measure healthcare quality. The information helps healthcare decision makers make more informed decisions and improve the quality of healthcare services.29One of the major contributions of the AHRQ is a set of Patient Safety Indicators (PSIs), initially released in 2003 and revised in 2010. PSIs are a tool to help health system leaders identify potential adverse events occurring during hospitaliza-tion. Developed after a comprehensive literature review, analy-sis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, review by a clini-cian panel, implementation of risk adjustment, and empirical analyses, these 27 indicators provide information on potential in-hospital complications and adverse events following surger-ies, procedures, and childbirth (Table 12-4).Provider-level indicators provide a measure of the poten-tially preventable complications for patients who received their initial care and the complication of care within the same hos-pitalization. They include only those cases where a secondary diagnosis code flags a potentially preventable complication. Area-level indicators capture all cases of the potentially pre-ventable complications that occur in a given area (e.g., metro-politan area or county), either during their initial hospitalization or resulting in subsequent hospitalization.30Currently, PSIs are considered indicators, not definitive measures, of patient safety concerns. They can identify potential safety problems that merit further investigation. They also can be used to better prioritize and evaluate local and national initiatives, and even as benchmarks for tracking progress in patient safety. In the future, further growth in electronic health data will make administrative data-based tools like the PSIs more useful.31The Surgical Care Improvement Project MeasuresThe Surgical Care Improvement Project (SCIP) was established in 2003 by a national partnership of organizations committed Table 12-4Agency for Healthcare Research and Quality patient safety indicatorsProvider-level patient safety indicators• Complications of anesthesia• Death in low mortality diagnosis-related groups• Decubitus ulcer• Failure to rescue• Foreign body left in during procedure• Iatrogenic pneumothorax• Selected infections due to medical care• Postoperative hip fracture• Postoperative hemorrhage or hematoma• Postoperative physiologic and metabolic derangements• Postoperative respiratory failure• Postoperative pulmonary embolism or deep vein thrombosis• Postoperative sepsis• Postoperative wound dehiscence in abdominopelvic surgical patients• Accidental puncture and laceration• Transfusion reaction• Birth trauma—injury to neonate• Obstetric trauma—vaginal delivery with instrument• Obstetric trauma—vaginal delivery without instrument• Obstetric trauma—cesarean deliveryArea-level patient safety indicators• Foreign body left in during procedure• Iatrogenic pneumothorax• Selected infections due to medical care• Postoperative wound dehiscence in abdominopelvic surgical patients• Accidental puncture and laceration• Transfusion reaction• Postoperative hemorrhage or hematomaReproduced with permission from Agency for Healthcare Research and Quality. Patient Safety Indicators Overview. AHRQ Quality Indicators. Rockville, MD: Agency for Healthcare Research and Quality; February 2006. Available at: https://www.qualityindicators.ahrq.gov/. Accessed October 24, 2018.to improving surgical care by reducing surgical complications. The steering committee is comprised of groups such as the Centers for Medicare & Medicaid Services, the American Hos-pital Association, Centers for Disease Control and Prevention (CDC), Institute for Healthcare Improvement, The Joint Com-mission, and others.The incidence of postoperative complications ranges from 6% for patients undergoing noncardiac surgery to more than 30% for patients undergoing high-risk surgery. Common post-operative complications include surgical site infections (SSIs), myocardial infarction, postoperative pneumonia, and thrombo-embolic complications. Patients who experience postoperative complications have increased hospital length of stay (3 to 11 days longer than those without complications), increased hospital costs (ranging from $1398 for an infectious complication to $18,310 for a thromboembolic event), and increased mortality (median patient survival decreases by up to 69%).32Despite well-established evidence that many of these adverse events are preventable, failure to comply with standards Brunicardi_Ch12_p0397-p0432.indd 40620/02/19 3:57 PM 407QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12of care known to prevent them results in unnecessary harm to a large number of patients. SCIP has identified three broad areas within surgery where potential complications have a high inci-dence and cost and there is a significant opportunity for pre-vention: SSIs, venous thromboembolism, and adverse cardiac events. The SCIP measures aim to reduce the incidence of these events during the perioperative period by advocating the use of proven process and outcome measures. These process and outcome measures are detailed in Table 12-5.SSIs account for 14% to 16% of all hospital-acquired infections and are a common complication of care, occurring in 2% to 5% of patients after clean extra-abdominal operations and up to 20% of patients undergoing intra-abdominal procedures. By implementing steps to reduce SSIs, hospitals could recog-nize a savings of $3152 and reduction in extended length of stay by 7 days on each patient developing an infection.33Adverse cardiac events occur in 2% to 5% of patients undergoing noncardiac surgery and as many as 34% of patients undergoing vascular surgery. Certain perioperative cardiac Table 12-5The Surgical Care Improvement Project measuresProcess of care performance measuresInfection• Prophylactic antibiotic received within 1 h before surgical incision• Prophylactic antibiotic selection for surgical patients• Prophylactic antibiotics discontinued within 24 h after surgery end time (48 h for cardiac patients)• Cardiac surgery patients with controlled 6 a.m. postoperative serum glucose• Surgery patients with appropriate hair removal• Colorectal surgery patients with immediate postoperative normothermiaVenous thromboembolism• Surgery patients with recommended venous thromboembolism prophylaxis ordered• Surgery patients who received appropriate venous thromboembolism prophylaxis within 24 h before surgery to 24 h after surgeryCardiac events• Surgery patients on a β-blocker prior to arrival who received a β-blocker during the perioperative periodProposed outcome measuresInfection• Postoperative wound infection diagnosed during index hospitalizationVenous thromboembolism• Intraor postoperative pulmonary embolism diagnosed during index hospitalization and within 30 d of surgery• Intraor postoperative deep vein thrombosis diagnosed during index hospitalization and within 30 d of surgeryCardiac events• Intraor postoperative acute myocardial infarction diagnosed during index hospitalization and within 30 d of surgeryGlobal measures• Mortality within 30 d of surgery• Readmission within 30 d of surgeryData from The Joint Commission, 2012.events, such as myocardial infarction, are associated with a mortality rate of 40% to 70% per event, prolonged hospitaliza-tion, and higher costs. Appropriately administered β-blockers reduce perioperative ischemia, especially in at-risk patients. It has been found that nearly half of the fatal cardiac events could be preventable with β-blocker therapy.33DVT occurs after approximately 25% of all major surgi-cal procedures performed without prophylaxis, and pulmonary embolism (PE) occurs after 7%. Despite the well-established efficacy and safety of preventive measures, studies show that prophylaxis often is underused or used inappropriately. Both low-dose unfractionated heparin and low molecular weight heparin have similar efficacy in DVT and PE prevention. Pro-phylaxis using low-dose unfractionated heparin has been shown to reduce the incidence of fatal PEs by 50%.33The SCIP effort provides an infrastructure and guidelines for data collection and quality improvement on a national scale. By achieving high levels of compliance with evidence-based practices to reduce SSIs, venous thromboembolism events, and perioperative cardiac complications, the potential number of lives saved in the Medicare patient population alone exceeds 13,000 annually.32National Surgical Quality Improvement ProgramThe National Surgical Quality Improvement Program (NSQIP) is a measurement program that allows hospitals to sample their rates of postoperative events and compare them to similar hos-pitals. Created by the Veterans Health Administration (VA) in 1991, NSQIP has been credited with measuring and improving morbidity and mortality outcomes at the VA, reducing 30-day mortality rate after major surgery by 31%, and 30-day postop-erative morbidity by 45% in its first decade.34 Beta testing at 18 non-VA sites from 2001 to 2004 demonstrated the feasibility and utility of the program in the private sector. The program was subsequently expanded to the private sector in 2004 when the American College of Surgeons endorsed the program and encouraged hospital participation to measure and evaluate out-comes on a large scale. A study of 118 hospitals participating in NSQIP between 2005 to 2007 showed that 82% of hospitals decreased their complication rates and there was a decrease in morbidity of 11% and mortality of 17% annually per hospital.35 Currently, over 400 private-sector U.S. hospitals participate in the program.NSQIP uses a risk-adjusted ratio of the observed to expected outcome (focusing primarily on 30-day morbidity and mortal-ity) to compare the performance of participating hospitals with their peers. The data the program has compiled also can be used to conduct observational studies using prospectively collected information on more than 1.5 million patients and operations. The expansion of NSQIP to the private sector has helped shift the focus from merely preventing the provider errors and sentinel events highlighted by the IOM publication “To Err Is Human” to the larger goal of preventing all adverse postoperative outcomes.Several insights about patient safety have arisen as a result of NSQIP. First, safety is indistinguishable from overall quality of surgical care and should not be addressed separately. Defin-ing quality in terms of keeping a patient safe from adverse out-comes allows the NSQIP data to be used to assess and improve quality of care by making improvements in patient safety. In other words, prevention of errors is synonymous with the reduc-tion of adverse outcomes and can be used as a reliable quality measure. Second, during an episode of surgical care, adverse Brunicardi_Ch12_p0397-p0432.indd 40720/02/19 3:57 PM 408BASIC CONSIDERATIONSPART Ioutcomes, and hence, patient safety, are primarily determined by the quality of the systems of care. Errors in hospitals with higher than expected observed to expected outcomes ratios are more likely to be from system errors than from provider incom-petence. This underscores the importance of adequate communi-cation, coordination, and teamwork in achieving quality surgical care. Finally, reliable comparative outcomes data are imperative for the identification of system problems. Risk-adjusted rates of adverse outcomes must be compared with those at peer institu-tions to appreciate more subtle system errors that lead to adverse outcomes to prompt changes in the quality of an institution’s processes and structures.The Leapfrog GroupOne of the largest efforts to standardize evidence-based med-icine in the United States is led by The Leapfrog Group, an alliance of large public and private healthcare purchasers rep-resenting more than 37 million individuals across the United States. This healthcare consortium was founded in 2000 with the aim to exert their combined leverage toward improving nation-wide standards of healthcare quality, optimizing patient out-comes, and ultimately lowering healthcare costs. The Leapfrog Group’s strategy to achieve these goals is through providing patient referral, financial incentives, and public recognition for hospitals that practice or implement evidence-based healthcare standards.The healthcare quality and safety practices (leaps) that Leapfrog initially identified to measure healthcare standards were hospital use of computerized physician order entry systems, 24-hour ICU physician staffing, and evidence-based hospital referral (EBHR) standards for five high-risk operations.36 In 2010, after the National Quality Forum (NQF) released its updated Safe Practices for Better Healthcare, Leapfrog added a safe practices leap, which includes eight practices from the NQF report.37Leapfrog collects data on these practices through adminis-tration of an ongoing, voluntary, web-based hospital quality and safety survey. This survey is conducted in 41 regions that cover over half of the U.S. population and 62% of all hospital beds in the country. In 2011, more than 1200 urban, suburban, and rural hospitals participated in the survey. Leapfrog asks for informa-tion on eight high-risk conditions or procedures, including coro-nary artery bypass graft, percutaneous coronary intervention, abdominal aortic aneurysm (AAA) repair, pancreatic resection, and esophagectomy. These procedures were chosen because evidence exists that adherence to certain process measures can dramatically improve the outcomes of these procedures. In addi-tion, more than 100 studies also have demonstrated that better results are obtained at high-volume hospitals when undergoing cardiovascular surgery, major cancer resections, and other high-risk procedures. Hospitals fulfilling the EBHR Safety Standard are expected to meet the hospital and surgeon volume criteria shown in Table 12-6. Hospitals that do not meet these criteria but adhere to the Leapfrog-endorsed process measures for coro-nary artery bypass graft surgery, percutaneous coronary inter-vention, AAA repair, and care for high-risk neonates, receive partial credit toward fulfilling the EBHR Safety Standard. Leap-frog purchasers work to recognize and reward hospitals that pro-vide care for their enrollees who meet EBHR standards.35In a recent study, Brooke and associates analyzed whether achieving Leapfrog’s established evidence-based standards for AAA repair, including meeting targets for case volume and Table 12-6Recommended annual volumes: hospitals and surgeons1. Coronary artery bypass graft≥450/1002. Percutaneous coronary intervention≥400/753. Abdominal aortic aneurysm repair≥50/224. Aortic valve replacement≥120/225. Pancreatic resection≥11/26. Esophagectomy≥13/27. Bariatric surgery>100/20Reproduced with permission from The Leapfrog Group. Available at: http://www.leapfroggroup.org/.perioperative β-blocker usage, correlated with improved patient outcomes over time.36 After controlling for differences in hos-pital and patient characteristics, hospitals that implemented a policy for perioperative β-blocker usage had an estimated 51% reduction in mortality following open AAA repair cases. Among 111 California hospitals in which endovascular AAA repair was performed, in-hospital mortality was reduced by an estimated 61% over time among hospitals meeting Leapfrog case volume standards, although this result was not statistically significant. These results suggest that hospital compliance with Leapfrog standards for elective AAA repair is an effective means to help improve in-hospital mortality outcomes over time and support further efforts aimed at standardizing patient referral to hospi-tals that comply with evidence-based medicine standards for other surgical procedures.The newest effort of the Leapfrog group is to promote transparency of hospital outcomes using a safety scorecard. This information can be viewed at www.hospitalsafetygrade.org.World Health Organization “Safe Surgery Saves Lives” InitiativeIn October 2004, the WHO launched a global initiative to strengthen healthcare safety and monitoring systems by creat-ing the World Alliance for Patient Safety. As part of the group’s efforts to improve patient safety, the alliance implemented a series of safety campaigns that brought together experts in spe-cific problem areas through individual Global Patient Safety Challenges. The second Global Patient Safety Challenge focuses on improving the safety of surgical care. The main goal of the campaign, called Safe Surgery Saves Lives, is to reduce surgical deaths and complications through the universal adaptation of a comprehensive perioperative surgical safety checklist in ORs worldwide (Fig. 12-4). In addition to the checklist, the WHO defined a set of uniform measures for national and international surveillance of surgical care to better assess the quantity and quality of surgical care being delivered worldwide.38 At the pop-ulation level, metrics include the number of surgeon, anesthesia, and nurse providers per capita, the number of ORs per capita, and overall surgical case volumes and mortality rates. At the hospital level, metrics include safety improvement structures and a surgical “Apgar score,” a validated method of prognos-ticating patient outcomes based on intraoperative events (i.e., hypotension, tachycardia, blood loss).39National Quality ForumThe National Quality Forum (NQF) is a coalition of health-care organizations that has worked to develop and implement a national strategy for healthcare quality measurement and Brunicardi_Ch12_p0397-p0432.indd 40820/02/19 3:57 PM 409QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12reporting. Their mission is to improve the quality of American healthcare by setting national priorities and goals for perfor-mance improvement, endorsing national consensus standards for measuring and publicly reporting on performance, and pro-moting the attainment of national goals through education and outreach programs.One of the major contributions of the NQF is the develop-ment of a list of Serious Reportable Events, which are frequently referred to as “never events.”40 According to the NQF, “never events” are errors in medical care that are clearly identifiable, preventable, and serious in their consequences for patients and that indicate a real problem in the safety and credibility of a healthcare facility. Examples of never events include surgery performed on the wrong body part; a foreign body left in a patient after surgery; a mismatched blood transfusion; a major medication error; a severe pressure ulcer acquired in the hospital; and preventable postoperative deaths. Criteria for inclusion as a never event are listed in Table 12-7. The event must be:• Unambiguous (i.e., the event must be clearly identifiable and measurable, and thus feasible to include in a reporting system);• Usually preventable, with the recognition that some events are not always avoidable, given the complexity of healthcare;• Serious, resulting in death or loss of a body part, disability, or more than transient loss of a body function; and• Any one of the following:• Adverse, and/or• Indicative of a problem in a healthcare facility’s safety sys-tems, and/or• Important for public credibility or public accountability.These events are not a reasonable medical risk of under-going surgery that the patient must accept but medical errors that should never happen (Case 12-4). The occurrence of any of these events signals that an organization’s patient safety culture or processes have defects that need to be evaluated and cor-rected (Table 12-8).“NEVER EVENTS” IN SURGERYNever events are errors in medical care that are clearly identifi-able, preventable, and serious in their consequences for patients and that indicate a real problem in the safety and credibility of a healthcare facility.40 Despite widespread agreement that surgi-cal never events are preventable and despite several national and local programs being launched to decrease them, never 8Table 12-7Surgical “never events”• Surgery performed on the wrong body part• Surgery performed on the wrong patient• Wrong surgical procedure performed on a patient• Unintended retention of a foreign object in a patient after surgery or other procedure• Intraoperative or immediately postoperative death in an ASA Class 1 patientASA = American Society of Anesthesiologists.Reproduced with permission from Serious Reportable Events in Healthcare 2011 Update: A Consensus Report. Washington, DC: National Quality Forum; 2011.Case 12-4 Surgical “never event”In 2002, Mike Hurewitz, a reporter for The Times Union of Albany, suddenly began vomiting blood 3 days after donating part of his liver to his brother while recovering on a hospital floor in which 34 patients were being cared for by one first-year resident. He aspirated and died immediately with no other physician available to assist the overworked first-year resident.Recognized for its advances in the field of liver trans-plantation, at the time, Mount Sinai Hospital was performing more adult-to-adult live-donor operations than any other hos-pital in the country. But the program was shut down by this event. Mount Sinai was held accountable for inadequate care and was banned from performing any live-donor adult liver transplants for more than 1 year. Of the 92 complaints inves-tigated by the state, 75 were filed against the liver transplant unit, with 62 involving patient deaths. The state concluded that most of the 33 serious violations exhibited by the hospital occurred within the liver transplant unit.As a result of the investigation, Mount Sinai revamped many of the procedures within its transplant unit. Among the changes, first-year residents no longer staffed the transplant service, two healthcare practitioners physically present in the hospital oversaw the transplant unit at all times, and any page coming from the transplant unit had to be answered within 5 minutes of the initial call. In addition, nurses monitored patients’ vital signs more closely after surgery, transplant sur-geons were required to make postoperative visits to both organ donor and recipient, and each registered nurse was assigned to four patients, rather than six or seven. The death also led New York to become the first state to develop guidelines for treating live organ donors. Finally, Mike Hurewitz’s widow became a patient safety advocate, urging stricter controls on live donor programs.events are still a significant problem. A study from Mehtsun and colleagues showed that from October 1990 to October 2010, nationwide there were 9744 paid malpractice claims for never events. Of these, mortality was reported in 6.6%, permanent injury in 33%, and temporary injury in 59%. The cost of the never events totaled $1.3 billion. Also, of physicians who were named in a surgical never event claim, 12.4% were named in a future never events claim.41 Another study in 2010 by The Joint Commission found that wrong-site surgery occurs 40 times per week nationwide.42 Future directions for decreasing these prob-lems include public reporting of never events by hospitals to increase hospital accountability, more formal training in team-work, and CUSP programs in hospitals that have higher rates of never events to help elucidate the root cause.Retained Surgical ItemsA retained surgical item refers to any surgical item found to be inside a patient after he or she has left the OR, thus requiring a second operation to remove the item.43 Estimates of retained for-eign bodies in surgical procedures range from one case per 8000 to 18,000 operations, corresponding to one case or more each year for a typical large hospital or approximately 1500 cases per year in the United States.44 This estimate is based on an analy-sis of malpractice claims and is likely to underestimate the true incidence. The risk of having a retained surgical item increases during emergency surgery, when there are unplanned changes in Brunicardi_Ch12_p0397-p0432.indd 40920/02/19 3:57 PM 410BASIC CONSIDERATIONSPART ITable 12-8Four patient events that advanced the modern field of patient safetyPATIENTINSTITUTIONYEAREVENTROOT CAUSEOUTCOMELibby ZionNew York Hospital, New York, NY1984Missed allergy to DemerolPhysician fatigueBell Commission shortened resident work hoursBetsy LehmanDana-Farber Cancer Institute, Boston, MA1994Chemotherapy overdoseLack of medication checks and triggersFired doctor, three pharmacists, 15 nurses; overhauled safety programJosie KingJohns Hopkins Hospital, Baltimore, MD2001Severe dehydrationPoor communicationIncreased safety research fundingMike HurewitzMt. Sinai Hospital, New York, NY2002Inadequate postoperative careInadequate supervisionTransplant program shut down until better patient safety safeguards implementedprocedure (due to new diagnoses encountered in the OR), and in patients with higher body mass index (Table 12-9).44The most common retained surgical item is a surgical sponge, but other items, such as surgical instruments and nee-dles, can also be inadvertently left inside a patient during an operation. Retained surgical sponges are commonly discovered as an incidental finding on a routine postoperative radiograph, but also have been discovered in patients presenting with a mass or abdominal pain. Patients with sponges that were originally left in an intracavitary position (such as inside the chest or abdomen) also can present with complications such as abscess, erosion through the skin, fistula formation, bowel obstruction, hematuria, or the development of a new, tumor-like lesion.Retained surgical needles usually are discovered inciden-tally, and reports of retained needles are uncommon. Retained surgical needles have not been reported to cause injury in the same way that nonsurgical needles (e.g., sewing needles, hypo-dermic needles) have been reported to perforate bowel or lodge in vessels and migrate. However, there have been reports of chronic pelvic pain and ocular irritation caused by retained sur-gical needles. A study of plain abdominal radiographs in pigs has demonstrated that mediumto large-size needles can eas-ily be detected. The decision to remove these retained needles depends on symptoms and patient preference. Needles smaller than 13 mm have been found to be undetectable on plain radio-graph in several studies, have not been shown to cause injury to vessels or visceral organs, and can probably be left alone.Although the actual incidence of retained surgical instru-ments is unknown, they are retained with far less frequency than surgical sponges. The initial presentation of a retained surgical instrument is most commonly pain in the surgical site or the Table 12-9Risk factors for retained surgical sponges• Emergency surgery• Unplanned changes in procedure• Patient with higher body mass index• Multiple surgeons involved in same operation• Multiple procedures performed on same patient• Involvement of multiple operating room nurses/staff members• Case duration covers multiple nursing “shifts”sensation of a mass of fullness after a surgical procedure that leads to the discovery of a metallic object on a radiographic study. Commonly retained instruments include the malleable and “FISH” instrument that are used to protect the viscera when closing abdominal surgery.A retained surgical foreign body should be included in the differential diagnosis of any postoperative patient who presents with pain, infection, a palpable mass, or a radiopaque structure on imaging. The diagnosis can usually be made using a com-puted tomographic (CT) scan, and this is often the only test needed. If a retained surgical item is identified in the setting of an acute clinical presentation, the treatment usually is removal of the item. However, if the attempt to remove the retained sur-gical item can potentially cause more harm than the item itself, as in the case of a needle or a small part of a surgical item, then removal is occasionally not recommended. Retained surgical sponges should always be removed.The American College of Surgeons and the Association of Perioperative Registered Nurses, in addition to The Joint Com-mission, have issued guidelines to try to prevent the occurrence of retained surgical items. Current recommendations include the use of standard counting procedures, performing a thorough wound exploration before closing a surgical site, and using only X-ray–detectable items in the surgical wound. These organiza-tions also strongly endorse the completion of a postoperative debriefing after every operation. An X-ray at the completion of an operation is encouraged if there is any concern for a foreign body based on confusion regarding the counts by even a single member of the OR team or in the presence of a risk factor.Surgical CountsThe benefit of performing surgical counts to prevent the occur-rence of retained surgical items is controversial. The increased risk of a retained surgical item during emergency surgery in the study by Gawande and colleagues appeared to be related to bypassing the surgical count in many of these cases.44 However, in another study, the “falsely correct count,” in which a count is performed and declared correct when it is actually incorrect, occurred in 21% to 100% of cases in which a retained surgical item was found.45 This type of count was the most common circumstance encountered in all retained surgical item cases, which suggests that performing a surgical count in and of itself does not prevent this error from taking place. The counting pro-tocol also imposes significant demands on the nursing staff and Brunicardi_Ch12_p0397-p0432.indd 41020/02/19 3:57 PM 411QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12distracts them from focusing on other primarily patient-centered tasks, often during critical portions of the case.19A retained surgical item can occur even in the presence of a known incorrect count. This event is usually a result of poor communication in which a surgeon will dismiss the incorrect count and/or fail to obtain a radiograph before the patient leaves the OR. Having stronger institutional policies in place in case of an incorrect count (such as requiring a mandatory radiograph while the patient is still in the OR) can avoid conflict among caregivers and mitigate the likelihood of a retained surgical item occurring as a result of a known incorrect count.Although there is no single tool to prevent all errors, the development of multiple lines of defense to prevent retained surgical items and universally standardizing and adhering to OR safety protocols by all members of the surgical team will help reduce the incidence of this never event.45 Surgeons should take the lead in the prevention of retained surgical items by avoid-ing the use of small or nonradiologically detectable sponges in large cavities, performing a thorough wound inspection before closing any surgical incision, and having a vested interest in the counting procedure performed by nursing staff. The value of routine radiography to prevent a retained surgical item in emergency cases or when major procedures involving multiple surgical teams are being performed is becoming more apparent.The widely accepted legal doctrine when a foreign body is erroneously left in a patient is that the mere presence of the item in the plaintiff’s body indicates that the patient did not receive proper surgical care. The characteristics of the surgeon and their style, bedside manner, honesty, and confidence demonstrated in the management of the case can go a long way in averting a lawsuit or mitigating damages.Wrong-Site SurgeryWrong-site surgery is any surgical procedure performed on the wrong patient, wrong body part, wrong side of the body, or wrong level of a correctly identified anatomic site. It is dif-ficult to determine the true incidence of wrong-site surgery for several reasons. First, there is no standard definition for what constitutes wrong-site surgery among various healthcare orga-nizations. Another factor is that wrong-site surgery is under-reported by healthcare providers. Finally, the total number of potential opportunities for each type of wrong-site error is unknown. However, various studies show incidences ranging from 1 in 112,994 cases to 1 in 15,500 cases.46 The Washington University School of Medicine suggests a rate of 1 in 17,000 operations, which adds up to approximately 4000 wrong-site surgeries in the United States each year. If these numbers are correct, wrong-site surgery is the third most frequent life-threat-ening medical error in the United States.47Several states now require mandatory reporting of all wrong-site surgery events, including near misses. These data provide some insight into the number of actual errors compared to the number of potential opportunities to perform wrong-site surgery. Of the 427 reports of wrong-site surgery submitted from June 2004 through December 2006 to the Pennsylvania Patient Safety Reporting System, more than 40% of the errors actually reached the patient, and nearly 20% involved comple-tion of a wrong-site procedure.46The risk of performing wrong-site surgery increases when there are multiple surgeons involved in the same operation or multiple procedures are performed on the same patient, espe-cially if the procedures are scheduled or performed on different areas of the body.47 Time pressure, emergency surgery, abnor-mal patient anatomy, and morbid obesity are also thought to be risk factors. Communication errors are the root cause in more than 70% of the wrong-site surgeries reported to The Joint Com-mission.46 Other risk factors include receiving an incomplete preoperative assessment; having inadequate procedures in place to verify the correct surgical site; or having an organizational culture that lacks teamwork or reveres the surgeon as someone whose judgment should never be questioned.There is a one in four chance that surgeons who work on symmetric anatomic structures will be involved in a wrong-site error sometime during their careers.47 The specialties most com-monly involved in reporting wrong-site surgeries according to The Joint Commission are orthopedic/podiatric surgery (41%); general surgery (20%); neurosurgery (14%); urology (11%); and maxillofacial, cardiovascular, otolaryngology, and oph-thalmology (14%).46 Most errors involved symmetric anatomic structures: lower extremities (30%), head/neck (24%), and geni-tal/urinary/pelvic/groin (21%).42 Although orthopedic surgery is the most frequently involved, this may be due to the higher volume of cases performed as well as the increased opportu-nity for lateralization errors inherent in the specialty. In addi-tion, because the American Academy of Orthopaedic Surgeons has historically tried as a professional organization to reduce wrong-site operations, orthopedic surgeons may be more likely to report these events when they do occur.47The Joint Commission Universal Protocol to Ensure Correct SurgeryThe movement to eliminate wrong-site surgery began among professional orthopedic societies in the mid-1990s, when both the Canadian Orthopaedic Association and the American Acad-emy of Orthopaedic Surgeons issued position statements and embarked on educational campaigns to prevent the occurrence of wrong-site surgery within their specialty.47 Other organiza-tions that issued position statements advocating for the elimina-tion of wrong-site surgery include the North American Spine Society, the American Academy of Ophthalmology, the Asso-ciation of Perioperative Registered Nurses, and the American College of Surgeons. After issuing a review of wrong-site sur-gery in their Sentinel Event Alert in 1998, The Joint Commis-sion made the elimination of wrong-site surgery one of their first National Patient Safety Goals in 2003 and adopted a uni-versal protocol for preventing wrong-site, wrong-procedure, and wrong-person surgery in 2004. The protocol has been endorsed by more than 50 professional associations and organizations.A preoperative “time-out” or “pause for the cause” to con-firm the patient, procedure, and site to be operated on before incision was recommended by The Joint Commission and is now mandatory for all ORs in the United States. Elements of the protocol include the following:• Verifying the patient’s identity• Marking the surgical site• Using a preoperative site verification process such as a checklist• Confirming the availability of appropriate documents and studies before the start of a procedure• Taking a brief time-out immediately before skin incision, in which all members of the surgical team actively communicate and provide oral verification of the patient’s identity, surgi-cal site, surgical procedure, administration of preoperative Brunicardi_Ch12_p0397-p0432.indd 41120/02/19 3:57 PM 412BASIC CONSIDERATIONSPART Imedications, and presence of appropriate medical records, imaging studies, and equipment• Monitoring compliance with protocol recommendationsFocusing on individual process components of the uni-versal protocol, such as surgical site marking or the time-out, is not enough to prevent wrong-site surgery. Over a 30-month period in Pennsylvania, 21 wrong-site errors occurred despite the proper use of time-out procedures, with 12 of these errors resulting in complete wrong-site procedures. During the same period, correct site markings failed to prevent another 16 wrong-site surgeries, of which six were not recognized until after the procedure had been completed.47Site verification begins with the initial patient encounter by the surgeon, continues throughout the preoperative verifica-tion process and during multiple critical points in the OR, and requires the active participation of the entire operating team, especially the surgeon and anesthesia provider. Based on a recent review of malpractice claims, two-thirds of wrong-site operations could have been prevented by a site-verification protocol.48Despite the proliferation of wrong-site protocols in the last decade, their effectiveness is difficult to measure as the inci-dence of wrong-site surgery is too rare to measure as a rate. Interestingly, the number of sentinel events reported to The Joint Commission has not changed significantly since the wide-spread implementation of the Universal Protocol in 2004.47 This could be due to an increase in reporting rather than an actual increase in the incidence of wrong-site surgery.The legal treatment of wrong-site surgery is similar to that of surgical items erroneously left in a patient: the mere fact that it occurred indicates that the patient did not receive proper surgical care. A malpractice claim may lead to a settlement or award on verdict in the sixor seven-figure range in 2011 U.S. dollars.41Ultimately, the occurrence of retained surgical items or wrong-site surgery is a reflection of the quality of professional communication between caregivers and the degree of teamwork among the members of the operating team. In addition to stan-dardizing procedures like the surgical count, instituting man-datory postoperative radiographs in the presence of a known miscount, and reforming the processes of patient identification and site verification, organizations should also strive to create a culture of safety, create independent and redundant checks for key processes, and create a system in which caregivers can learn from their mistakes (Table 12-10).49TRANSPARENCY IN HEALTHCAREDespite a large increase in data being collected about patient safety and harm, much of it is not available to the public or other hospitals. This lack of transparency allows some hos-pitals to continue to practice outdated medicine and, in some cases, puts patients at a higher risk of serious complications. In a study by Mark Chassin, the health commissioner of New York State, having hospitals publicly disclose their mortality rates for coronary artery bypass graft (CABG) procedures resulted in a 41% decline in mortality from CABGs statewide.50 In this study, when CABG mortality data were initially made public, there was a wide range in cardiac surgery-related mortality from 1% to 18%, depending on the hospital; the standard of care is 2%. The reasons for higher mortality in the poorly performing Table 12-10Best practices for operating room safety• Conduct The Joint Commission Universal Protocol (“time-out”) to prevent wrong-site surgery.• Perform an operating room briefing (checklist) to identify and mitigate hazards early.• Promote a culture of speaking up about safety concerns.• Use a screening X-ray to detect foreign bodies in high-risk cases.• Begin patient sign-outs with the most likely immediate safety hazard.Data from Michaels RK, Makary MA, Dahab Y, et al. Achieving the National Quality Forum’s “Never Events”: Prevention of wrong site, wrong procedure, and wrong patient operations, Ann Surg. 2007 Apr;245(4):526-532.hospitals ranged from poor communication between care teams to one rogue surgeon operating when the surgeon should not have been. The consequence of making this data transparent was that the hospitals held multidisciplinary, CUSP-like meetings, where as a team they decided on the measures to implement for improvement. Through this, over the next year, most hospitals decreased their mortality rate to below 2%. Even the hospital that had an 18% mortality rate decreased it to 7% within 3 years and 1.7% over the next several years.Transparency in healthcare is becoming central to the healthcare quality discussion. A new SCIP core measure is pub-lishing practitioner performance, and all Leapfrog survey results are published online where other hospitals and the public can see them. Additionally, different large medical societies, includ-ing the Society for Thoracic Surgery (STS), are encouraging and rewarding practitioners and hospitals that are transparent with their outcomes. Making hospital outcomes transparent makes hospitals accountable to the public for their outcomes and, in the case of New York, caused a radical improvement in the quality of care provided to patients. It also empowers patients by mak-ing them better informed about which hospital they choose for their care, which will further incentivize hospitals to improve.Public Reporting and Patient Assessment of CareThe epiphany moment in contemporary healthcare created by the Institute of Medicine report2 generated far-reaching effects. One important aspect has been development of a variety of ini-tiatives focused on the generation, endorsement, and reporting of numerous measures related to the safety and quality of health-care—primarily process and outcomes measures. However, the science of measure development is slow paced and, unfortu-nately, has difficulty evolving at the same pace of change as clinical medicine or healthcare delivery systems.Given the strong interest for improved knowledge and information by consumers of healthcare, the trend toward public reporting has rapidly gained momentum and outpaced report-ing from the measurement science community. This has sub-sequently created occasional confusion and uncertainty in the marketplace—simply because the generation of public reports are not necessarily always based upon solid scientific data or evidence. The resulting net effect can be creation of a prema-ture focus by organizations and providers on achieving success within influential public reporting venues (e.g., U.S. News Best Hospitals) and uncertainty by patients on what are optimal healthcare information resources.Brunicardi_Ch12_p0397-p0432.indd 41220/02/19 3:57 PM 413QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12Ideally centered on the public good, federal government sponsored healthcare payment plans are also focused upon mea-surement and reporting within the industry. One such initiative funded and overseen by the Agency for Healthcare Research and Quality (AHRQ) is the Hospital Consumer Assessment of Health-care Providers and Systems (HCAHPS) program.51 AHRQ works closely with a consortium of public and private research organi-zations to develop and maintain the HCAHPS surveys, but they do not administer any of the surveys to patients or require use of the surveys. The intent of the HCAHPS initiative is to provide a standardized survey instrument and data collection methodology for measuring patients’ perspectives on hospital care (Fig. 12-7).While many hospitals have collected information on patient satisfaction, prior to HCAHPS there was no national standard for collecting or publicly reporting patients’ perspec-tives of care information that would enable valid comparisons to be made across all hospitals. Three broad goals have shaped the HCAHPS Survey. First, the survey is designed to produce comparable data on the patient’s perspective on care that allows objective and meaningful comparisons between hospitals on domains that are important to consumers. Second, public report-ing of the survey results is designed to create incentives for hospitals to improve their quality of care. Hospitals frequently distribute the results of HCAHPS surveys of individual ser-vices or physicians to incentivize corrective steps and improve patients’ perceptions of their care. Third, public reporting will serve to enhance public accountability in healthcare by increas-ing the transparency of the quality of hospital care provided in return for the public investment (www.hcahpsonline.org).HCAHPS scores are now directly tied to a hospital’s CMS reimbursement by federal law, and survey results account for 25% of the value-based purchasing score—directly impacting a hospital’s Medicare payments.52 In May 2005, the National Quality Forum (NQF), an organization established to standard-ize healthcare quality measurement and reporting, formally endorsed the HCAHPS Hospital Survey. The NQF endorsement represents the consensus of many healthcare providers, consumer groups, professional associations, purchasers, federal agencies, and research and quality organizations (www.qualityforum.org).While the American College of Surgeons and other profes-sional societies continue to develop and implement scientifically based healthcare measures, the escalating prevalence of less robust measures developed outside of scientific communities will also continue to expand. The patient population, provider organizations, payer organization, and the surgical community will necessarily need to find the balance of developing and uti-lizing valid patient-based information for decision-making.RISK MANAGEMENTBetween one-half to two-thirds of hospital-wide adverse events are attributable to surgical care. Most surgical errors occur in the OR and are technical in nature. Surgical complications and adverse outcomes have previously been linked to lack of surgeon specialization, low hospital volume, communication breakdowns, fatigue, surgical residents and trainees, and numer-ous other factors.53However, poor surgical outcomes are not necessarily cor-related with a surgeon’s level of experience in performing a cer-tain procedure. In one study, three-fourths of the technical errors that occurred in a review of malpractice claims data involved fully trained and experienced surgeons operating within their area of expertise, and 84% occurred in routine operations that do not require advanced training. Rather than surgeon expertise, these errors likely occurred due to situations complicated by patient comorbidity, complex anatomy, repeat surgery, or equip-ment problems (Table 12-11). Because these errors occurred during routine operations, previous suggestions to limit the per-formance of high-complexity operations using selective refer-ral, regionalization, or limitation of privileging may not actually be effective in reducing the incidence of technical error among surgical patients.53In any event, although there has been much emphasis on reducing the prevalence of surgical technical errors as a way of improving surgical care, a technical error in the OR may not be the most important indicator of whether a surgeon will be sued by a patient. Recent studies point to the importance of a surgeon’s communication skills in averting malprac-tice litigation. In the American College of Surgeons’ Closed Claims Study, although intraoperative organ injuries occurred in 40% of patients, a surgical technical misadventure was the most deficient component of care in only 12% of patients. In fact, communication and practice pattern violations were the most common deficiency in care for one third of patients in the Closed Claims Study who received the expected standard of surgical care.54The Importance of Communication in Managing RiskThe manner and tone in which a physician communicates is potentially more important to avoiding a malpractice claim than the actual content of the dialogue. For example, a physician relating to a patient in a “negative” manner may trigger litigious feelings when there is a bad result, whereas a physician relating in a “positive” manner may not. Expressions of dominance, in which the voice tone is deep, loud, moderately fast, unaccented, and clearly articulated, may communicate a lack of empathy and understanding for the patient, whereas concern or anxiety in the surgeon’s voice is often positively related to expressing concern and empathy. General and orthopedic surgeons whose tone of voice was judged to be more dominant were more likely to have been sued than those who sounded less dominant.55When significant medical errors do occur, physicians have an ethical and professional responsibility to immediately dis-close them to patients. Failure to disclose errors to patients undermines public confidence in medicine and can create legal liability related to fraud. Physicians’ fear of litigation represents a major barrier to error disclosure. However, when handled appropriately, immediate disclosure of errors frequently leads to improved patient rapport, improved satisfaction, and fewer malpractice claims.56 In fact, rapport is the most important factor in determining whether a lawsuit is filed against a physician.In 1987, the Department of Veterans Affairs Hospital in Lexington, Kentucky, implemented the nation’s first formal apology and medical error full disclosure program, which called for the hospital and its doctors to work with patients and their families to settle a case. As a result, the hospital improved from having one of the highest malpractice claims totals in the VA system to being ranked among the lowest quartile of a com-parative group of similar hospitals for settlement and litiga-tion costs over a 7-year period. Its average payout in 2005 was $16,000 per settlement vs the national VA average of $98,000 per settlement, and only two lawsuits went to trial during a 9Brunicardi_Ch12_p0397-p0432.indd 41320/02/19 3:57 PM 414BASIC CONSIDERATIONSPART IYOUR CARE FROM DOCTORSDuring this hospital stay, how oftendid doctors treat you with courtesyand respect?5.NeverSometimesUsuallyAlways1234During this hospital stay, how oftendid doctors listen carefully to you?6.NeverSometimesUsuallyAlways1234During this hospital stay, how oftendid doctors explain things in a wayyou could understand?7.During this hospital stay, how oftenwere your room and bathroom keptclean?8.NeverSometimesUsuallyAlways1234THE HOSPITAL ENVIRONMENTNeverSometimesUsuallyAlways1234During this hospital stay, how oftenwas the area around your room quietat night?9.NeverSometimesUsuallyAlways1234YOUR EXPERIENCES IN THIS HOSPITALDuring this hospital stay, did youneed help from nurses or otherhospital staff in getting to thebathroom or in using a bedpan?10.YesNo If No, Go to Question 1212During this hospital stay, did youhave any pain?12.YesNo If No, Go to Question 1512NeverSometimesUsuallyAlways1234How often did you get help in gettingto the bathroom or in using a bedpanas soon as you wanted?11.NeverSometimesUsuallyAlways1234During this hospital stay, how oftendid hospital staff talk with you abouthow much pain you had?13.During this hospital stay, how oftendid hospital staff talk with you abouthow to treat your pain?14.NeverSometimesUsuallyAlways12342January 2018Table 12-11Common causes of lawsuits in surgery• Positional nerve injury• Common bile duct injury• Failure to diagnose or delayed diagnosis• Failure to treat, delayed treatment, or wrong treatment• Inadequate documentation• Inappropriate surgical indication• Failure to call a specialist• Cases resulting in amputation/limb lossFigure 12-7. Survey page from 2018 HCAHPS patient questionnaire. (Modified with permission from Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) https://www.hcahpsonline.org/en/survey-instruments/. Accessed October 24, 2018.)10-year period. As a result of the success of this program, the Department of Veteran Affairs expanded the program to all VA hospitals nationwide in October 2005. This model also was rep-licated at the University of Michigan Health System with simi-lar results. Its full-disclosure program cut the number of pending lawsuits by one half and reduced litigation costs per case from $65,000 to $35,000, saving the hospital approximately $2 mil-lion in defense litigation bills each year. In addition, University of Michigan’s doctors, patients, and lawyers are happier with this system. The cultural shift toward honesty and openness also has led to the improvement of systems and processes to reduce medical errors, especially repeat medical errors.57Brunicardi_Ch12_p0397-p0432.indd 41420/02/19 3:57 PM 415QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12With regard to risk management, the importance of good communication by surgeons and other care providers cannot be overemphasized. Whether alerting other members of the care team about a patient’s needs, openly discussing concerns the patient and/or family might have, or disclosing the cause of a medical error, open communication with all parties involved can reduce anger and mistrust of the medical system; the frequency, morbidity, and mortality of preventable adverse events; and the likelihood of litigation.COMPLICATIONSDespite the increased focus on improving patient safety and minimizing medical errors, it is impossible to eliminate human error entirely. Individual errors in judgment or technique can cause minor or major complications during or after a surgical procedure. Although these types of errors may not be quantified as easily as wrong-site surgery or a retained surgical item, they can still lead to surgical complications that prolong the course of illness, lengthen hospital stay, and increase morbidity and mortality rates. In addition to technical and management errors, patient comorbidities also increase the risk of complications. The recognition and management of complications is a critical component of surgical care.Robotic SurgerySurgical advancements would not exist without intellectual curi-osity, innovation, and technical developments; robotic surgery is a prime example of such an advance. With these advance-ments, however, errors and complications appear to be an inevi-table and recognized risk by institutions and stakeholders due to unforeseen risks inherent in the new technology and the failure or delay of achieving expertise with a new device or technology. Although the reward for adopting new advances may be noto-riety, increased patient referrals, improved patient satisfaction, decreased pain, and possibly decreased length of stay, the risks of adopting new technologies and methods become apparent only after widespread use.Multiple surgical specialties have begun or continue to develop their experiences using robotic surgery from general surgery procedures such as inguinal hernia repairs to pancreati-coduodenectomies to complex thoracic, urologic and ear, nose, and throat procedures. When robotic surgery goes awry, how-ever, the complications can be serious. The MAUDE (Manu-facturer and User Facility Device Experience) is an open access database where mandatory and voluntary adverse events are collected. As it relates to robotic surgery, some important infor-mation has been elucidated. Device failures (electrocautery, instrument malfunctions), make up roughly half of the com-plications. A retrospective study over the past 14 years in the United States documented over 10,000 robotic device-related complications that have occurred, of which 98% were reported by the manufacturers and distributers, and 2% were voluntary reports by hospitals and physicians. The data revealed that 1535 adverse events (14.4%) led to significant negative patient expe-riences (1391 injuries and 144 deaths). Additionally, the abso-lute number of reports increased 32 times since 2006, while in the same time period, the number of cases performed has only increased tenfold.58 Despite the large number of reports con-tained within this database, the extent to which it is a true rep-resentation of the complications associated with robotic surgery is uncertain due to the lack of comprehensive and mandatory reporting.59Despite the numbers and trends reported from this data-base, few prospective, controlled trials exist that examine the risks and benefits of robotic surgery with those of open and laparoscopic surgery. The data from 5 to 10 years ago may also be misleading as the approved use of robotic surgery continues to expand to additional specialties. The more recent adoption of robotic surgery by specialties such as gynecologic surgery, for example, appears to be accompanied by a disproportionately high rate of morbidity and mortality in robotically assisted pro-cedures.59 Teaching institutions are producing a newer genera-tion of robotic surgeons who will continue important advances in surgery and identify those patients who would benefit most from this type of approach. The challenge for the surgical com-munity is to develop robust and effective training programs to allow trainees and practicing surgeons to acquire the skills nec-essary to perform robotic procedures with the highest degree of safety. This need replicates the development of skill acquisition processes that reversed the high number of bile duct injuries after the introduction of laparoscopic cholecystectomy and sug-gests that validated curricula and the use of robotic simulation applications will be crucial to achieve these goals (see Chapter 53, Skills and Simulation).Complications in Minor ProceduresWhen performing procedures such as central line insertion or arterial line insertion, one should consider the necessity of the access, the use of less invasive or lower risk alternatives such as PICC line insertion instead of central line insertion, and non-invasive cardiac monitoring instead of arterial line insertion. While these alternatives may not be reliable substitutes in all patients, considering less invasive procedures can reduce the problem of avoidable harm.Central Venous Access Catheters. Complications of central venous access catheters are common. Improvements in ultra-sound technology and mass education surrounding the use and techniques in ultrasonography have led to increased employ-ment and enthusiasm for its use in central venous catheter placement. Numerous institutions have mandated the use of ultrasound for placement of all central venous lines. In addition, many subclavian catheters have been alternatively placed at the internal jugular position due to a perceived benefit of decreasing the complication of pneumothorax. This theoretical benefit may be offset by an increase in line infections as the neck is a dif-ficult site to keep clean and the dressing intact. Steps to decrease complications include:• Ensure that central venous access is indicated.• Experienced personnel should insert the catheter or should supervise the insertion.• Use proper positioning and sterile technique.• Ultrasound is recommended for internal jugular vein insertion.• All central venous catheters should be assessed on a daily basis and should be exchanged only for specific indications (not as a matter of routine).• All central catheters should be removed as soon as possible.Common complications of central venous access include the following.Pneumothorax Occurrence rates from both subclavian and internal jugular vein approaches are 1% to 6%. Prevention requires proper positioning of the patient and correct insertion technique. A postprocedure chest X-ray is recommended to confirm the presence or absence of a pneumothorax, regardless Brunicardi_Ch12_p0397-p0432.indd 41520/02/19 3:57 PM 416BASIC CONSIDERATIONSPART Iof whether a pneumothorax is suspected. Recent reports have questioned whether a chest X-ray is required when the line is placed and confirmed under ultrasound guidance. Pneumotho-rax rates are higher among inexperienced providers and under-weight patients but occur with experienced operators as well. If the patient is stable, and the pneumothorax is small (<15%), close expectant observation may be adequate. If the patient is symptomatic, a thoracostomy tube should be placed. Occasion-ally, pneumothorax will occur as late as 48 to 72 hours after central venous access attempts. This usually creates sufficient compromise that a tube thoracostomy is required.Arrhythmias Arrhythmias can result from myocardial irritabil-ity secondary to guidewire placement and usually resolve when the catheter or guidewire is withdrawn from the right heart. Pre-vention requires electrocardiogram (ECG) monitoring whenever possible during catheter insertion and rapid recognition when a new arrhythmia occurs.Arterial Puncture Inadvertent puncture or laceration of an adja-cent artery with bleeding can occur, but the majority will resolve with direct pressure on or near the arterial injury site. Rarely will angiography, stent placement, or surgery be required to repair the puncture site, but close observation and a chest X-ray are indi-cated. Ultrasound-guided insertion has not mitigated this com-plication, but it may decrease the incidence of arterial puncture. Ultrasound use has also been shown to decrease the number of attempts and the time it takes to complete insertion.Lost Guidewire A guidewire or catheter that inadvertently migrates further into the vascular space away from the insertion site can be readily retrieved with interventional angiography techniques. A prompt chest X-ray and close monitoring of the patient until retrieval are indicated.Air Embolus Although estimated to occur in only 0.2% to 1% of patients, an air embolism can be dramatic and fatal. If an embolus is suspected, the patient should immediately be placed into a left lateral decubitus Trendelenburg position so the entrapped air can be stabilized within the right ventricle. Aus-cultation over the precordium may reveal a “crunching” sound, but a portable chest X-ray will help confirm the diagnosis. Aspi-ration via a central venous line accessing the heart may decrease the volume of gas in the right side of the heart and minimize the amount traversing into the pulmonary circulation. Subsequent recovery of intracardiac and intrapulmonary air may require open surgical or angiographic techniques. Treatment may prove futile if the air bolus is larger than 50 mL, however.Pulmonary Artery Rupture Flow-directed, pulmonary artery (Swan-Ganz) catheters can cause pulmonary artery rupture due to excessive advancement of the catheter into the pulmonary cir-culation. There usually is a sentinel bleed with coughing noted when a pulmonary artery catheter balloon is inflated, followed by uncontrolled hemoptysis. Reinflation of the catheter balloon is the initial step in management, followed by immediate airway intubation with mechanical ventilation, an urgent portable chest X-ray, and notification of the OR that an emergent thoracotomy may be required. If there is no further bleeding after the bal-loon is reinflated, the X-ray shows no significant consolidation of lung fields from ongoing bleeding, and the patient is easily ventilated, then a conservative nonoperative approach may be considered. However, more typically a pulmonary angiogram with angioembolization or vascular stenting is required. Hemo-dynamically unstable patients rarely survive because of the time needed to initiate and perform interventional procedures or a thoracotomy and to identify the ruptured branch of the pulmo-nary artery.Central Venous Line Infection The CDC reports mortal-ity rates of 12% to 25% when a central venous line infection becomes systemic, with a cost of approximately $25,000 per episode.60-62 The CDC does not recommend routine central line changes, but when the clinical suspicion of infection is high, the site of venous access must be changed. Nearly 15% of hospital-ized patients will acquire central venous line sepsis. In many instances, once an infection is recognized as central line sepsis, removing the line is adequate. Staphylococcus aureus infections, however, present a unique problem because of the potential for metastatic seeding of bacterial emboli. The required treatment is 4 to 6 weeks of tailored antibiotic therapy. Using a check-list when inserting central venous catheters has been shown to significantly decrease rates of line infections.63 Following a checklist strategy and close monitoring of catheters has resulted in significant reductions in infection rates for numerous institu-tions, and many are now reporting zero annual infection rates.Arterial Lines. Arterial lines are placed to facilitate arterial blood gas sampling and hemodynamic monitoring. The use of ultrasound to assist in placement of these catheters has become commonplace and markedly reduces the number of attempts and time for insertion completion.Arterial access requires a sterile Seldinger technique, and a variety of arteries are used, including the radial, femoral, bra-chial, axillary, dorsalis pedis, or superficial temporal arteries. Although complications occur less than 1% of the time, they can be catastrophic. Complications include thrombosis, bleed-ing, hematoma, arterial spasm (nonthrombotic pulselessness), and infection. Thrombosis or embolization of an extremity arte-rial catheter can result in the loss of a digit, hand, or foot, and the risk is nearly the same for both femoral and radial cannula-tion. Thrombosis with distal tissue ischemia is treated with anti-coagulation, but occasionally surgical intervention is required. Pseudoaneurysms and arteriovenous fistulae can also occur.Endoscopy and Bronchoscopy. The principal risk of gastro-intestinal (GI) endoscopy is perforation. Perforations occur in 1 in 10,000 patients with endoscopy alone but have a higher incidence rate when biopsies are performed (up to 10%). This increased risk is due to complications of intubating a GI diver-ticulum (either esophageal or colonic) or from the presence of weakened or inflamed tissue in the intestinal wall (e.g., diver-ticulitis, glucocorticoid use, or inflammatory bowel disease).Patients will usually complain of diffuse abdominal pain shortly after the procedure and then progress with worsen-ing abdominal discomfort and peritonitis on examination. In obtunded or elderly patients, a change in clinical status may be delayed for 24 to 48 hours. Radiologic studies to look for free intraperitoneal air, retroperitoneal air, or a pneumothorax are diagnostic. Open or laparoscopic exploration locates the perfo-ration and allows repair and local decontamination of the sur-rounding tissues.The occasional patient who may be a candidate for nonop-erative management is one in whom perforation arises during an elective, bowel-prepped endoscopy and who does not have sig-nificant pain or clinical signs of infection. These patients must be closely observed in a monitored setting and must be on strict dietary restriction and broad-spectrum antibiotics.Complications of bronchoscopy include bronchial plug-ging, hypoxemia, pneumothorax, lobar collapse, and bleeding. Brunicardi_Ch12_p0397-p0432.indd 41620/02/19 3:57 PM 417QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12When diagnosed in a timely fashion, they are rarely life-threatening. Bleeding usually resolves spontaneously and rarely requires surgery but may require repeat endoscopy for thermocoagula-tion or fibrin glue application. The presence of a pneumothorax necessitates placement of a thoracostomy tube when significant deoxygenation occurs or the pulmonary mechanics are compro-mised. Lobar collapse or mucous plugging usually responds to aggressive pulmonary toilet but occasionally requires repeat bronchoscopy. If biopsies have been performed, the risk for these complications increases.Tracheostomy. Tracheostomy facilitates weaning from a ventilator, may decrease length of ICU or hospital stay, and improves pulmonary toilet. Tracheostomies are performed open, percutaneously, with or without bronchoscopy, and with or without Doppler guidance. The advantages of percutaneous tracheostomy include efficiency and cost containment over open tracheostomy. A recent literature review examining early (<3–7 days) vs late (>14 days) tracheostomy after endotracheal intubation demonstrates little difference in outcomes but does demonstrate greater patient comfort in those patients with tra-cheostomy than those with an endotracheal tube. Complications and outcomes between the two different methods remain largely equivalent.Recent studies do not support obtaining a routine chest X-ray after percutaneous or open tracheostomy.64,65 However, significant lobar collapse can occur from copious tracheal secre-tions or mechanical obstruction. The most dramatic complica-tion of tracheostomy is tracheoinnominate artery fistula (TIAF) (Fig. 12-8).66,67 This occurs rarely (∼0.3%) but carries a 50% to 80% mortality rate. TIAFs can occur as early as 2 days or as late as 2 months after tracheostomy. A sentinel bleed occurs in 50% of TIAF cases, followed by a large-volume bleed. Should a TIAF be suspected, the patient should be transported imme-diately to the OR for fiberoptic evaluation. If needed, remove the tracheostomy and place a finger through the tracheostomy site to apply direct pressure anteriorly for compression of the innominate artery while preparation for a more definitive approach is organized.Percutaneous Endogastrostomy. A misplaced percutane-ous endogastrostomy (PEG) tube may lead to intra-abdominal sepsis with peritonitis and/or an abdominal wall abscess with necrotizing fasciitis. As in other minor procedures, the initial placement technique must be fastidious to avoid complications. Figure 12-8. This illustration depicts improper positioning of the percutaneous needle. It is possible to access the innominate artery via the trachea, thus placing the patient at risk for early tracheoin-nominate artery fistula.XEndoscopic transillumination of the abdomen from within the stomach has been proposed to decrease the risk for error, but this is without supporting evidence. Inadvertent colotomies, intraperitoneal placement of the tube and subsequent leakage of tube feeds with peritonitis, and abdominal wall abscesses require surgery to correct the complications and to replace the PEG with an alternate feeding tube, usually a jejunostomy.A dislodged or prematurely removed PEG tube should be replaced as early as possible after dislodgment because the gas-trostomy site closes rapidly. A contrast X-ray (sinogram) should be performed to confirm the tube’s intragastric position before feeding. If there is uncertainty of the tube location, conversion to an open tube placement procedure is required.Tube Thoracostomy. Chest tube insertion is performed for pneumothorax, hemothorax, pleural effusions, or empyema. In most patients, a chest tube can be easily placed with a combina-tion of local analgesia and light conscious sedation. Common complications include inadequate analgesia or sedation, incom-plete penetration of the pleura with formation of a subcutaneous tube track, lacerations to the lung or diaphragm, intraperitoneal placement of the tube through the diaphragm, and bleeding. Additional problems include slippage of the tube out of posi-tion or mechanical problems related to the drainage system. In patients with bullous disease, there can be significant intrapleu-ral scarring, and it can be easy to mistakenly place the chest tube into bullae. All of these complications can be avoided with proper initial insertion techniques, plus a daily review of the drainage system and follow-up radiographs. Tube removal can create a residual pneumothorax if the patient does not maintain positive intrapleural pressure by Valsalva maneuver during tube removal and dressing application.Complications of Angiography. Intramural dissection of a cannulated artery can lead to complications such as ischemic stroke from a carotid artery dissection or occlusion, mesenteric ischemia from dissection of the superior mesenteric artery, or a more innocuous finding of “blue toe syndrome” from a dissected artery in a peripheral limb. Invasive or noninvasive imaging studies confirm the suspected problem. The severity of ischemia and extent of dissection determine if anticoagulation therapy or urgent surgical exploration is indicated.Bleeding from a vascular access site usually is obvious, but may not be visible when the blood loss is tracking into the retroperitoneal tissue planes after femoral artery cannulation. These patients can present with hemorrhagic shock; an abdomi-nopelvic CT scan delineates the extent of bleeding along the retroperitoneum. Initial management is direct compression at the access site and resuscitation as indicated. Urgent surgical exploration may be required to control the bleeding site and evacuate larger hematomas.Renal complications of angiography occur in 1% to 2% of patients. Contrast nephropathy is a temporary and prevent-able complication of radiologic studies such as CT, angiogra-phy, and/or venography. Intravenous (IV) hydration before and after the procedure is the most efficient method for preventing contrast nephropathy. Nonionic contrast also may be of benefit in higher-risk patients. Close communication between provid-ers is often required to resolve the priorities in care as well as to balance the risks versus benefits of renal protection when managing patients in need of angiographic procedures.Complications of Biopsies. Lymph node biopsies have direct and indirect complications that include bleeding, infection, Brunicardi_Ch12_p0397-p0432.indd 41720/02/19 3:57 PM 418BASIC CONSIDERATIONSPART Ilymph leakage, and seromas. Measures to prevent direct com-plications include proper surgical hemostasis, proper skin prepa-ration, and a single preoperative dose of antibiotic to cover skin flora 30 to 60 minutes before incision. Bleeding at a biopsy site usually can be controlled with direct pressure. Infection at a biopsy site will appear 5 to 10 days postoperatively and may require opening of the wound to drain the infection. Seromas or lymphatic leaks resolve with aspiration of seromas and the application of pressure dressings but may require repeated treat-ments or even placement of a vacuum drain.Organ System ComplicationsNeurologic System. Neurologic complications that occur after surgery include motor or sensory deficits and mental sta-tus changes. Peripheral motor and sensory deficits are often due to neurapraxia secondary to improper positioning and/or pad-ding during operations. Treatment is largely clinical observa-tion, and the majority of deficits resolve spontaneously within 1 to 3 months.Direct injury to nerves during a surgical intervention is a well-known complication of several specific operations, includ-ing superficial parotidectomy (facial nerve), carotid endarterec-tomy (hypoglossal nerve), thyroidectomy (recurrent laryngeal nerve), prostatectomy (nervi erigentes), inguinal herniorrhaphy (ilioinguinal nerve), and mastectomy (long thoracic and thora-codorsal nerves). The nerve injury may be a stretch injury or an unintentionally severed nerve. In addition to loss of function, severed nerves can result in a painful neuroma that may require subsequent surgery.Mental status changes in the postoperative patient can have numerous causes (Table 12-12). Mental status changes must be continually assessed. A noncontrast CT scan should be used early to detect new or evolving intracranial causes.Atherosclerotic disease increases the risk for intraoperative and postoperative stroke (cerebrovascular accident). Postopera-tively, hypotension and hypoxemia are the most likely causes of a cerebrovascular accident. Neurologic consultation should be obtained immediately to confirm the diagnosis. Management is largely supportive and includes adequate intravascular volume replacement plus optimal oxygen delivery. Advents in inter-ventional radiology by radiologists and vascular and neurologic Table 12-12Common causes of mental status changesELECTROLYTE IMBALANCETOXINSTRAUMAMETABOLICMEDICATIONSSodiumEthanolClosed head injuryThyrotoxicosisAspirinMagnesiumMethanolPainAdrenal insufficiencyβ-BlockersCalciumVenoms and poisonsShockHypoxemiaNarcoticsInflammationEthylene glycolPsychiatricAcidosisAntiemeticsSepsisCarbon monoxideDementiaSevere anemiaMAOIsAIDS DepressionHyperammonemiaTCAsCerebral abscess ICU psychosisPoor glycemic controlAmphetaminesMeningitis SchizophreniaHypothermiaAntiarrhythmicsFever/hyperpyrexia  HyperthermiaCorticosteroids, anabolic steroidsAIDS = acquired immunodeficiency syndrome; ICU = intensive care unit; MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant.surgeons have proven successful alternatives in patients requir-ing diagnostic and therapeutic care in the immediate and acute postoperative period. Catheter-directed therapy with anticoagu-lants such as the kinases and tissue plasminogen activator (tPA) has potential benefit in postoperative thrombosis where reopera-tion carries significant risk. In addition, endoluminal stents with drug-eluting stents (DESs) or non-DESs have been used with some degree of success. DESs do require systemic antiplatelet therapy due to the alternative coagulation pathway. Duration of antiplatelet therapy of 1 year is routine.Eyes, Ears, and Nose. Corneal abrasions are unusual, but are due to inadequate protection of the eyes during anesthe-sia. Overlooked contact lenses in patients occasionally cause conjunctivitis.Persistent epistaxis can occur after nasogastric tube place-ment or removal, and nasal packing is the best treatment option if prolonged persistent direct pressure on the external nares fails. Anterior and posterior nasal gauze packing with balloon tam-ponade, angioembolization, and fibrin glue placement may be required in refractory cases. The use of antibiotics for posterior packing is controversial.External otitis and otitis media occasionally occur post-operatively. Patients complain of ear pain or decreased hearing, and treatment includes topical antibiotics and nasal deconges-tion for symptomatic improvement.Ototoxicity due to aminoglycoside administration occurs in up to 10% of patients and is often irreversible. Vancomycin-related ototoxicity occurs about 3% of the time when used alone, and as often as 6% when used with other ototoxic agents.68Vascular Problems of the Neck. Complications of carotid endarterectomy include central or regional neurologic defi-cits or bleeding with an expanding neck hematoma. An acute change in mental status or the presence of localized neurologic deficit requires an immediate return to the OR. An expanding hematoma may warrant emergent airway intubation and subse-quent transfer to the OR for control of hemorrhage. Intraopera-tive anticoagulation with heparin during carotid surgery makes bleeding a postoperative risk. Other complications include arte-riovenous fistulae, pseudoaneurysms, and infection, all of which are treated surgically.Brunicardi_Ch12_p0397-p0432.indd 41820/02/19 3:57 PM 419QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12Intraoperative hypotension during manipulation of the carotid bifurcation can occur and is related to increased tone from baroreceptors that reflexively cause bradycardia. Should hypotension occur when manipulating the carotid bifurcation, an injection of 1% lidocaine solution around this structure should attenuate this reflexive response.The most common delayed complication following carotid endarterectomy remains myocardial infarction. The possibility of a postoperative myocardial infarction should be considered as a cause of labile blood pressure and arrhythmias in high-risk patients.Thyroid and Parathyroid Glands. Surgery of the thyroid and parathyroid glands can result in hypocalcemia in the immedi-ate postoperative period. Manifestations include ECG changes (shortened P-R interval), muscle spasm (tetany, Chvostek’s sign, and Trousseau’s sign), paresthesias, and laryngospasm. Treatment includes calcium gluconate infusion and, if tetany ensues, chemical paralysis with intubation. Maintenance treat-ment is thyroid hormone replacement (after thyroidectomy) in addition to calcium carbonate and vitamin D.Recurrent laryngeal nerve (RLN) injury occurs in less than 5% of patients. Of those with injury, approximately 10% are permanent. Dissection near the inferior thyroid artery is a com-mon area for RLN injury. At the conclusion of the operation, if there is suspicion of an RLN injury, direct laryngoscopy is diag-nostic. The cord on the affected side will be in the paramedian position. With bilateral RLN injury, the chance of a successful extubation is poor. If paralysis of the cords is not permanent, function may return 1 to 2 months after injury. Permanent RLN injury can be treated by various techniques to stent the cords in a position of function.Superior laryngeal nerve injury is less debilitating, as the common symptom is loss of projection of the voice. The glottic aperture is asymmetrical on direct laryngoscopy, and manage-ment is limited to clinical observation.Respiratory System. Surgical complications that put the respiratory system in jeopardy are not confined to techni-cal errors. Malnutrition, inadequate pain control, inadequate mechanical ventilation, inadequate pulmonary toilet, and aspi-ration can cause serious pulmonary problems.Pneumothorax can occur from central line insertion during anesthesia or from a diaphragmatic injury during an abdomi-nal procedure. Hypotension, hypoxemia, and tracheal deviation away from the affected side may be present. A tension pneumo-thorax can cause complete cardiovascular collapse. Treatment is by needle thoracostomy, followed by tube thoracostomy. The chest tube is inserted at the fifth intercostal space in the anterior axillary line. The anterior chest wall is up to 1 cm thicker than the lateral chest wall, so needle decompression is more effec-tive in the lateral position. Attempted prehospital needle decom-pression in the traditional anterior position results in only 50% needle entry into the thoracic cavity.Hemothoraces should be evacuated completely. Delay in evacuation of a hemothorax leaves the patient at risk for empy-ema and entrapped lung. If evacuation is incomplete with tube thoracostomy, video-assisted thoracoscopy or open evacuation and pleurodesis may be required.Pulmonary atelectasis results in a loss of functional resid-ual capacity (FRC) of the lung and can predispose to pneumo-nia. Poor pain control in the postoperative period contributes to poor inspiratory effort and collapse of the lower lobes in particular. The prevention of atelectasis is facilitated by sit-ting the patient up as much as possible, early ambulation, and adequate pain control. An increase in FRC by 700 mL or more can be accomplished by sitting patients up to greater than 45°. For mechanically ventilated patients, simply placing the head of the bed at 30° to 45° elevation and delivering adequate tidal volumes (8–10 mL/kg) improves pulmonary outcomes.69Patients with inadequate pulmonary toilet are at increased risk for bronchial plugging and lobar collapse. Patients with copious and tenacious secretions develop these plugs most often, but foreign bodies in the bronchus can be the cause of lobar collapse as well. The diagnosis of bronchial plugging is based on chest X-ray and clinical suspicion with acute pulmo-nary decompensation with increased work of breathing and hypoxemia. Fiberoptic bronchoscopy can be useful to clear mucous plugs and secretions.Aspiration complications include pneumonitis and pneu-monia. The treatment of pneumonitis is similar to that for acute respiratory distress syndrome (see later in this section) and includes oxygenation with general supportive care. Antibiotics are not indicated. Hospitalized patients who develop aspiration pneumonitis have a mortality rate as high as 70% to 80%. Early, aggressive, and repeated bronchoscopy for suctioning of aspi-rated material from the tracheobronchial tree will help mini-mize the inflammatory reaction of pneumonitis and facilitate improved pulmonary toilet. Forced diuresis to overcome ana-sarca and over-resuscitation remains controversial and unsub-stantiated. Complications of forced diuresis include electrolyte disturbances, replacement of those electrolytes, metabolic alka-losis, hypotension, and acute kidney injury.Pneumonia is the second most common nosocomial infec-tion and is the most common infection in ventilated patients. Ventilator-associated pneumonia (VAP) occurs in 15% to 40% of ventilated ICU patients, with a probability rate of 5% per day, up to 70% at 30 days. The 30-day mortality rate of nosocomial pneumonia can be as high as 40% and depends on the micro-organisms involved and the timeliness of initiating appropri-ate antimicrobials. Protocol-driven approaches for prevention and treatment of VAP are recognized as beneficial in managing these difficult infectious complications.Once the diagnosis of pneumonia is suspected (an abnormal chest X-ray, fever, productive cough with purulent sputum, and no other obvious fever sources), it is invariably necessary to ini-tially begin treatment with broad-spectrum antibiotics until proper identification, colony count (≥100,000 colony-forming units [CFU]), and sensitivity of the microorganisms are determined. The spectrum of antibiotic coverage should be narrowed as soon as the culture sensitivities are determined. Double-coverage anti-biotic strategy for the two pathogens, Pseudomonas and Acineto-bacter spp., may be appropriate if the local prevalence of these particularly virulent organisms is high. One of the most helpful tools in treating pneumonia and other infections is the tracking of a medical center’s antibiogram every 6 to 12 months.70Epidural analgesia decreases the risk of perioperative pneumonia. This method of pain control improves pulmonary toilet and the early return of bowel function; both have a sig-nificant impact on the potential for aspiration and for acquir-ing pneumonia. The routine use of epidural analgesia results in a lower incidence of pneumonia than patient-controlled analgesia.71Acute lung injury (ALI) was a diagnosis applied to patients with similar findings to those with acute respiratory distress Brunicardi_Ch12_p0397-p0432.indd 41920/02/19 3:57 PM 420BASIC CONSIDERATIONSPART Isyndrome (ARDS). The Berlin definition of ARDS developed by the American-European Consensus Conference of 2012 not only simplifies the definition of ARDS but also eliminates the term ALI from critical care vernacular. ARDS is now classified by partial pressure of oxygen in arterial blood (Pao2)/fraction of inspired oxygen (Fio2) ratios as mild (300–201 mmHg), moder-ate (200–101 mmHg), and severe (<100 mmHg). Elements of modification of the definition include the following: <7 days of onset; removal of pulmonary artery occlusion pressure; and clinical judgment for characterizing hydrostatic pulmonary edema is acceptable, unless risk factors for ARDS have been eliminated, in which case objective analysis is necessary.72-75The definition of ARDS traditionally included five crite-ria (Table 12-13). The multicenter ARDS Research Network (ARDSnet) research trial demonstrated improved clinical out-comes for ARDS patients ventilated at tidal volumes of only 5 to 7 mL/kg.76 This strategy is no longer prescribed solely for patients with ARDS but is also recommended for patients with normal pulmonary physiology who are intubated for reasons other than acute respiratory failure. The beneficial effects of positive end-expiratory pressure (PEEP) for ARDS were con-firmed in this study as well. The maintenance of PEEP during ventilatory support is determined based on blood gas analysis, pulmonary mechanics, and requirements for supplemental oxy-gen. As gas exchange improves with resolving ARDS, the initial step in decreasing ventilatory support should be to decrease the levels of supplemental oxygen first, and then to slowly bring the PEEP levels back down to minimal levels.77 This is done to minimize the potential for recurrent alveolar collapse and a worsening gas exchange.Not all patients can be weaned easily from mechanical ventilation. When the respiratory muscle energy demands are not balanced or there is an ongoing active disease state external to the lungs, patients may require prolonged ventilatory sup-port. Protocol-driven ventilator weaning strategies are success-ful and have become part of the standard of care. The use of a weaning protocol for patients on mechanical ventilation greater than 48 hours reduces the incidence of VAP and the overall length of time on mechanical ventilation. Unfortunately, there is still no reliable way of predicting which patient will be suc-cessfully extubated after a weaning program, and the decision for extubation is based on a combination of clinical parameters and measured pulmonary mechanics.78 The Tobin Index (fre-quency [breaths per minute]/tidal volume [L]), also known as the rapid shallow breathing index, is perhaps the best negative predictive instrument.79 If the result equals less than 105, then Table 12-13Inclusion criteria for the acute respiratory distress syndromeAcute onsetPredisposing conditionPao2:Fio2 <200 (regardless of positive end-expiratory pressure)Bilateral infiltratesPulmonary artery occlusion pressure <18 mmHgNo clinical evidence of right heart failureFio2 = fraction of inspired oxygen; Pao2 = partial pressure of arterial oxygen.there is nearly a 70% chance the patient will pass extubation. If the score is greater than 105, the patient has an approximately 80% chance of failing extubation. Other parameters such as the negative inspiratory force, minute ventilation, and respiratory rate are used, but individually these have no better predictive value than the rapid shallow breathing index.80Malnutrition and poor nutritional support may adversely affect the respiratory system. The respiratory quotient (RQ), or respiratory exchange ratio, is the ratio of the rate of carbon dioxide (CO2) produced to the rate of oxygen uptake (RQ = Vco2/V.O2). Lipids, carbohydrates, and protein have differing effects on CO2 production. Patients consuming a diet of mostly carbohydrates have an RQ of 1 or greater. The RQ for a diet of mostly lipids is closer to 0.7, and that for a diet of mostly protein is closer to 0.8. Ideally, an RQ of 0.75 to 0.85 suggests adequate balance and composition of nutrient intake. An excess of car-bohydrate may negatively affect ventilator weaning because of the abnormal RQ due to higher CO2 production and altered pul-monary gas exchange.Although not without risk, tracheostomy decreases the pulmonary dead space and provides for improved pulmonary toilet. When performed before the tenth day of ventilatory sup-port, tracheostomy may decrease the incidence of VAP, the overall length of ventilator time, and the number of ICU patient days.The occurrence of PE is probably underdiagnosed. Its eti-ology is thought to stem from DVT. This concept, however, has recently been questioned by Spaniolas et al.81 The diagno-sis of PE is made when a high degree of clinical suspicion for PE leads to imaging techniques such as ventilation–perfusion nuclear scans or CT pulmonary angiogram. Clinical findings include elevated central venous pressure, hypoxemia, shortness of breath, hypocarbia secondary to tachypnea, and right heart strain on ECG. Ventilation–perfusion nuclear scans are often indeterminate in patients who have an abnormal chest X-ray and are less sensitive than a CT angiogram or pulmonary angio-gram for diagnosing PE. The pulmonary angiogram remains the gold standard for diagnosing PE, but spiral CT angiogram has become an alternative method because of its relative ease of use and reasonable rates of diagnostic accuracy. For cases without clinical contraindications to therapeutic anticoagula-tion, patients should be empirically started on heparin infusion until the imaging studies are completed if the suspicion of a PE is high.Sequential compression devices on the lower extremities and low-dose subcutaneous heparin or low molecular weight heparinoid administration are routinely used to prevent DVT and, by inference, the risk of PE. Neurosurgical and orthopedic patients have higher rates of PE, as do obese patients and those at prolonged bed rest.When anticoagulation is contraindicated, or when a known clot exists in the inferior vena cava (IVC), decreasing the risk for PE includes insertion of an IVC filter. The Greenfield filter has been most widely studied, and it has a failure rate of less than 4%. Newer devices include those with nitinol wire that expands with body temperature and retrievable filters. Retrievable filters, however, must be considered as permanent. In most studies, the actual retrievable rate only reached about 20%. Some studies recognize the benefit of automated reminders and diligence of outlying patient follow-up, where higher retrieval rates have been achieved.82 Patients with spinal cord injury and multiple long-bone or pelvic fractures frequently receive IVC filters, and Brunicardi_Ch12_p0397-p0432.indd 42020/02/19 3:57 PM 421QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12there appears to be a low, but not insignificant, long-term com-plication rate with their use. However, IVC filters do not prevent PEs that originate from DVTs of the upper extremities.Cardiac System. Arrhythmias are often seen preoperatively in elderly patients but may occur postoperatively in any age group. Atrial fibrillation is the most common arrhythmia83 and occurs between postoperative days 3 to 5 in high-risk patients. This is typically when patients begin to mobilize their intersti-tial fluid into the vascular fluid space. Contemporary evidence suggests that rate control is more important than rhythm con-trol for atrial fibrillation.84,85 The first-line treatment includes β-blockade and/or calcium channel blockade. β-Blockade must be used judiciously because hypotension, as well as withdrawal from β-blockade with rebound hypertension, is possible. Cal-cium channel blockers are an option if β-blockers are not toler-ated by the patient, but caution must be exercised in those with a history of congestive heart failure. Although digoxin is still a standby medication, it has limitations due to the need for opti-mal dosing levels. Cardioversion may be required if patients become hemodynamically unstable and the rhythm cannot be controlled.Ventricular arrhythmias and other tachyarrhythmias may occur in surgical patients as well. Similar to atrial rhythm prob-lems, these are best controlled with β-blockade, but the use of other antiarrhythmics or cardioversion may be required if patients become hemodynamically unstable.Cardiac ischemia is a cause of postoperative mortality. Acute myocardial infarction (AMI) can present insidiously, or it can be more dramatic with the classic presentation of short-ness of breath, severe angina, and sudden cardiogenic shock. The workup to rule out an AMI includes an ECG and cardiac enzyme measurements. The patient should be transferred to a monitored (telemetry) floor. Morphine, supplemental oxygen, nitroglycerine, and aspirin (MONA) are the initial therapeutic maneuvers for those being investigated for AMI.Gastrointestinal System. Surgery of the esophagus is poten-tially complicated because of its anatomic location and blood supply. Nutritional support strategies should be considered for esophageal resection patients to maximize the potential for sur-vival. The two primary types of esophageal resection performed are the transhiatal resection and the transthoracic (Ivor-Lewis) resection.86 The transhiatal resection has the advantage that a formal thoracotomy incision is avoided. However, dissection of the esophagus is blind, and anastomotic leaks occur more than with other resections. However, when a leak does occur, simple opening of the cervical incision and draining the leak is all that is usually required.The transthoracic Ivor-Lewis resection includes an esoph-ageal anastomosis performed in the chest near the level of the azygos vein. These have lower leak rates, but the leaks that do occur result in mediastinitis and can be difficult to control. The reported mortality is about 50% with an anastomotic leak, and the overall mortality of the procedure is about 5%, which is similar to transhiatal resection.Postoperative ileus is related to dysfunction of the neural reflex axis of the intestine. Excessive narcotic use may delay return of bowel function. Epidural anesthesia results in better pain control, and there is an earlier return of bowel function and a shorter length of hospital stay. The limited use of naso-gastric tubes and the initiation of early postoperative feeding are associated with an earlier return of bowel function.87 The use of chewing gum and other oral stimulants to minimize ileus remains controversial.Pharmacologic agents commonly used to stimulate bowel function include metoclopramide and erythromycin. Metoclo-pramide’s action is limited to the stomach and duodenum, and it may help primarily with gastroparesis. Erythromycin is a motilin agonist that works throughout the stomach and bowel. Several studies demonstrate significant benefit from the administration of erythromycin in those suffering from an ileus.88 Alvimopan, a newer agent and a µ-opioid receptor antagonist, has shown some promise in many studies for earlier return of gut function and subsequent reduction in length of stay.89,90 Neostigmine has been used in refractory pan-ileus patients (Ogilvie’s syndrome) with some degree of success. It is recommended for patients receiving this type of therapy to be in a monitored unit.91Small bowel obstruction occurs in less than 1% of early postoperative patients. When it does occur, adhesions are usu-ally the cause. Internal and external hernias, technical errors, and infections or abscesses are also causative. Hyaluronidase is a mucolytic enzyme that degrades connective tissue, and the use of a methylcellulose form of hyaluronidase, Seprafilm®, has been shown to result in a 50% decrease in adhesion formation in some patients.92,93 This may translate into a lower occurrence of postoperative bowel obstruction, but has yet to be proven.Fistulae are the abnormal communication of one structure to an adjacent structure or compartment and are associated with extensive morbidity and mortality. Common causes for fistula formation are summarized in the mnemonic FRIENDS (Foreign body, Radiation, Ischemia/Inflammation/Infection, Epitheli-alization of a tract, Neoplasia, Distal obstruction, and Steroid use). Postoperatively, they are most often caused by infection or obstruction leading to an anastomotic leak. The cause of the fis-tula must be recognized early, and treatment may include non-operative management with observation and nutritional support, or a delayed operative management strategy that also includes nutritional support and wound care.Gastrointestinal (GI) bleeding can occur perioperatively (Table 12-14). Technical errors such as a poorly tied suture, a nonhemostatic staple line, or a missed injury can all lead to Table 12-14Common causes of upper and lower gastrointestinal (GI) hemorrhageUPPER GI BLEEDLOWER GI BLEEDErosive esophagitisAngiodysplasiaGastric varicesRadiation proctitisEsophageal varicesHemangiomaDieulafoy’s lesionDiverticulosisAortoduodenal fistulaNeoplastic diseasesMallory-Weiss tearTraumaPeptic ulcer diseaseVasculitisTraumaHemorrhoidsNeoplastic diseaseAortoenteric fistulaIntussusceptionIschemic colitisInflammatory bowel diseasePostprocedure bleedingBrunicardi_Ch12_p0397-p0432.indd 42120/02/19 3:57 PM 422BASIC CONSIDERATIONSPART Ipostoperative intestinal bleeding.94,95 The source of bleeding is in the upper GI tract about 85% of the time and is usually detected and treated endoscopically. Surgical control of intesti-nal bleeding is required in up to 40% of patients.96When patients in the ICU have a major bleed from stress gastritis, the mortality risk is as high as 50%. It is important to keep the gastric pH greater than 4 to decrease the overall risk for stress gastritis in patients mechanically ventilated for 48 hours or greater and patients who are coagulopathic.97 Proton pump inhibitors, H2-receptor antagonists, and intragastric antacid installation are all effective measures. However, patients who are not mechanically ventilated or who do not have a history of gastritis or peptic ulcer disease should not be placed on gastritis prophylaxis postoperatively because it carries a higher risk of causing pneumonia.Hepatobiliary-Pancreatic System. Complications involv-ing the hepatobiliary system are usually due to technical errors. Laparoscopic cholecystectomy has become the standard of care for cholecystectomy, but common bile duct injury remains a nemesis of this approach. Intraoperative cholangiography has not been shown to decrease the incidence of common bile duct injuries because the injury to the bile duct usually occurs before the cholangiogram.98,99 Early recognition and immediate repair of an injury are important because delayed bile duct leaks often require a more complex repair.Ischemic injury due to devascularization of the common bile duct has a delayed presentation days to weeks after an operation. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrates a stenotic, smooth common bile duct, and liver function studies are elevated. The recommended treatment is a Roux-en-Y hepaticojejunostomy.A bile leak due to an unrecognized injury to the ducts may present after cholecystectomy as a biloma. These patients may present with abdominal pain and hyperbilirubinemia. The diag-nosis of a biliary leak can be confirmed by CT scan, ERCP, or radionuclide scan. Once a leak is confirmed, a retrograde biliary stent and external drainage are the treatment of choice.Hyperbilirubinemia in the surgical patient can be a com-plex problem. Cholestasis makes up the majority of causes for hyperbilirubinemia, but other mechanisms of hyperbiliru-binemia include reabsorption of blood (e.g., hematoma from trauma), decreased bile excretion (e.g., sepsis), increased unconjugated bilirubin due to hemolysis, hyperthyroidism, and impaired excretion due to congenital abnormalities or acquired disease. Errors in surgery that cause hyperbilirubinemia largely involve missed or iatrogenic injuries.The presence of cirrhosis predisposes to postoperative complications. Abdominal or hepatobiliary surgery is problem-atic in the cirrhotic patient. Ascites leak in the postoperative period can be an issue when any abdominal operation has been performed. Maintaining proper intravascular oncotic pressure in the immediate postoperative period can be difficult, and resus-citation should be maintained with crystalloid solutions. Pre-vention of renal failure and the management of the hepatorenal syndrome can be difficult, as the demands of fluid resuscitation and altered glomerular filtration become competitive. Spirono-lactone with other diuretic agents may be helpful in the post-operative care. These patients often have a labile course, and bleeding complications due to coagulopathy are common. The operative mortality in cirrhotic patients is 10% for Child class A, 30% for Child class B, and 82% for Child class C patients.100Pyogenic liver abscess occurs in less than 0.5% of adult admissions, due to retained necrotic liver tissue, occult intesti-nal perforations, benign or malignant hepatobiliary obstruction, sepsis, and hepatic arterial occlusion. The treatment is long-term antibiotics with percutaneous drainage of large abscesses.Pancreatitis can occur following injection of contrast dur-ing cholangiography and after endoscopic cholangiopancreatog-raphy (ERCP). These episodes range from a mild elevation in amylase and lipase with abdominal pain, to a fulminant course of pancreatitis with necrosis requiring surgical debridement. The incidence of post-ERCP pancreatitis has been shown to be reduced by the administration of rectal indomethacin.101 Stud-ies are underway to determine whether the prophylactic use of pancreatic duct stenting in patients at high risk for post-ERCP pancreatitis can be avoided with the use of rectal indomethacin.Traumatic injuries to the pancreas can occur during surgi-cal procedures on the kidneys, GI tract, and spleen most com-monly. Treatment involves serial CT scans and percutaneous drainage to manage infected fluid and abscess collections; ster-ile collections should not be drained because drain placement can introduce infection. A pancreatic fistula may respond to antisecretory therapy with a somatostatin analogue. Manage-ment of these fistulae initially includes ERCP with or without pancreatic stenting, percutaneous drainage of any fistula fluid collections, total parenteral nutrition (TPN) with bowel rest, and repeated CT scans. The majority of pancreatic fistulae will eventually heal spontaneously.Renal System. Renal failure can be classified as prerenal failure, intrinsic renal failure, and postrenal failure. Postrenal failure, or obstructive renal failure, should always be consid-ered when low urine output (oliguria) or anuria occurs. The most common cause is a misplaced or clogged urinary catheter. Other, less common causes to consider are unintentional ligation or transection of ureters during a difficult surgical dissection (e.g., colon resection for diverticular disease) or a large retro-peritoneal hematoma (e.g., ruptured aortic aneurysm).Oliguria is initially evaluated by flushing the urinary cath-eter using sterile technique. Urine electrolytes should also be measured (Table 12-15). A hemoglobin and hematocrit level should be checked immediately. Patients in compensated shock from acute blood loss may manifest anemia and end-organ mal-perfusion as oliguria.Acute tubular necrosis (ATN) carries a mortality risk of 25% to 50% due to the many complications that can cause, or result from, this insult. When ATN is due to poor inflow (prer-enal failure), the remedy begins with IV administration of crys-talloid or colloid fluids as needed. If cardiac insufficiency is the problem, the optimization of vascular volume is achieved first, followed by inotropic agents, as needed. Intrinsic renal failure Table 12-15Urinary electrolytes associated with acute renal failure and their possible etiologies FENaOSMOLARITYURNaETIOLOGYPrerenal<1>500<20CHF, cirrhosisIntrinsic failure>1<350>40Sepsis, shockCHF = congestive heart failure; FENa = fractional excretion of sodium; URNa = urinary excretion of sodium.Brunicardi_Ch12_p0397-p0432.indd 42220/02/19 3:57 PM 423QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12and subsequent ATN are often the result of direct renal toxins. Aminoglycosides, vancomycin, and furosemide, among other commonly used agents, contribute directly to nephrotoxicity. Contrast-induced nephropathy usually leads to a subtle or tran-sient rise in creatinine. In patients who are volume depleted or have poor cardiac function, contrast nephropathy may perma-nently impair renal function.102-105The treatment of renal failure due to myoglobinuria has shifted away from the use of sodium bicarbonate for alkalinizing the urine, to merely maintaining brisk urine output of 100 mL per hour with crystalloid fluid infusion. Mannitol and furosemide are not recommended. Patients who do not respond to resusci-tation are at risk for needing renal replacement therapy. Fortu-nately, most of these patients eventually recover from their renal dysfunction.Musculoskeletal System. A compartment syndrome can develop in any compartment of the body. Compartment syn-drome of the extremities generally occurs after a closed fracture. The injury alone may predispose the patient to compartment syndrome, but aggressive fluid resuscitation can exacerbate the problem. Pain with passive motion is the hallmark of com-partment syndrome, and the anterior compartment of the leg is usually the first compartment to be involved. Confirmation of the diagnosis is obtained by direct pressure measurement of the individual compartments. If the pressures are greater than 20 to 25 mmHg in any of the compartments, then a four-compartment fasciotomy is considered. Compartment syndrome can be due to ischemia-reperfusion injury, after an ischemic time of 4 to 6 hours. Renal failure (due to myoglobinuria), tissue loss, and a permanent loss of function are possible results of untreated compartment syndrome.Decubitus ulcers are preventable complications of pro-longed bed rest due to traumatic paralysis, dementia, chemi-cal paralysis, or coma. Unfortunately, they are still occurring despite extensive research and clinical initiatives that demon-strate successful prevention strategies. Ischemic changes in the microcirculation of the skin can be significant after 2 hours of sustained pressure. Routine skin care and turning of the patient help ensure a reduction in skin ulceration. This can be labor intensive, and special mattresses and beds are available to help. The treatment of a decubitus ulcer in the noncoagulopathic patient is surgical debridement. Once the wound bed has a via-ble granulation base without an excess of fibrinous debris, a vacuum-assisted closure dressing can be applied. Wet to moist dressings with frequent dressing changes is the alternative and is labor intensive. Expensive topical enzyme preparations are also available. If the wounds fail to respond to these measures, soft tissue coverage by flap is considered.Contractures are the result of muscle disuse. Whether from trauma, amputation, or vascular insufficiency, contractures can be prevented by physical therapy and splinting. If not attended to early, contractures will prolong rehabilitation and may lead to further wounds and wound healing issues. Depending on the functional status of the patient, contracture releases may be required for long-term care.Hematologic System. The traditional transfusion guideline of maintaining the hematocrit level in all patients at greater than 30% is no longer valid. Only patients with symptomatic anemia, who have significant cardiac disease, or who are critically ill and require increased oxygen-carrying capacity to adequately perfuse end organs require higher levels of hemoglobin. Other than these select patients, the decision to transfuse should gener-ally not occur until the hemoglobin level falls to 7 mg/dL or the hematocrit reaches 21%.Transfusion reactions are common complications of blood transfusion. These can be attenuated with a leukocyte filter, but not completely prevented. The manifestations of a transfusion reaction include simple fever, pruritus, chills, muscle rigidity, and renal failure due to myoglobinuria secondary to hemolysis. Discontinuing the transfusion and returning the blood products to the blood bank is an important first step, but administration of antihistamine and possibly steroids may be required to control the reaction symptoms. Severe transfusion reactions are rare but can be fatal.Infectious complications in blood transfusion range from cytomegalovirus transmission, which is benign in the nontrans-plant patient, to human immunodeficiency virus (HIV) infec-tion, to passage of the hepatitis viruses (Table 12-16).Patients on warfarin (Coumadin) who require surgery can have anticoagulation reversal by administration of fresh frozen plasma. Each unit of fresh frozen plasma contains 200 to 250 mL of plasma and includes one unit of coagulation factor per milliliter of plasma.Thrombocytopenia may require platelet transfusion for a platelet count less than 20,000/mL when invasive procedures are performed, or when platelet counts are low and ongoing bleed-ing from raw surface areas persists. One unit of platelets will increase the platelet count by 5000 to 7500 per mL in adults. It is important to delineate the cause of the low platelet count. Usually there is a self-limiting or reversible condition such as sepsis. Rarely, it is due to heparin-induced thrombocytopenia I and II. Complications of heparin-induced thrombocytopenia II can be serious because of the diffuse thrombogenic nature of the disorder. Simple precautions to limit this hypercoagulable state include saline solution flushes instead of heparin solutions and limiting the use of heparin-coated catheters. The treatment is anticoagulation with synthetic agents such as argatroban.For patients with uncontrollable bleeding due to dissemi-nated intravascular coagulopathy (DIC), a potentially useful drug is factor VIIa, but its use should be judicious.106-109 Origi-nally used in hepatic trauma and obstetric emergencies, this agent was lifesaving in some circumstances. The CONTROL Trial,109 however, has largely decreased overuse of this agent because investigators demonstrated no benefit over simple fac-tor replacement in severely coagulopathic patients. Factor VIIa use may also be limited due to its potential thrombotic com-plications. For some situations, the combination of ongoing, Table 12-16Rate of viral transmission in blood product transfusionsaHIV1:1.9 millionHBVb1:137,000HCV1:1 millionaPost-nucleic acid amplification technology (1999). Earlier rates were erroneously reported higher due to lack of contemporary technology.bHBV is reported with prenucleic acid amplification technology. Statistical information is unavailable with postnucleic acid amplification technology at this writing.Note that bacterial transmission is 50 to 250 times higher than viral transmission per transfusion.HBV = hepatitis B virus; HCV = hepatitis C virus.Brunicardi_Ch12_p0397-p0432.indd 42320/02/19 3:57 PM 424BASIC CONSIDERATIONSPART Inonsurgical bleeding and renal failure can occasionally be suc-cessfully treated with desmopressin.In addition to classic hemophilia, other inherited coagula-tion factor deficiencies can be difficult to manage in surgery. When required, transfusion of appropriate replacement products is coordinated with the regional blood bank center before sur-gery. Other blood dyscrasias seen by surgeons include hyper-coagulopathic patients. Those who carry congenital anomalies such as the most common factor V Leiden deficiency, as well as protein C and S deficiencies, are likely to form thromboses if inadequately anticoagulated, and these patients should be man-aged in consultation with a hematologist.Abdominal Compartment Syndrome. Multisystem trauma, thermal burns, retroperitoneal injuries, and surgery related to the retroperitoneum are the major initial causative factors that may lead to abdominal compartment syndrome (ACS). Ruptured AAA, major pancreatic injury and resection, or multiple intes-tinal injuries are also examples of clinical situations in which a large volume of IV fluid resuscitation puts these patients at risk for intra-abdominal hypertension. Manifestations of ACS typically include progressive abdominal distention followed by increased peak airway ventilator pressures, oliguria followed by anuria, and an insidious development of intracranial hyperten-sion.110 These findings are related to elevation of the diaphragm and inadequate venous return from the vena cava or renal veins secondary to the transmitted pressure on the venous system.Measurement of abdominal pressures is easily accom-plished by transducing bladder pressures from the urinary catheter after instilling 100 mL of sterile saline into the urinary bladder.111 A pressure greater than 20 mmHg constitutes intra-abdominal hypertension, but the diagnosis of ACS requires intra-abdominal pressure greater than 25 to 30 mmHg, with at least one of the following: compromised respiratory mechan-ics and ventilation, oliguria or anuria, or increasing intracranial pressures.112-114The treatment of ACS is to open any recent abdominal incision to release the abdominal fascia or to open the fascia directly if no abdominal incision is present. Immediate improve-ment in mechanical ventilation pressures, intracranial pressures, and urine output is usually noted. When expectant management for ACS is considered in the OR, the abdominal fascia should be left open and covered under sterile conditions (e.g., a vac-uum-assisted open abdominal wound closure system) with plans made for a second-look operation and delayed fascial closure. Patients with intra-abdominal hypertension should be monitored closely with repeated examinations and measurements of blad-der pressure, so that any further deterioration is detected and operative management can be initiated. Left untreated, ACS may lead to multiple system end-organ dysfunction or failure and has a high mortality.Abdominal wall closure should be attempted every 48 to 72 hours until the fascia can be reapproximated. If the abdo-men cannot be closed within 5 to 7 days following release of the abdominal fascia, a large incisional hernia is the net result. A variety of surgical options have evolved for prevention and closure of the resultant hernias, but no standard approach has yet evolved.Wounds, Drains, and InfectionWound (Surgical Site) Infection. No prospective, random-ized, double-blind, controlled studies exist that demonstrate antibiotics used beyond 24 hours in the perioperative period prevent infections. Prophylactic use of antibiotics should sim-ply not be continued beyond this time. Irrigation of the operative field and the surgical wound with saline solution has shown benefit in controlling wound inoculum.115 Irrigation with an antibiotic-based solution has not demonstrated significant ben-efit in controlling postoperative infection.Antibacterial-impregnated polyvinyl placed over the oper-ative wound area for the duration of the surgical procedure has not been shown to decrease the rate of wound infection.116-120 Although skin preparation with 70% isopropyl alcohol has the best bactericidal effect, it is flammable and could be hazard-ous when electrocautery is used. The contemporary formulas of chlorhexidine gluconate with isopropyl alcohol remain more advantageous.121-123There is a difference between wound colonization and infection. Overtreating colonization is just as injurious as under-treating infection. The strict definition of wound (soft tissue) infection is more than 105 CFU per gram of tissue. This warrants expeditious and proper antibiotic/antifungal treatment.124 Often, however, clinical signs raise enough suspicion that the patient is treated before a confirmatory culture is undertaken. The clinical signs of wound infection include rubor, tumor, calor, and dolor (redness, swelling, heat, and pain). Once the diagnosis of wound infection has been established, the most definitive treatment remains open drainage of the wound. The use of antibiotics for wound infection treatment should be limited.125-128One type of wound dressing/drainage system that has gained popularity is the vacuum-assisted closure dressing. The principle of the system is to decrease local wound edema and to promote healing through the application of a sterile dressing that is then covered and placed under controlled suction for a period of 2 to 4 days at a time. Although costly, the benefits are frequently dramatic and may offset the costs of nursing care, frequent dressing changes, and operative wound debridement.Drain Management. The four indications for applying a surgi-cal drain are:• To collapse surgical dead space in areas of redundant tissue (e.g., neck and axilla)• To provide focused drainage of an abscess or grossly infected surgical site• To provide early warning notice of a surgical leak (either bowel contents, secretions, urine, air, or blood)—the so-called sentinel drain• To control an established fistula leakOpen drains are often used for large contaminated wounds such as perirectal or perianal fistulas and subcutaneous abscess cavities. They prevent premature closure of an abscess cavity in a contaminated wound. More commonly, surgical sites are drained by closed suction drainage systems, but data do not sup-port closed suction drainage to “protect an anastomosis” or to “control a leak” when placed at the time of surgery. Closed suc-tion devices can exert a negative pressure of 70 to 170 mmHg at the level of the drain; therefore, the presence of this excess suction may call into question whether an anastomosis breaks down on its own or whether the drain creates a suction injury that promotes leakage (Fig. 12-9).129On the other hand, CTor ultrasound-guided placement of percutaneous drains is now the standard of care for abscesses, loculated infections, and other isolated fluid collections such Brunicardi_Ch12_p0397-p0432.indd 42420/02/19 3:57 PM 425QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12ABFigure 12-9 This illustration demonstrates typical intraoperative placement of closed suction devices in pancreatic or small bowel surgery, where there may be an anastomosis. At negative pressures of 70 to 170 mmHg, these devices may actually encourage anas-tomotic leaks and not prevent them or become clogged by them.as pancreatic leaks. The risk of surgery is far greater than the placement of an image-guided drain.The use of antibiotics when drains are in place is often unnecessary as the drain provides direct source control. Twenty-four to 48 hours of antibiotic use after drain placement is pro-phylactic, and after this period, only specific treatment of positive cultures should be performed to avoid increased drug resistance and superinfection.Urinary Catheters. Several complications of urinary cath-eters can occur that lead to an increased length of hospital stay and morbidity. In general, use of urinary catheters should be minimized and every opportunity to expeditiously remove them should be encouraged. If needed, it is recommended that the catheter be inserted its full length up to the hub and that urine flow is established before the balloon is inflated because mis-placement of the catheter in the urethra with premature inflation of the balloon can lead to tears and disruption of the urethra.Enlarged prostatic tissue can make catheter insertion dif-ficult, and a catheter coudé may be required. If this attempt is also unsuccessful, then a urologic consultation for endoscopic placement of the catheter may be required to prevent harm to the urethra. For patients with urethral strictures, filiform-tipped catheters and followers may be used, but these can potentially cause bladder injury. If endoscopic attempts fail, the patient may require a percutaneously placed suprapubic catheter to obtain decompression of the bladder. Follow-up investigations of these patients are recommended so definitive care of the ure-thral abnormalities can be pursued.The most frequent nosocomial infection is urinary tract infection (UTI). These infections are classified into compli-cated and uncomplicated forms. The uncomplicated type is a UTI that can be treated with outpatient antibiotic therapy. The complicated UTI usually involves a hospitalized patient with an indwelling catheter whose UTI is diagnosed as part of a fever workup. The interpretation of urine culture results of less than 100,000 CFU/mL is controversial. Before treating such a patient, one should change the catheter and then repeat the cul-ture to see if the catheter was simply colonized with organisms. Cultures with more than 100,000 CFU/mL should be treated with the appropriate antibiotics and the catheter changed or removed as soon as possible. Undertreatment or misdiagnosis of a UTI can lead to urosepsis and septic shock.Recommendations are mixed on the proper way to treat Candida albicans fungal bladder infections. Continuous blad-der washings with fungicidal solution for 72 hours have been recommended, but this is not always effective. Replacement of the urinary catheter and a course of fluconazole are appropriate treatments, but some infectious disease specialists claim that C. albicans in the urine may serve as an indication of fungal infection elsewhere in the body. If this is the case, then screen-ing cultures for other sources of fungal infection should be per-formed whenever a fungal UTI is found.Empyema. One of the most debilitating infections is an empyema, or infection of the pleural space. Frequently, an overwhelming pneumonia is the source of an empyema, but a retained hemothorax, systemic sepsis, esophageal perforation from any cause, and infections with a predilection for the lung (e.g., tuberculosis) are potential etiologies as well. The diag-nosis is confirmed by chest X-ray or CT scan, followed by aspiration of pleural fluid for bacteriologic analysis. Gram’s stain, lactate dehydrogenase, protein, pH, and cell count are obtained, and broad-spectrum antibiotics are initiated while the laboratory studies are performed. Once the specific organisms are confirmed, anti-infective agents are tailored appropriately. Placement of a thoracostomy tube is needed to evacuate and drain the infected pleural fluid, but depending on the specific nidus of infection, video-assisted thoracoscopy may also be Brunicardi_Ch12_p0397-p0432.indd 42520/02/19 3:57 PM 426BASIC CONSIDERATIONSPART Ihelpful for irrigation and drainage of the infection. Refractory empyemas require specialized surgical approaches.Abdominal Abscesses. Postsurgical intra-abdominal abscesses can present with vague complaints of intermittent abdominal pain, fever, leukocytosis, and a change in bowel habits. Depending on the type and timing of the original pro-cedure, the clinical assessment of these complaints is some-times difficult, and a CT scan is usually required. When a fluid collection within the peritoneal cavity is found on CT scan, antibiotics and percutaneous drainage of the collection is the treatment of choice. Initial antibiotic treatment is usually with broad-spectrum antibiotics such as piperacillin-tazobactam or imipenem. Should the patient exhibit signs of peritonitis and/or have free air on X-ray or CT scan, then re-exploration should be considered.For patients who present primarily (i.e., not postopera-tively) with the clinical and radiologic findings of an abscess but are clinically stable, the etiology of the abscess must be determined. A plan for drainage of the abscess and decisions about further diagnostic studies with consideration of the tim-ing of any definitive surgery all need to be balanced. This can be a complex set of decisions, depending on the etiology (e.g., appendicitis or diverticulitis), but if the patient exhibits signs of peritonitis, urgent surgical exploration should be performed.Necrotizing Fasciitis. Postoperative infections that progress to the fulminant soft tissue infection known as necrotizing fas-ciitis are uncommon. Group A streptococcal (M types 1, 3, 12, and 28) soft tissue infections, as well as infections with Clos-tridium perfringens and C. septicum, carry a mortality of 30% to 70%. Septic shock can be present, and patients can become hypotensive less than 6 hours following inoculation. Manifesta-tions of a group A Streptococcus pyogenes infection in its most severe form include hypotension, renal insufficiency, coagu-lopathy, hepatic insufficiency, ARDS, tissue necrosis, and ery-thematous rash.These findings constitute a surgical emergency, and the mainstay of treatment remains wide debridement of the necrotic tissue to the level of bleeding, viable tissue. A gray serous fluid at the level of the necrotic tissue is usually noted, and as the infection spreads, thrombosed blood vessels are noted along the tissue planes involved with the infection. Typically, the patient requires serial trips to the OR for wide debridement until the infection is under control. Antibiotics are an important adjunct to surgical debridement, and broad-spectrum coverage should be used because these infections may be polymicrobial (i.e., so-called mixed-synergistic infections). Streptococcus pyogenes is eradicated with penicillin, and it should still be used as the initial drug of choice.Systemic Inflammatory Response Syndrome, Sepsis, and Multiple-Organ Dysfunction Syndrome. The systemic inflammatory response syndrome (SIRS) and the multiple-organ dysfunction syndrome (MODS) carry significant mortal-ity risks (Table 12-17). Specific criteria have been established for the diagnosis of SIRS (Table 12-18), but two criteria are not required for the diagnosis of SIRS: lowered blood pressure and blood cultures positive for infection. SIRS is the result of proin-flammatory cytokines related to tissue malperfusion or injury. The dominant cytokines implicated in this process include interleukin (IL)-1, IL-6, and tissue necrosis factor (TNF). Other mediators include nitric oxide, inducible macrophage-type nitric oxide synthase, and prostaglandin I2.Table 12-17Mortality associated with patients exhibiting two or more criteria for systemic inflammatory response syndrome (SIRS)PROGNOSISMORTALITY (%)2 SIRS criteria53 SIRS criteria104 SIRS criteria15–20Table 12-18Inclusion criteria for the systemic inflammatory response syndromeTemperature >38°C or <36°C (>100.4°F or <96.8°F)Heart rate >90 beats/minRespiratory rate >20 breaths/min or Paco2 <32 mmHgWhite blood cell count <4000 or >12,000 cells/mm3 or >10% immature formsPaco2 = partial pressure of arterial carbon dioxide.Sepsis is categorized as sepsis, severe sepsis, and septic shock. Sepsis is SIRS plus infection. Severe sepsis is sepsis plus signs of cellular hypoperfusion or end-organ dysfunction. Septic shock is sepsis plus hypotension after adequate fluid resuscitation.MODS is the culmination of septic shock and multiple end-organ failure.130 Usually there is an inciting event (e.g., perforated sigmoid diverticulitis), and as the patient undergoes resuscitation, he or she develops cardiac hypokinesis and oli-guric or anuric renal failure, followed by the development of ARDS and eventually septic shock with death.The international Surviving Sepsis Campaign (www.sccm.org/Documents/SSC-Guidelines.pdf) continues to dem-onstrate the importance of early recognition and initiation of specific treatment guidelines for optimal management of sep-sis. Management of SIRS/MODS includes aggressive global resuscitation and support of end-organ perfusion, correction of the inciting etiology, control of infectious complications, and management of iatrogenic complications.131-133 Drotrecogin-α, or recombinant activated protein C, appears to specifically counteract the cytokine cascade of SIRS/MODS, but its use is still limited.134,135 Other adjuncts for supportive therapy include tight glucose control, low tidal volumes in ARDS, vasopressin in septic shock, and steroid replacement therapy.Nutritional and Metabolic Support ComplicationsNutrition-Related Complications. A basic principle is to use enteral feeding whenever possible, but complications can inter-vene such as aspiration, ileus, and to a lesser extent, sinusitis. There is no difference in aspiration rates when a small-caliber feeding tube is placed postpyloric or if it remains in the stom-ach. Patients who are fed via nasogastric tubes are at risk for aspiration pneumonia because these large-bore tubes stent open the gastroesophageal junction, creating the possibility of gas-tric reflux. The use of enteric and gastric feeding tubes obviates Brunicardi_Ch12_p0397-p0432.indd 42620/02/19 3:57 PM 427QUALITY, PATIENT SAFETY, ASSESSMENTS OF CARE, AND COMPLICATIONSCHAPTER 12complications of TPN, such as pneumothorax, line sepsis, upper extremity DVT, and the related expense. There is growing evi-dence to support the initiation of enteral feeding in the early postoperative period, before the return of bowel function, where it is usually well tolerated.In patients who have had any type of nasal intubation who are having high, unexplained fevers, sinusitis must be enter-tained as a diagnosis. CT scan of the sinuses is warranted, fol-lowed by aspiration of sinus contents so the organism(s) are appropriately treated.Patients who have not been enterally fed for prolonged periods secondary to multiple operations, those who have had enteral feeds interrupted for any other reason, or those with poor enteral access are at risk for the refeeding syndrome, which is characterized by severe hypophosphatemia and respiratory fail-ure. Slow progression of the enteral feeding administration rate can avoid this complication.Common TPN problems are mostly related to electrolyte abnormalities that may develop. These electrolyte errors include deficits or excesses in sodium, potassium, calcium, magnesium, and phosphate. Acid-base abnormalities can also occur with the improper administration of acetate or bicarbonate solutions.The most common cause for hypernatremia in hospitalized patients is under-resuscitation, and, conversely, hyponatremia is most often caused by fluid overload. Treatment for hyponatre-mia is fluid restriction in mild or moderate cases and the admin-istration of hypertonic saline for severe cases. An overly rapid correction of the sodium abnormality may result in central pon-tine myelinolysis, which results in a severe neurologic deficit. Treatment for hyponatremic patients includes fluid restriction to correct the free water deficit by 50% in the first 24 hours. An overcorrection of hyponatremia can result in severe cerebral edema, a neurologic deficit, or seizures.Glycemic Control. In 2001, Van den Berghe and colleagues demonstrated that tight glycemic control by insulin infusion is associated with a 50% reduction in mortality in the critical care setting.136 This prospective, randomized, controlled trial of 1500 patients had two study arms: the intensive-control arm, where the serum glucose was maintained between 80 and 110 mg/dL with insulin infusion; and the control arm, where patients received an insulin infusion only if blood glucose was greater than 215 mg/dL, but serum glucose was then maintained at 180 to 200 mg/dL.The tight glycemic control group had an average serum glucose level of 103 mg/dL, and the average glucose level in the control group was 153 mg/dL. Hypoglycemic episodes (glu-cose <40 mg/dL) occurred in 39 patients in the tightly controlled group, while the control group had episodes in six patients. The overall mortality was reduced from 8% to 4.6%, but the mortal-ity of those patients whose ICU stay lasted longer than 5 days was reduced from 20% to 10%. Secondary findings included an improvement in overall morbidity, a decreased percentage of ventilator days, less renal impairment, and a lower incidence of bloodstream infections. These finding have been corrobo-rated by subsequent similar studies, and the principal benefit appears to be a greatly reduced incidence of nosocomial infec-tions and sepsis. It is not known whether the benefits are due to strict euglycemia, to the anabolic properties of insulin, or both, but the maintenance of strict euglycemia between 140 and 180 mg/dL appears to be a powerful therapeutic strategy.136-138 A number of studies followed this sentinel publication of tight glycemic control. The NICE-SUGAR139 and COIITSS140 trials revisited the Van den Berghe study and found that the glyce-mic goals found initially to improve outcomes in critically ill patients were now found to be associated with a higher mortality when glucose was kept below 180 mg/dL, due to an increase in incidents of hypoglycemia. When targeted goals of 180 mg/dL are achieved, fewer occurrences of hypoglycemia have been docu-mented, and improved survivorship has been achieved. In addi-tion, some studies find no relationship between glycemic control and improved outcomes. Thus, glycemic control in the critically ill still remains unclear and elusive at best.141,142 Part of the dif-ficulty in achieving “tight glycemic control” is the necessity for frequent (every 1–2 hours) blood glucose determinations. When this is performed, glycemic control is enhanced and hypoglyce-mia is avoided.Metabolism-Related Complications. “Stress dose steroids” have been advocated for the perioperative treatment of patients on corticosteroid therapy, but recent studies strongly discour-age the use of supraphysiologic doses of steroids when patients are on low or maintenance doses (e.g., 5–15 mg) of prednisone daily. Parenteral glucocorticoid treatment need only replicate physiologic replacement steroids in the perioperative period. When patients are on steroid replacement doses equal to or greater than 20 mg per day of prednisone, it may be appropriate to administer additional glucocorticoid doses for no more than 2 perioperative days.143-145Adrenal insufficiency may be present in patients with a baseline serum cortisol less than 20 μg/dL. A rapid provocative test with synthetic adrenocorticotropic hormone may confirm the diagnosis. After a baseline serum cortisol level is drawn, 250 μg of cosyntropin is administered. At exactly 30 and 60 minutes follow-ing the dose of cosyntropin, serum cortisol levels are obtained. There should be an incremental increase in the cortisol level of between 7 and 10 μg/dL for each half hour. If the patient is below these levels, a diagnosis of adrenal insufficiency is made, and glucocorticoid and mineralocorticoid administration is then warranted. Mixed results are common, but the complication of performing major surgery on an adrenally insufficient patient is sudden or profound hypotension that is not responsive to fluid resuscitation.131Thyroid hormone abnormalities usually consist of previ-ously undiagnosed thyroid abnormalities. Hypothyroidism and the so-called sick-euthyroid syndrome are more commonly recognized in the critical care setting. When surgical patients are not progressing satisfactorily in the perioperative period, screening for thyroid abnormalities should be performed. If the results show mild to moderate hypothyroidism, then thyroid replacement should begin immediately, and thyroid function studies should be monitored closely. All patients should be reas-sessed after the acute illness has subsided regarding the need for chronic thyroid replacement therapy.Problems with ThermoregulationHypothermia. Hypothermia is defined as a core tempera-ture less than 35°C (95°F) and is divided into subsets of mild (35°C–32°C [95°F–89.6°F]), moderate (32°C–28°C [89.6°F –82.4°F]), and severe (<28°C [<82.4°F]) hypothermia. Shiver-ing, the body’s attempt to reverse the effects of hypothermia, occurs between 37°C and 31°C (98.6°F and 87.8°F), but ceases at temperatures below 31°C (87.8°F). Patients who are moder-ately hypothermic are at higher risk for complications than are those who are more profoundly hypothermic.Brunicardi_Ch12_p0397-p0432.indd 42720/02/19 3:57 PM 428BASIC CONSIDERATIONSPART IHypothermia creates a coagulopathy that is related to platelet and clotting cascade enzyme dysfunction. This triad of metabolic acidosis, coagulopathy, and hypothermia is com-monly found in long operative cases and in patients with blood dyscrasias. The enzymes that contribute to the clotting cascade and platelet activity are most efficient at normal body tempera-tures; therefore, all measures must be used to reduce heat loss intraoperatively.146The most common cardiac abnormality is the develop-ment of arrhythmias when body temperature drops below 35°C (95°F). Bradycardia occurs with temperatures below 30°C (86°F). It is well known that hypothermia may induce CO2 retention, resulting in respiratory acidosis. Renal dysfunction of hypothermia manifests itself as a paradoxic polyuria and is related to an increased glomerular filtration rate, as peripheral vascular constriction creates central shunting of blood. This is potentially perplexing in patients who are undergoing resuscita-tion for hemodynamic instability because the brisk urine output provides a false sense of an adequate intravascular fluid volume.Induced peripheral hypothermia for hyperpyrexia due to infection (not to include neurologic or cardiac disease) is likely deleterious and does not appear to be beneficial. Plac-ing cooling blankets on or under the patient or ice packs in the axillae or groin may be effective in cooling the skin, and when this occurs, a subsequent feedback loop triggers the hypothalamus to raise the internally regulated set point, thus raising core temperature even higher. This paradoxical reac-tion may be why those who feel the need to treat a fever in the ICU by cooling the skin and arguably the core have worse outcomes. Cooling core temperatures can be achieved reli-ably with catheter-directed therapy with commercially avail-able devices. Whether this is a worthwhile practice or not may be controversial. Poor data exist in support of treating fevers lower than 42°C in any fashion.147-149Adult trauma patients who underwent induced hypother-mia had poor outcomes in a recent investigation, and thus, this remains a procedure to be avoided. In a similar vein, pediatric patients who were induced did not show any improvement, and therefore, induced hypothermia is not recommended. Compli-cations with induced hypothermia include, but are not limited to, hypokalemia, diuresis, DVT (due to catheter-related vein injury), arrhythmias, shivering, undiagnosed catheter-related bloodstream infection, and bacteremia.150-152Neurologic dysfunction is inconsistent in hypothermia, but a deterioration in reasoning and decision-making skills progresses as body temperature falls, and profound coma (and a flat electroencephalogram) occurs as the temperature drops below 30°C (86°F). The diagnosis of hypothermia is important, so accurate measurement techniques are required to get a true core temperature.Methods used to warm patients include warm air circu-lation over the patient and heated IV fluids, as well as more aggressive measures such as bilateral chest tubes with warm solution lavage, intraperitoneal rewarming lavage, and extra-corporeal membrane oxygenation. A rate of temperature rise of 2°C to 4°C (3.6°F–7.2°F) per hour is considered adequate, but the most common complication for nonbypass rewarming is arrhythmia with ventricular arrest.Hyperthermia. Hyperthermia is defined as a core temperature greater than 38.6°C (101.5°F) and has a host of etiologies (Table 12-19).147 Hyperthermia can be environmentally induced (e.g., summer heat with inability to dissipate heat or control exposure), iatrogenically induced (e.g., heat lamps and medica-tions), endocrine in origin (e.g., thyrotoxicosis), or neurologi-cally induced (i.e., hypothalamic dysfunction).Malignant hyperthermia occurs intraoperatively after exposure to agents such as succinylcholine and some halothane-based inhalational anesthetics. The presentation is dramatic, with rapid onset of increased temperature, rigors, and myoglo-binuria related to myonecrosis. Medications must be discontin-ued immediately and dantrolene administered (2.5 mg/kg every 5 minutes) until symptoms subside. Aggressive cooling meth-ods are also implemented, such as an alcohol bath, or packing in ice. In cases of severe malignant hyperthermia, the mortality rate is nearly 30%.153,154Thyrotoxicosis can occur after surgery due to undiagnosed Graves’ disease. Hallmarks of the syndrome include hyperther-mia (>40°C [104°F]), anxiety, copious diaphoresis, congestive heart failure (present in about one fourth of episodes), tachycar-dia (most commonly atrial fibrillation), and hypokalemia (in up to 50% of patients). The treatment of thyrotoxicosis includes glucocorticoids, propylthiouracil, β-blockade, and iodide (Lugol’s solution) delivered in an emergent fashion. As the name suggests, these patients are usually toxic and require sup-portive measures as well. Acetaminophen, the cooling modali-ties noted in the previous paragraph, and vasoactive agents often are indicated.REFERENCESEntries highlighted in bright blue are key references. 1. Makary MA, Daniel M. 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Physiologic Monitoring of the Surgical PatientAnthony R. Cyr and Louis H. Alarcon 13chapterINTRODUCTIONThe Latin verb monere, which means “to warn, or advise” is the origin for the English word monitor. In modern medical prac-tice, patients undergo monitoring to detect pathologic varia-tions in physiologic parameters, providing advanced warning of impending deterioration in the status of one or more organ systems. The intended goal of this endeavor is to allow the clini-cian to take appropriate actions in a timely fashion to prevent or ameliorate the physiologic derangement. Furthermore, physi-ologic monitoring is used not only to warn, but also to titrate therapeutic interventions, such as fluid resuscitation or the infu-sion of vasoactive or inotropic drugs. The intensive care unit (ICU) and operating room are the two locations where the most advanced monitoring capabilities are routinely employed in the care of critically ill patients.In the broadest sense, physiologic monitoring encom-passes a spectrum of endeavors, ranging in complexity from the routine and intermittent measurement of the classic vital signs (i.e., temperature, heart rate, arterial blood pressure, and respira-tory rate) to the continuous recording of the oxidation state of cytochrome oxidase, the terminal element in the mitochondrial electron transport chain. The ability to assess clinically relevant parameters of tissue and organ status and employ this knowl-edge to improve patient outcomes represents the “holy grail” of critical care medicine. Unfortunately, consensus is often lacking regarding the most appropriate parameters to monitor in order to achieve this goal. Furthermore, making an inappropriate ther-apeutic decision due to inaccurate physiologic data or misinter-pretation of good data can lead to a worse outcome than having no data at all. Of the highest importance is the integration of physiologic data obtained from monitoring into a coherent and evidenced-based treatment plan. Current technologies available to assist the clinician in this endeavor are summarized in this chapter. Also presented is a brief look at emerging tech-niques that may soon enter into clinical practice.In essence, the goal of hemodynamic monitoring is to ensure that the flow of oxygenated blood through the microcir-culation is sufficient to support aerobic metabolism at the cel-lular level. In general, mammalian cells cannot store oxygen for subsequent use in oxidative metabolism, although a relatively tiny amount is stored in muscle tissue as oxidized myoglobin. Thus, aerobic synthesis of adenosine triphosphate (ATP), the energy “currency” of cells, requires the continuous delivery of oxygen by diffusion from hemoglobin in red blood cells to the oxidative machinery within mitochondria. Delivery of oxygen to mitochondria may be insufficient for several reasons. For example, cardiac output, hemoglobin concentration of blood, or the oxygen content of arterial blood each can be inadequate 1Introduction 433Arterial Blood Pressure 434Noninvasive Measurement of Arterial Blood Pressure / 434Invasive Monitoring of Arterial Blood Pressure / 435Electrocardiographic  Monitoring 435Algorithmic Integrative  Monitoring 436Cardiac Output and Related  Parameters 436Determinants of Cardiac Performance / 436Placement of the Pulmonary  Artery Catheter 437Hemodynamic Measurements 438Measurement of Cardiac Output by Thermodilution / 439Mixed Venous Oximetry / 439Effect of Pulmonary Artery  Catheterization on Outcome 440Minimally Invasive Alternatives  to the Pulmonary Artery  Catheter 442Transpulmonary Thermodilution / 442Doppler Ultrasonography / 443Impedance Cardiography / 443Pulse Contour Analysis / 443Partial Carbon Dioxide Rebreathing / 444Transesophageal Echocardiography / 444Assessing Preload Responsiveness / 444Near-Infrared Spectroscopic Measurement of Tissue Hemoglobin Oxygen Saturation / 444Respiratory Monitoring 445Arterial Blood Gases / 445Determinants of Oxygen Delivery / 445Peak and Plateau Airway Pressure / 446Pulse Oximetry / 446Pulse CO-Oximetry / 446Capnometry /447Renal Monitoring 447Urine Output / 447Bladder Pressure / 447Neurologic Monitoring 447Intracranial Pressure / 447Electroencephalogram and Evoked Potentials / 448Transcranial Doppler Ultrasonography / 448Jugular Venous Oximetry / 448Transcranial Near-Infrared Spectroscopy / 449Brain Tissue Oxygen Tension / 449Conclusions 449Brunicardi_Ch13_p0433-p0452.indd 43322/02/19 2:20 PM 434Figure 13-1. Graphical representation of the relationship between oxygen utilization (VO2) and oxygen delivery (DO2). Under most normal physiologic conditions oxygen utilization does not depend on oxygen delivery, but below the critical value DO2crit oxygen utili-zation decreases linearly as a function of oxygen delivery, rendering tissues susceptible to ischemic injury.Key Points1 The delivery of modern critical care is predicated on the abil-ity to monitor a large number of physiologic variables and formulate evidenced-based therapeutic strategies to manage these variables. Technological advances in monitoring have at least a theoretical risk of exceeding our ability to under-stand the clinical implications of the derived information. This could result in the use of monitoring data to make inap-propriate clinical decisions. Therefore, the implementation of any new monitoring technology must take into account the relevance and accuracy of the data obtained, the risks to the patient, and the evidence supporting any intervention directed at correcting the detected abnormality.2 The routine use of invasive monitoring devices, specifically the pulmonary artery catheter, must be questioned in light of the available evidence that does not demonstrate a clear ben-efit to its widespread use in various populations of critically ill patients. The future of physiologic monitoring will be dominated by the application of noninvasive and highly accurate devices which guide evidenced-based therapy.for independent reasons. Alternatively, despite adequate cardiac output, perfusion of capillary networks can be impaired as a consequence of dysregulation of arteriolar tone, microvascular thrombosis, or obstruction of nutritive vessels by sequestered leukocytes or platelets. Hemodynamic monitoring that does not take into account all of these factors will portray an incomplete and perhaps misleading picture of cellular physiology.Under normal conditions when the supply of oxygen is plentiful, aerobic metabolism is determined by factors other than the availability of oxygen. These factors include the hor-monal milieu and mechanical workload of contractile tissues. However, in pathologic circumstances when oxygen availabil-ity is inadequate, oxygen utilization (VO2) becomes dependent upon oxygen delivery (DO2). The relationship of VO2 to DO2 over a broad range of DO2 values is commonly represented as two intersecting straight lines (Fig. 13-1). In the region of higher DO2 values, the slope of the line is approximately equal to zero, indicating that VO2 is largely independent of DO2. In contrast, in the region of low DO2 values, the slope of the line is nonzero and positive, indicating that VO2 is supply-dependent. The region where the two lines intersect is called the point of critical oxy-gen delivery (DO2crit), and represents the transition from supplyindependent to supply-dependent oxygen uptake. Below a critical Oxygen delivery, DO2Tissue hypoxiaSupply-dependentoxygen consumptionSupply-independentoxygen consumptionTissue normoxiaOxygen utilization, VO2DO2critthreshold of oxygen delivery, increased oxygen extraction can-not compensate for the delivery deficit; hence, oxygen con-sumption begins to decrease. The slope of the supply-dependent region of the plot reflects the maximal oxygen extraction capa-bility of the vascular bed being evaluated.The subsequent sections will describe the techniques and utility of monitoring various physiologic parameters.ARTERIAL BLOOD PRESSUREThe pressure exerted by blood in the systemic arterial system, commonly referred to simply as “blood pressure,” is a cardinal parameter measured as part of the hemodynamic monitoring of patients. Extremes in blood pressure are either intrinsically deleterious or are indicative of a serious perturbation in normal physiology. Arterial blood pressure is a complex function of both cardiac output and vascular input impedance. Thus, inex-perienced clinicians may assume that the presence of a normal blood pressure is evidence that cardiac output and tissue perfu-sion are adequate. This assumption is frequently incorrect and is the reason why some critically ill patients may benefit from forms of hemodynamic monitoring in addition to measurement of arterial pressure.Blood pressure can be determined directly by measuring the pressure within the arterial lumen or indirectly using a cuff around an extremity. When the equipment is properly set up and calibrated, direct intra-arterial monitoring of blood pressure pro-vides accurate and continuous data. Additionally, intra-arterial catheters provide a convenient way to obtain samples of blood for measurements of arterial blood gases and other laboratory studies. Despite these advantages, intra-arterial catheters are invasive devices and occasionally are associated with serious complications.Noninvasive Measurement of Arterial Blood PressureBoth manual and automated means for the noninvasive determi-nation of blood pressure use an inflatable sphygmomanometer cuff to increase pressure around an extremity and to detect the presence or absence of arterial pulsations. Several methods exist for this purpose. The time-honored approach is the auscultation of the Korotkoff sounds, which are heard over an artery distal to the cuff as the cuff is deflated from a pressure higher than systolic pressure to one less than diastolic pressure. Systolic pressure is defined as the pressure in the cuff when tapping sounds are first audible. Diastolic pressure is the pressure in the cuff when audible pulsations first disappear.Brunicardi_Ch13_p0433-p0452.indd 43422/02/19 2:20 PM 435PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13Another means for pulse detection when measuring blood pressure noninvasively depends upon the detection of oscillations in the pressure within the bladder of the cuff. This approach is simple, and unlike auscultation, can be performed even in a noisy environment (e.g., a busy emergency depart-ment or medical helicopter). Unfortunately, this approach is neither accurate nor reliable. Other methods, however, can be used to reliably detect the reappearance of a pulse distal to the cuff and thereby estimate systolic blood pressure. Two excellent and widely available approaches for pulse detection are use of a Doppler stethoscope (reappearance of the pulse produces an audible amplified signal) or a pulse oximeter (reappearance of the pulse is indicated by flashing of a light-emitting diode).A number of automated devices are capable of repeti-tively measuring blood pressure noninvasively. Some of these devices measure pressure oscillations in the inflatable bladder encircling the extremity to detect arterial pulsations as pressure in the cuff is gradually lowered from greater than systolic to less than diastolic pressure. Other automated noninvasive devices use a piezoelectric crystal positioned over the brachial artery as a pulse detector. The accuracy of these devices is variable, and often dependent on the size mismatch between the arm cir-cumference and the cuff size.1 If the cuff is too narrow (relative to the extremity), the measured pressure will be artifactually elevated. Therefore, the width of the cuff should be approxi-mately 40% of its circumference.Another noninvasive approach for measuring blood pres-sure relies on a technique called photoplethysmography. This method is capable of providing continuous information, since systolic and diastolic blood pressures are recorded on a beat-to-beat basis. Photoplethysmography uses the transmission of infrared light to estimate the amount of hemoglobin (directly related to the volume of blood) in a finger placed under a servo-controlled inflatable cuff. A feedback loop controlled by a microprocessor continually adjusts the pressure in the cuff to maintain the blood volume of the finger constant. Under these conditions, the pressure in the cuff reflects the pressure in the digi-tal artery. The measurements obtained using photoplethysmog-raphy generally agree closely with those obtained by invasive monitoring of blood pressure.2 However, these readings may be less accurate in patients with hypotension or hypothermia.Invasive Monitoring of Arterial Blood PressureDirect and continuous monitoring of arterial pressure in criti-cally ill patients may be performed by using fluid-filled tubing to connect an intra-arterial catheter to an external strain-gauge transducer. The signal generated by the transducer is electroni-cally amplified and displayed as a continuous waveform by an oscilloscope or computerized display. Digital values for systolic and diastolic pressure also are displayed. Mean pressure, calcu-lated by electronically averaging the amplitude of the pressure waveform, can also be displayed. The fidelity of the catheter-tubing-transducer system is determined by numerous factors, including the compliance of the tubing, the surface area of the transducer diaphragm, and the compliance of the diaphragm. If the system is underdamped, then the inertia of the system, which is a function of the mass of the fluid in the tubing and the mass of the diaphragm, causes overshoot of the points of maximum positive and negative displacement of the diaphragm during sys-tole and diastole, respectively. Thus, in an underdamped system, systolic pressure will be overestimated and diastolic pressure will be underestimated. In an overdamped system, displacement of the diaphragm fails to track the rapidly changing pressure waveform, and systolic pressure will be underestimated and diastolic pressure will be overestimated. It is important to note that even in an underdamped or overdamped system, mean pres-sure will be accurately recorded, provided the system has been properly calibrated. For these reasons, when using direct mea-surement of intra-arterial pressure to monitor patients, clinicians should make clinical decisions based primarily on the measured mean arterial blood pressure.The radial artery at the wrist is the site most commonly used for intra-arterial pressure monitoring. Other sites include the femoral and axillary artery. It is important to recognize, however, that measured arterial pressure is determined in part by the site where the pressure is monitored. Central (i.e., aortic) and peripheral (e.g., radial artery) pressures typically are dif-ferent as a result of the impedance and inductance of the arte-rial tree. Systolic pressures typically are higher and diastolic pressures are lower in the periphery, whereas mean pressure is approximately the same in the aorta and more distal sites.Distal ischemia is an uncommon complication of intra-arterial catheterization. The incidence of thrombosis is increased when larger-caliber catheters are employed and when catheters are left in place for an extended period of time. The incidence of thrombosis can be minimized by using a 20-gauge (or smaller) catheter in the radial artery and removing the catheter as soon as feasible. The risk of distal ischemic injury can be reduced by ensuring that adequate collateral flow is present prior to catheter insertion. At the wrist, adequate collateral flow can be documented by performing a modified version of the Allen test, wherein the artery to be cannulated is digitally compressed while using a Doppler stethoscope to listen for perfusion in the palmar arch vessels.Another potential complication of intra-arterial monitor-ing is retrograde embolization of air bubbles or thrombi into the intracranial circulation. In order to minimize this risk care should be taken to avoid flushing arterial lines when air is pres-ent in the system, and only small volumes of fluid (less than 5 mL) should be employed for this purpose. Catheter-related infections can occur with any intravascular monitoring device. However, catheter-related bloodstream infection is a relatively uncommon complication of intra-arterial lines used for monitor-ing, occurring in 0.4% to 0.7% of catheterizations.3 The inci-dence increases with longer duration of arterial catheterization.ELECTROCARDIOGRAPHIC MONITORINGThe electrocardiogram (ECG) records the electrical activity associated with cardiac contraction by detecting voltages on the body surface. A standard 3-lead ECG is obtained by placing electrodes that correspond to the left arm (LA), right arm (RA), and left leg (LL). The limb leads are defined as lead I (LA-RA), lead II (LL-RA), and lead III (LL-LA). The ECG waveforms can be continuously displayed on a monitor, and the devices can be set to sound an alarm if an abnormality of rate or rhythm is detected. Continuous ECG monitoring is widely available and applied to critically ill and perioperative patients. Monitoring of the ECG waveform is essential in patients with acute coronary syndromes or blunt myocardial injury because dysrhythmias are the most common lethal complication. In patients with shock or sepsis, dysrhythmias can occur as a consequence of inadequate myocardial oxygen delivery or as a complication of vasoactive or inotropic drugs used to support blood pressure and cardiac Brunicardi_Ch13_p0433-p0452.indd 43522/02/19 2:20 PM 436BASIC CONSIDERATIONSPART Ioutput. Dysrhythmias can be detected by continuously moni-toring the ECG tracing, and timely intervention may prevent serious complications. With appropriate computing hardware and software, continuous ST-segment analysis also can be per-formed to detect ischemia or infarction.Additional information can be obtained from a 12-lead ECG, which is essential for patients with potential myocardial ischemia or to rule out cardiac complications in other acutely ill patients. Continuous monitoring of the 12-lead ECG may be beneficial in certain patient populations. In a study of 185 vas-cular surgical patients, continuous 12-lead ECG monitoring was able to detect transient myocardial ischemic episodes in 20.5% of the patients.4 This study demonstrated that the precordial lead V4, which is not routinely monitored on a standard 3-lead ECG, is the most sensitive for detecting perioperative ischemia and infarction. To detect 95% of the ischemic episodes, two or more precordial leads were necessary. Furthermore, in a pro-spective observational study, 51 peripheral artery vascular sur-gery patients underwent ambulatory continuous 12-lead ECG monitoring in the postoperative setting. Ischemic load, defined as the area under the curve defined by ischemic ST-segment deviation and ischemic time, was shown to predict perioperative myocardial infarction with an area under the receiver operating characteristics curve of 0.87. Notably, ischemia was asymptom-atic in 14 of the 17 identified patients, demonstrating value of this modality as a warning tool.5 Thus, continuous 12-lead ECG monitoring may provide greater sensitivity than 3-lead ECG for the detection of perioperative myocardial ischemia, and may become standard for monitoring high-risk surgical patients.Currently, there is considerable interest in using comput-erized approaches to analyze ECG waveforms and patterns to uncover hidden information that can be used to predict sudden cardiac death or the development of serious dysrhythmias. ECG patterns of interest include repetitive changes in the morphol-ogy of the T-wave (T-wave alternans; TWA)6 and heart rate variability.7ALGORITHMIC INTEGRATIVE MONITORINGIntegrated monitoring systems employ software that integrates vital signs to produce a single-parameter index that allows early detection of physiologic perturbations. The input variables include noninvasive measurements of heart rate, respiratory rate, blood pressure, SpO2, and temperature. The software uses neural networking to develop a probabilistic model of normal-ity, previously developed from a representative sample patient training set. Variance from this data set is used to evaluate the probability that the patient-derived vital signs are within the normal range. An abnormal index can occur while no single vital sign parameter is outside the range of normal if their com-bined patterns are consistent with known instability patterns. Employing such an integrated monitoring system in step-down unit patients has been shown to be a sensitive method to detect early physiologic abnormalities that may precede hemodynamic instability.8 This subsequently was demonstrated to reduce the amount of overall patient instability by facilitating earlier iden-tification and appropriate intervention by the medical team.9The large expansion of the electronic medical record (EMR) is also driving the development of new algorithmic assessment tools for inpatient monitoring. The Rothman Index (RI) is a proprietary data analysis toolkit encompassing a total of 26 variables including vital signs, nursing assessments, laboratory test values, and cardiac rhythms and was developed to make use of the vast amount of data input into the EMR on a real-time basis to help provide a global assessment of patient status. In the initial derivation, Rothman and colleagues dem-onstrated concordance of the RI with the Modified Early Warning Score (MEWS) system, which is designed to alert medical teams to clinical deterioration that precedes cardiac or pulmonary arrest events.10 Subsequent publications evaluated performance of the RI in predicting both readmission to surgical ICUs in the postoperative setting as well as for rapid response team activations.11-13 Although more work is required to evalu-ate the broad applicability of the RI and similar measures, the evidence to date is compelling. Furthermore, as EMR interfaces become more sophisticated, other real-time data analysis soft-ware packages will likely be developed that provide further insight into the care of postsurgical patients.CARDIAC OUTPUT AND RELATED PARAMETERSBedside catheterization of the pulmonary artery was introduced into clinical practice in the 1970s. Although the pulmonary artery catheter initially was used primarily to manage patients with cardiogenic shock and other acute cardiac diseases, indi-cations for this form of invasive hemodynamic monitoring gradually expanded to encompass a wide variety of clinical con-ditions. Clearly, many clinicians believe that information valu-able for the management of critically ill patients is afforded by having a pulmonary artery catheter (PAC) in place. However, unambiguous data in support of this view are scarce, and several studies suggest that bedside pulmonary artery catheterization may not benefit most critically ill patients and in fact may lead to some serious complications (see “Effect of Pulmonary Artery Catheterization on Outcome”).Determinants of Cardiac PerformanceCardiac performance requires the integration of multiple mechanical and physiologic parameters of both the heart itself and of the circulatory system through which blood flows. The following sections discuss some of these factors, including preload, contractility, and afterload. A brief review of some of the graphical tools for evaluating cardiac physiology is demon-strated in Fig. 13-2.Preload. Starling’s law of the heart states that the force of muscle contraction depends on the initial length of the cardiac fibers. Using terminology that derives from early experiments using isolated cardiac muscle preparations, preload is the stretch of ventricular myocardial tissue just prior to the next contrac-tion. Strictly speaking, preload is determined by end-diastolic volume (EDV). In practice, EDV is challenging to measure precisely during the cardiac cycle, and so clinicians utilize the end-diastolic pressure (EDP) as a reasonable surrogate. For the right ventricle, central venous pressure (CVP) approximates right ventricular EDP. For the left ventricle, pulmonary artery occlusion pressure (PAOP), which is measured by transiently inflating a balloon at the end of a pressure monitoring catheter positioned in a small branch of the pulmonary artery, approxi-mates left ventricular EDP. The presence of atrioventricular val-vular stenosis may alter this relationship.There are limits to the utilization of EDP as a surrogate for EDV when evaluating preload. For example, EDP is deter-mined not only by volume but also by the diastolic compliance of the ventricular chamber. Ventricular compliance is altered by Brunicardi_Ch13_p0433-p0452.indd 43622/02/19 2:20 PM 437PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13Figure 13-2 A-D.  Left ventricular pressure-volume loops constructed for various clinically relevant scenarios. For further information refer to the text. A. Standard left ventricular pressure-volume loop, with stroke volume, end systolic volume, and end diastolic volume highlighted for reference. Note the directionality of the pressure-volume loop, which is not annotated in the other figures for clarity. B-D. Demonstration of the effect of changing preload (B), contractility (C), or afterload (D) on the pressure-volume relationships in the left ventricle. Note the differences in stroke volume for various conditions, as well as the end-systolic volume and pressures, as these represent clinically significant parameters that govern patient care.various pathologic conditions and pharmacologic agents. Fur-thermore, the relationship between EDP and true preload is not linear, but rather is exponential (Fig. 13-2A,B). This fact limits the utility of EDP as a surrogate marker at extremes of EDV.Contractility. Contractility is defined as the inotropic state of the myocardium. Contractility is said to increase when the force of ventricular contraction increases at constant preload and afterload. Clinically, contractility is difficult to quantify because virtually all of the available measures are dependent to a certain degree on preload and afterload. If pressure-volume loops are constructed for each cardiac cycle, small changes in preload and/or afterload will result in shifts of the point defining the end of systole. These end-systolic points on the pressure-versus-volume diagram describe a straight line, known as the end-systolic pressure-volume line. A steeper slope of this line indicates greater contractility, as illustrated in Fig. 13-2C.Afterload. Afterload is another term derived from in vitro experiments using isolated strips of cardiac muscle and is defined as the force resisting fiber shortening once systole begins. Defined specifically for the in vivo system, afterload is the resistance to the expulsion of blood from the heart chamber of interest, usually the left ventricle. Several factors comprise the in vivo correlate of ventricular afterload, including ven-tricular chamber geometry, intracavitary pressure generation, and the arterial impedance in the systemic circulation. Since these factors are difficult to assess clinically, afterload is com-monly approximated by calculating systemic vascular resistance (SVR), defined as mean arterial pressure (MAP) divided by car-diac output (Fig. 13-2D).PLACEMENT OF THE PULMONARY ARTERY CATHETERIn its simplest form, the PAC has four channels. One channel terminates in a balloon at the tip of the catheter. The proximal end of this channel is connected to a syringe to permit inflation of the balloon with air. Prior to insertion of the PAC, the integ-rity of the balloon should be verified by inflating it. In order to minimize the risk of vascular or ventricular perforation by the relatively inflexible catheter, it also is important to verify that the inflated balloon extends just beyond the tip of the device. A second channel in the catheter contains wires that are connected Brunicardi_Ch13_p0433-p0452.indd 43722/02/19 2:21 PM 438BASIC CONSIDERATIONSPART Ito a thermistor located near the tip of the catheter. At the proxi-mal end of the PAC, the wires terminate in a fitting that permits connection to appropriate hardware for the calculation of car-diac output using the thermodilution technique. The final two channels are used for pressure monitoring and the injection of the thermal indicator for determinations of cardiac output. One of these channels terminates at the tip of the catheter; the other terminates 20 cm proximal to the tip.Placement of a PAC requires access to the central venous circulation. Such access can be obtained at a variety of sites, including the antecubital, femoral, jugular, and subclavian veins. Percutaneous placement through either the jugular or sub-clavian vein generally is preferred. Right internal jugular vein cannulation carries the lowest risk of complications, and the path of the catheter from this site into the right atrium is straight. In the event of inadvertent arterial puncture, local pressure is significantly more effective in controlling bleeding from the carotid artery as compared to the subclavian artery. Neverthe-less, it is more difficult to keep occlusive dressings in place on the neck than in the subclavian fossa. Furthermore, the anatomic landmarks in the subclavian position are quite constant, even in patients with anasarca or massive obesity; the subclavian vein is always attached to the deep (concave) surface of the clavicle. In contrast, the appropriate landmarks to guide jugular venous cannulation are sometimes difficult to discern in obese or very edematous patients. However, ultrasonic guidance, which should be used routinely, has been shown to facilitate bedside jugular venipuncture.14Cannulation of the vein is normally performed percuta-neously, using the Seldinger technique. A small-bore needle is inserted through the skin and subcutaneous tissue into the vein. After documenting return of venous blood, a guidewire with a flexible tip is inserted through the needle into the vein, and the needle is withdrawn. A dilator/introducer sheath is passed over Figure 13-3. Representative pressure traces at different stages of insertion of the PAC. In the central venous circulation, the pressure remains low, with characteristic waves from atrial filling and tricuspid valve closing. Upon entry into the right ventricle, the pressure increases sharply, with the broadest range between systole and diastole. When in the main pulmonary artery, the systolic pressure remains elevated to the same degree, but the diastolic pressure is now significantly elevated due to the closure of the pulmonic valve during the cardiac cycle. Upon further advancement with the balloon inflated, the pressure differences become smaller and the magnitude of the mean pressure drops, reflecting an estimate of the left atrial pressure.the wire, and the wire and the dilator are removed. The proxi-mal terminus of the distal port of the PAC is connected through low-compliance tubing to a strain-gauge transducer, and the tubing-catheter system is flushed with fluid. While constantly observing the pressure tracing on a monitor screen, the PAC is advanced with the balloon deflated until respiratory excur-sions are observed. The balloon is then inflated, and the catheter advanced further, while monitoring pressures sequentially in the right atrium and right ventricle en route to the pulmonary artery. The pressure waveforms for the right atrium, right ventricle, and pulmonary artery are each characteristic (Fig. 13-3). The cath-eter is advanced out the pulmonary artery until a damped tracing indicative of the “wedged” position is obtained. The balloon is then deflated, taking care to ensure that a normal pulmonary arterial tracing is again observed on the monitor; leaving the balloon inflated can increase the risk of pulmonary infarction or perforation of the pulmonary artery. Unnecessary measurements of the pulmonary artery occlusion pressure are discouraged as rupture of the pulmonary artery may occur.HEMODYNAMIC MEASUREMENTSEven in its simplest embodiment, the PAC is capable of pro-viding clinicians with a remarkable amount of information about the hemodynamic status of patients. Additional informa-tion may be obtained if various modifications of the standard PAC are employed. By combining data obtained through use of the PAC with results obtained by other means (i.e., blood hemoglobin concentration and oxyhemoglobin saturation), derived estimates of systemic oxygen transport and utilization can be calculated. Direct and derived parameters obtainable by bedside pulmonary arterial catheterization, along with sev-eral associated approximate normal ranges, are summarized in Table 13-1.Brunicardi_Ch13_p0433-p0452.indd 43822/02/19 2:21 PM 439PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13Table 13-1Directly measured and derived hemodynamic data obtainable by bedside pulmonary artery catheterization, with normal associated rangesPARAMETERNORMAL RANGECVP0–6 mmHgPAPVariesPAOP6–12 mmHgSv–O2 (intermittent or continuous)65%–70%QT (intermittent or continuous)4–6 L/minQT* (intermittent or continuous)2.5–3.5 L·min-1·m-2RVEF>55%SV40–80 mLSVR800–1400 dyne·sec·cm-5SVRI1500–2400 dyne·sec·cm-5·m-2PVR100–150 dyne·sec·cm-5PVRI200–400 dyne·sec·cm-5·m-2RVEDVVariableD.O2400–660 mL·min-1·m-2V–O2115–165 mL·min-1·m-2ERVariableQS/QTVariableCVP = mean central venous pressure; D.O2 = systemic oxygen delivery; ER = systemic oxygen extraction ratio; PAOP = pulmonary artery occlusion (wedge) pressure; PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; PVRI = pulmonary vascular resistance index; QS/QT = fractional pulmonary venous admixture (shunt fraction); QT = cardiac output; QT* = cardiac output indexed to body surface area (cardiac index); RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; SV = stroke volume; SVI = stroke volume index; Sv–O2= fractional mixed venous (pulmonary artery) hemoglobin saturation; SVR = systemic vascular resistance; SVRI = systemic vascular resistance index; V–O2 = systemic oxygen utilization.Measurement of Cardiac Output by ThermodilutionBefore the development of the PAC, determining cardiac output (QT) at the bedside required careful measurements of oxygen consumption (Fick method) or spectrophotometric determina-tion of indocyanine green dye dilution curves. Measurements of QT using the thermodilution technique are simple and reason-ably accurate. The measurements can be performed repetitively, and the principle is straightforward. If a bolus of an indicator is rapidly and thoroughly mixed with a moving fluid upstream from a detector, then the concentration of the indicator at the detector will increase sharply and then exponentially diminish back to zero. The area under the resulting time-concentration curve is a function of the volume of indicator injected and the flow rate of the moving stream of fluid. Larger volumes of indi-cator result in greater areas under the curve, and faster flow rates of the mixing fluid result in smaller areas under the curve. When QT is measured by thermodilution, the indicator is heat and the detector is a temperature-sensing thermistor at the distal end of the PAC. The relationship used for calculating QT is called the Stewart-Hamilton equation:QVKK(TT)T(t)dtT12BIB=−˛where V is the volume of the indicator injected, TB is the tem-perature of blood (i.e., core body temperature), TI is the tem-perature of the indicator, K1 is a constant that is the function of the specific heats of blood and the indicator, K2 is an empiri-cally derived constant that accounts for several factors (the dead space volume of the catheter, heat lost from the indicator as it traverses the catheter, and the injection rate of the indicator), and ∫TB(t)dt is the area under the time-temperature curve. In clinical practice, the Stewart-Hamilton equation is solved by a microprocessor.Determination of cardiac output by the thermodilution method is generally quite accurate, although it tends to system-atically overestimate QT at low values. Changes in blood tem-perature and QT during the respiratory cycle can influence the measurement. Therefore, results generally should be recorded as the mean of two or three determinations obtained at random points in the respiratory cycle. Using cold injectate widens the difference between TB and TI and thereby increases signal-to-noise ratio. Nevertheless, most authorities recommend using room temperature injectate (normal saline or 5% dextrose in water) to minimize errors resulting from warming of the fluid as it transferred from its reservoir to a syringe for injection.Technologic innovations have been introduced that per-mit continuous measurement of QT by thermodilution. In this approach, thermal transients are not generated by injecting a bolus of a cold indicator, but rather by heating the blood with a tiny filament located on the PAC upstream from the thermistor. By correlating the amount of current supplied to the heating element with the downstream temperature of the blood, it is pos-sible to estimate the average blood flow across the filament and thereby calculate QT. Based upon the results of several studies, continuous determinations of QT using this approach agree well with data generated by conventional measurements using bolus injections of a cold indicator.15 Information is lacking regarding the clinical value of being able to monitor QT continuously.Mixed Venous OximetryThe Fick equation can be written as222QVO(COCO)Tav=−where CaO2 is the content of oxygen in arterial blood and CvO2 is the content of oxygen in mixed venous blood. The oxygen content in both arterial and venous blood is a function of the hemoglobin concentration in the blood, the hemoglobin satura-tion, and the partial pressure of oxygen:CO1.36HgbSO1000.0031POa/v2a/v2a/v2=×ײ˝˙ˆˇ˘+×CO1.36HgbSO100//av2av2=×ײ˝˙ˆˇ˘where Sa/vO2 is the fractional saturation of hemoglobin in either arterial or venous blood, Hgb is the concentration of hemoglobin Brunicardi_Ch13_p0433-p0452.indd 43922/02/19 2:21 PM 440BASIC CONSIDERATIONSPART Iin blood, and Pa/vO2 is the partial pressure of oxygen in the arte-rial or venous blood. Under most circumstances the contribution of dissolved oxygen to both CaO2 and CvO2 is negligible, allow-ing the second portion of equation to be functionally eliminated (see previous equation). Given that, if the Fick equation is rear-ranged to the following:2COCOVOQv2a2T=−Oxygen saturation can replace oxygen content, yielding the final clinically valuable equation:(1.36)222SOSOVOQHgbvaT=−××where SVO2 is the fractional saturation of hemoglobin in mixed venous blood, SaO2 is the fractional saturation of hemoglobin in arterial blood, and Hgb is the concentration of hemoglobin in blood. Thus, it can be seen that SVO2 is a function of VO2 (i.e., metabolic rate), QT, SaO2, and Hgb. Accordingly, subnormal val-ues of SVO2 can be caused by a decrease in QT (due, for example, to heart failure or hypovolemia), a decrease in SaO2 (due, for example, to intrinsic pulmonary disease), a decrease in Hgb (i.e., anemia), or an increase in metabolic rate (due, for example, to seizures or fever). With a conventional PAC, measurements of SVO2 require aspirating a sample of blood from the distal (i.e., pulmonary arterial) port of the catheter and injecting the sample into a blood gas analyzer. Therefore, for practical purposes, mea-surements of SVO2 can be performed only intermittently.By adding a fifth channel to the PAC, it is possible to mon-itor SVO2 continuously. The fifth channel contains two fiber-optic bundles, which are used to transmit and receive light of the appropriate wavelengths to permit measurements of hemoglobin saturation by reflectance spectrophotometry. Continuous SVO2 devices provide measurements of SVO2 that agree quite closely with those obtained by conventional analyses of blood aspi-rated from the pulmonary artery. Despite the theoretical value of being able to monitor SVO2 continuously, data are lacking to show that this capability favorably improves outcomes. In a prospective, observational study of 3265 patients undergoing cardiac surgery with either a standard PAC or a PAC with con-tinuous SVO2 monitoring, the oximetric catheter was associated with fewer arterial blood gases and thermodilution cardiac out-put determinations but no difference in patient outcome.16 Since pulmonary artery catheters that permit continuous monitoring of SVO2 are more expensive than conventional PACs, the routine use of these devices cannot be recommended.The saturation of oxygen in the right atrium or superior vena cava (ScvO2) correlates closely with SvO2 over a wide range of conditions,17 although the correlation between ScvO2 and SvO2 has been questioned.18 Since measurement of ScvO2 requires placement of a central venous catheter rather than a PAC, it is somewhat less invasive and easier to carry out. By using a cen-tral venous catheter equipped to permit fiber-optic monitoring of ScvO2, it may be possible to titrate the resuscitation of patients with shock using a less invasive device than the PAC.17,19 The Surviving Sepsis Campaign international guidelines for the management of severe sepsis and septic shock recommends that during the first 6 hours of resuscitation, the goals of initial resuscitation of sepsis-induced hypoperfusion should include all of the following: CVP 8 to 12 mm Hg, MAP ≥65 mm Hg, urine output ≥0.5 mL/kg per hour, and ScvO2 of 70% or SvO2 65%.20EFFECT OF PULMONARY ARTERY CATHETERIZATION ON OUTCOMEDespite initial enthusiasm for using the PAC in the manage-ment of critically ill patients, several studies have failed to show improved outcomes with their use. Connors and col-leagues reported results of a major observational study evaluat-ing the value of pulmonary artery catheterization in critically ill patients.21 These researchers compared two groups of patients: those who did undergo placement of a PAC during their first 24 hours of ICU care and those who did not. The investiga-tors recognized that the value of their intended analysis was completely dependent on the robustness of their methodology for case-matching because sicker patients (i.e., those at greater risk of mortality based upon the severity of their illness) were presumably more likely to undergo pulmonary artery catheter-ization. Accordingly, the authors used sophisticated statistical methods for generating a cohort of study (i.e., PAC) patients, each one having a paired control matched carefully for severity of illness. Connors and associates concluded that placement of a pulmonary artery catheter during the first 24 hours of stay in an ICU is associated with a significant increase in the risk of mortality, even when statistical methods are used to account for severity of illness.A number of prospective, randomized controlled trials of pulmonary artery catheterization are summarized in Table 13-2. The study by Pearson and associates was underpowered with only 226 patients enrolled.22 In addition, the attending anes-thesiologists were permitted to exclude patients from the CVP group at their discretion; thus randomization was compromised. The study by Tuman and coworkers was large (1094 patients were enrolled), but different anesthesiologists were assigned to the different groups.23 Furthermore, 39 patients in the CVP group underwent placement of a PAC because of hemodynamic complications. All of the individual single-institution studies of vascular surgery patients were relatively underpowered, and all excluded at least certain categories of patients (e.g., those with a history of recent myocardial infarction).24,25In the largest randomized controlled trial of the PAC, Sandham and associates randomized nearly 2000 American Society of Anesthesiologists (ASA) classes III and IV patients undergoing major thoracic, abdominal, or orthopedic surgery to placement of a PAC or CVP catheter.26 In the patients assigned to receive a PAC, physiologic goal-directed therapy was imple-mented by protocol. There were no differences in mortality at 30 days, 6 months, or 12 months between the two groups, and ICU length of stay was similar. There was a significantly higher rate of pulmonary emboli in the PAC group (0.9% vs. 0%). This study has been criticized because most of the patients enrolled were not in the highest risk category.In the “PAC-Man” trial, a multicenter, randomized trial in 65 UK hospitals, over 1000 ICU patients were managed with or without a PAC.27 The specifics of the clinical management were then left up to the treating clinicians. There was no dif-ference in hospital mortality between the 2 groups (with PAC 68% vs. without PAC 66%, P = 0.39). However, a 9.5% com-plication rate was associated with the insertion or use of the PAC, although none of these complications were fatal. Clearly, these were critically ill patients, as noted by the high hospital mortality rates. Supporters of the PAC may cite methodology problems with this study, such as loose inclusion criteria and the lack of a defined treatment protocol.Brunicardi_Ch13_p0433-p0452.indd 44022/02/19 2:21 PM 441PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13Table 13-2Summary of randomized, prospective clinical trials comparing pulmonary artery catheter (PAC) with central venous pressure (CVP) monitoringAUTHORSTUDY POPULATIONGROUPSOUTCOMESSTRENGTHS/WEAKNESSESPearson et al22“Low risk” patients undergoing cardiac or vascular surgeryCVP catheter (group 1); PAC (group 2); PAC with continuous Sv–O2 readout (group 3)No differences among groups for mortality or length of ICU stay; significant differences in costs (group 1 < group 2 < group 3)Underpowered (266 total patients enrolled); compromised randomization protocolsTuman et al23Cardiac surgical patientsPAC; CVPNo differences between groups for mortality, length of ICU stay, or significant noncardiac complicationsLarge trial (1094 patients); different anesthesiologists for different groupsBender et al24Vascular surgery patientsPAC; CVPNo differences between groups for mortality, length of ICU stay, or length of hospital stayRelatively underpoweredValentine et al25Aortic surgery patientsPAC + hemodynamic optimization in ICU night before surgery; CVPNo difference between groups for mortality or length of ICU stay; significantly higher incidence of postoperative complications in PAC groupRelatively underpoweredSandham et al26“High risk” major surgeryPAC; CVPNo differences between groups for mortality, length of ICU stay; increased incidence of pulmonary embolism in PAC groupLargest RCT of PAC utilization; commonly criticized for smaller number of highest risk category patientsHarvey S et al27PAC-Man TrialMedical and surgical ICU patientsPAC vs no PAC, with option for alternative CO measuring device in non-PAC groupNo difference in hospital mortality between the 2 groups, increased incidence of complications in the PAC groupLoose inclusion criteria with lack of a defined treatment protocol for use of PAC dataBinanay et al29ESCAPE TrialPatients with CHFPAC vs no PACNo difference in hospital mortality between the groups, increased incidence of adverse events in the PAC groupNo formal treatment protocol for PAC-driven therapyWheeler et al30FACTT TrialPatients with ALIPAC vs CVC with a fluid and inotropic management protocolNo difference in ICU or hospital mortality, or incidence of organ failure between the groups; increased incidence of adverse events in the PAC group ALI = acute lung injury; CHF = congestive heart failure; CO = cardiac output; CVC = central venous catheter; ICU = intensive care unit; PAC = pulmonary artery catheter; Sv–O2 = fractional mixed venous (pulmonary artery) hemoglobin saturation.A meta-analysis of 13 randomized studies of the PAC that included over 5000 patients was published in 2005.28 A broad spectrum of critically ill patients was included in these hetero-geneous trials, and the hemodynamic goals and treatment strate-gies varied. While the use of the PAC was associated with an increased use of inotropes and vasodilators, there were no differ-ences in mortality or hospital length of stay between the patients managed with a PAC and those managed without a PAC.The ESCAPE trial (which was one of the studies included in the previous meta-analysis)29 evaluated 433 patients with severe or recurrent congestive heart failure (CHF) admitted to the ICU. Patients were randomized to management by clinical assessment and a PAC or clinical assessment without a PAC. The goal in both groups was resolution of CHF, with addi-tional PAC targets of a pulmonary capillary occlusion pressure of 15 mmHg and a right atrial pressure of 8 mmHg. There was no formal treatment protocol, but inotropic support was dis-couraged. Substantial reduction in symptoms, jugular venous pressure, and edema was noted in both groups. There was no significant difference in the primary end point of days alive and out of the hospital during the first 6 months, or hospital mortality (PAC 10% vs without PAC 9%). Adverse events Brunicardi_Ch13_p0433-p0452.indd 44122/02/19 2:21 PM 442BASIC CONSIDERATIONSPART Iwere more common among patients in the PAC group (21.9% vs 11.5%; P = 0.04).Finally, the Fluids and Catheters Treatment Trial (FACTT) conducted by the Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network was published in 2006.30 The risks and benefits of PAC compared with central venous catheters (CVC) were evaluated in 1000 patients with acute lung injury. Patients were randomly assigned to receive either a PAC or a CVC to guide management for 7 days via an explicit protocol. Patients also were randomly assigned to a conservative or liberal fluid strategy in a 2 × 2 factorial design (outcomes based on the fluid management strategy were published separately). Mortality dur-ing the first 60 days was similar in the PAC and CVC groups (27% and 26%, respectively; P = .69). The duration of mechani-cal ventilation and ICU length of stay also were not influenced by the type of catheter used. The type of catheter employed did not affect the incidence of shock, respiratory or renal failure, ventilator settings, or requirement for hemodialysis or vaso-pressors. There was a 1% rate of crossover from CVC-guided therapy to PAC-guided therapy. The catheter used did not affect the administration of fluids or diuretics, and the fluid balance was similar in the two groups. The PAC group had approxi-mately twice as many catheter-related adverse events (mainly arrhythmias).Few subjects in critical care medicine have historically gen-erated more emotional responses among experts in the field than the use of the PAC. As these studies demonstrate, it is not possible to show that therapy directed by use of the PAC saves lives when it is evaluated in a large population of patients. Certainly, given the available evidence, routine use of the PAC cannot be justified. Whether selective use of the device in a few relatively uncommon clinical situations is warranted or valuable remains a controversial issue. Consequently, a marked decline in the use of the PAC from 5.66 per 1000 medical admissions in 1993 to 1.99 per 1000 medical admissions in 2004 has been seen.31 Based upon the results and exclusion criteria in these pro-spective randomized trials, reasonable criteria for perioperative monitoring without use of a PAC are presented in Table 13-3.One of the reasons for using a PAC to monitor critically ill patients is to optimize cardiac output and systemic oxygen delivery. Defining what constitutes the optimum cardiac out-put, however, has proven to be difficult. A number of random-ized trials evaluating the effect on outcome of goal-directed as compared to conventional hemodynamic resuscitation have 2Table 13-3Suggested criteria for perioperative monitoring without use of a pulmonary artery catheter in patients undergoing cardiac or major vascular surgical proceduresNo anticipated need for suprarenal or supraceliac aortic cross-clampingNo history of myocardial infarction during 3 months prior to operationNo history of poorly compensated congestive heart failureNo history of coronary artery bypass graft surgery during 6 weeks prior to operationNo history of ongoing symptomatic mitral or aortic valvular heart diseaseNo history of ongoing unstable angina pectorisbeen published. Some studies provide support for the notion that interventions designed to achieve supraphysiologic goals for DO2, VO2, and QT improve outcome.32,33 However, other pub-lished studies do not support this view, and a meta-analysis con-cluded that interventions designed to achieve supraphysiologic goals for oxygen transport do not significantly reduce mortality rates in critically ill patients.34,35 At this time, supraphysiologic resuscitation of patients in shock cannot be endorsed.There is no simple explanation for the apparent lack of effectiveness of pulmonary artery catheterization, although sev-eral concurrent possibilities exist. First, even though bedside pulmonary artery catheterization is quite safe, the procedure is associated with a finite incidence of serious complications, including ventricular arrhythmias, catheter-related sepsis, cen-tral venous thrombosis, pulmonary arterial perforation, and pul-monary embolism.26 The adverse effects of these complications on outcome may equal or even outweigh any benefits associated with using a PAC to guide therapy. Second, the data generated by the PAC may be inaccurate, leading to inappropriate thera-peutic interventions. Third, the measurements, even if accurate, are often misinterpreted.36 Furthermore, the current state of understanding is primitive when it comes to deciding what is the best management for certain hemodynamic disturbances, par-ticularly those associated with sepsis or septic shock. Taking all of this into consideration, it may be that interventions prompted by measurements obtained with a PAC are actually harmful to patients. As a result, the marginal benefit now available by placing a PAC may be quite small. Less invasive modalities are available that may provide clinically useful hemodynamic information.It may be true that aggressive hemodynamic resusci-tation of patients, guided by various forms of monitoring, is valuable only during certain critical periods, such as the first few hours after presentation with septic shock or during surgery. For example, Rivers and colleagues reported that survival of patients with septic shock is significantly improved when resus-citation in the emergency department is guided by a protocol that seeks to keep ScvO2 greater than 70%.19 Similarly, a study using an ultrasound-based device (see “Doppler Ultrasonogra-phy”) to assess cardiac filling and SV showed that maximizing SV intraoperatively results in fewer postoperative complications and shorter hospital length of stay.37MINIMALLY INVASIVE ALTERNATIVES TO THE PULMONARY ARTERY CATHETERBecause of the cost, risks, and questionable benefit associated with bedside pulmonary artery catheterization, there has been interest in the development of practical means for less invasive monitoring of hemodynamic parameters. Several approaches have been developed that have achieved variable degrees of suc-cess. None of these methods render the standard thermodilution technique of the pulmonary artery catheter obsolete. However, these strategies may contribute to improvements in the hemody-namic monitoring of critically ill patients.Transpulmonary ThermodilutionIn the standard PAC thermodilution technique, measurements rely on the detection of temperature changes in a relatively small area from the injection port to the thermistor on the same catheter. In contrast, the transpulmonary thermodilution (TPTD) technique measures temperature changes from cold Brunicardi_Ch13_p0433-p0452.indd 44222/02/19 2:21 PM 443PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13bolus solution injected centrally, then measured using an arte-rial thermistor on a special arterial line, generally placed in the femoral artery. Both standard PAC thermodilution and TPTD make use of the Stewart-Hamilton equation to subsequently cal-culate cardiac output. Studies have demonstrated that this tech-nique provides comparable estimates of cardiac output when compared to routine PAC thermodilution and can accurately detect changes in cardiac output as small as 12%.38 However, due to the large blood circuit between the central injection point and the thermistor, data can be challenging to interpret in cer-tain pathophysiologic conditions (e.g., in pulmonary edema, as excess lung water serves as a temperature sink). On the other hand, thoughtful application of TPTD data allows clinicians access to several additional variables that the traditional PAC does not provide, such as estimation of the global end-diastolic volume (GEDV) and the extravascular lung water volume (EVLW).38 While these variables are of scientific interest, they are not yet in wide clinical use, and further studies are required to determine their utility. However, TPTD does currently play a prominent in the real-time calibration of pulse contour analysis, described in greater detail later in this chapter.Doppler UltrasonographyWhen ultrasonic sound waves are reflected by moving erythro-cytes in the bloodstream, the frequency of the reflected signal is increased or decreased, depending on whether the cells are mov-ing toward or away from the ultrasonic source. This change in frequency is called the Doppler shift, and its magnitude is deter-mined by the velocity of the moving red blood cells. Therefore, measurements of the Doppler shift can be used to calculate red blood cell velocity. With knowledge of both the cross-sectional area of a vessel and the mean red blood cell velocity of the blood flowing through it, one can calculate blood flow rate. If the ves-sel in question is the aorta, then QT can be calculated as:QT = HR × A × ∫ V(t)dtwhere A is the cross-sectional area of the aorta and ∫V(t)dt is the red blood cell velocity integrated over the cardiac cycle.Two approaches have been developed for using Doppler ultrasonography to estimate QT. The first approach uses an ultrasonic transducer, which is manually positioned in the suprasternal notch and focused on the root of the aorta. Aortic cross-sectional area can be estimated using a nomogram, which factors in age, height, and weight, back-calculated if an indepen-dent measure of QT is available, or by using two-dimensional transthoracic or transesophageal ultrasonography. While this approach is completely noninvasive, it requires a highly-skilled operator in order to obtain meaningful results and is labor-intensive. Moreover, unless QT measured using thermodilution is used to back-calculate aortic diameter, accuracy using the suprasternal notch approach is not acceptable. Accordingly, the method is useful only for obtaining very intermittent estimates of QT, and it has not been widely adopted by clinicians.A more promising, albeit more invasive, approach has been introduced. In this method blood flow velocity is con-tinuously monitored in the descending thoracic aorta using a continuous-wave Doppler transducer introduced into the esoph-agus. The probe is connected to a monitor which continuously displays the blood flow velocity profile in the descending aorta as well as the calculated QT. In order to maximize the accuracy of the device, the probe position must be adjusted to obtain the peak velocity in the aorta. In order to transform blood flow in the descending aorta into QT, a correction factor is applied that is based on the assumption that only 70% of the flow at the root of the aorta is still present in the descending thoracic aorta. Aortic cross-sectional area is estimated using a nomogram based on the patient’s age, weight, and height. Results using these methods appear to be reasonably accurate across a broad spectrum of patients. A meta-analysis of the available data shows a good correlation between cardiac output estimates obtained by trans-esophageal Doppler and PAC in critically ill patients.39 The ultrasonic device also calculates a derived parameter termed flow time corrected (FTc), which is the systolic flow time in the descending aorta corrected for heart rate. FTc is a function of preload, contractility, and vascular input impedance. Although it is not a pure measure of preload, Doppler-based estimates of SV and FTc have been used successfully to guide volume resuscitation in high-risk surgical patients undergoing major operations.37Impedance CardiographyThe impedance to flow of alternating electrical current in regions of the body is commonly called bioimpedance. In the thorax, changes in the volume and velocity of blood in the tho-racic aorta lead to detectable changes in bioimpedance. The first derivative of the oscillating component of thoracic bio-impedance (dZ/dt) is linearly related to aortic blood flow. On the basis of this relationship, empirically derived formulas have been developed to estimate SV, and subsequently QT, nonin-vasively. This methodology is called impedance cardiography. The approach is attractive because it is noninvasive, provides a continuous readout of QT, and does not require extensive train-ing. Despite these advantages, measurements of QT obtained by impedance cardiography are not sufficiently reliable to be used for clinical decision making and have poor correlation with thermodilution.40Because of the limitations of bioimpedance devices, a newer approach for processing the impedance signal was devel-oped and commercialized. This approach is based on the recog-nition that the impedance signal has two components: amplitude and phase. Whereas the amplitude of the thoracic impedance signal is determined by all of the components of the thoracic cavity (bone, blood, muscle, and other soft tissues), phase shifts are determined entirely by pulsatile flow. The vast majority of pulsatile flow is related to blood moving within the aorta. There-fore, the “bioreactance” signal correlates closely with aortic flow, and cardiac output determined using this approach agrees closely with cardiac output measured using conventional indica-tor dilution techniques.41Pulse Contour AnalysisAnother method for determining cardiac output is an approach called pulse contour analysis for estimating SV on a beat-to-beat basis. The mechanical properties of the arterial tree and SV determine the shape of the arterial pulse waveform. The pulse contour method of estimating QT uses the arterial pressure waveform as an input for a model of the systemic circulation in order to determine beat-to-beat flow through the circulatory system. The parameters of resistance, compliance, and imped-ance are initially estimated based on the patient’s age and sex and can be subsequently refined by using a reference standard measurement of QT. The reference standard estimation of QT is obtained periodically using the indicator dilution approach by injecting the indicator into a central venous catheter and Brunicardi_Ch13_p0433-p0452.indd 44322/02/19 2:21 PM 444BASIC CONSIDERATIONSPART Idetecting the transient increase in indicator concentration in the blood using an arterial catheter. In one commercially available embodiment of this approach, the lithium ion (Li+) is the indi-cator used for the periodic calibrations of the device. The lith-ium carbonate indicator can be injected into a peripheral vein, and the doses do not exert pharmacologically relevant effects in adult patients. The Li+ indicator dilution method has shown to be at least as reliable as other thermodilution methods over a broad range of CO in a variety of patients.41 In another com-mercially available system, a conventional bolus of cold fluid is used as the indicator for calibration, via TPTD approaches as described previously. When the pulse contour analysis is com-bined with intermittent TPTD in this fashion, the continuous data provided by contour analysis is more precise than TPTD alone.38Measurements of QT based on pulse contour monitoring using these two approaches are comparable in accuracy to stan-dard pulmonary artery catheter (PAC)-thermodilution methods, but they are less invasive because transcardiac catheterization is not needed.42 Using online pressure waveform analysis, the computerized algorithms can calculate SV, QT, SVR, and an estimate of myocardial contractility, the rate of rise of the arte-rial systolic pressure (dP/dT). The use of pulse contour analy-sis has been applied using noninvasive photoplethysmographic measurements of arterial pressure. However, the accuracy of this technique has been questioned, and its clinical utility remains to be determined.43One commercially available device that can be used for estimating cardiac output does not require external calibration. Instead, the relationship between pulse pressure and stroke vol-ume is determined using a proprietary algorithm that uses bio-metric data, such as age, gender and height, as inputs. Although this methodology is gaining fairly wide acceptance in critical care medicine, reported accuracy (in comparison to “gold stan-dard” approaches) is not very good.41Partial Carbon Dioxide RebreathingPartial carbon dioxide (CO2) rebreathing uses the Fick prin-ciple to estimate QT noninvasively. By intermittently altering the dead space within the ventilator circuit via a rebreathing valve, changes in CO2 production (VCO2) and end-tidal CO2 (ETCO2) are used to determine cardiac output using a modified Fick equation:Q=VETTCOCO22˜˜Commercially available devices use this Fick principle to cal-culate QT using intermittent partial CO2 rebreathing through a disposable rebreathing loop. These devices consist of a CO2 sen-sor based on infrared light absorption, an airflow sensor, and a pulse oximeter. Changes in intrapulmonary shunt and hemody-namic instability impair the accuracy of QT estimated by partial CO2 rebreathing. Continuous inline pulse oximetry and inspired fraction of inspired O2 (Fio2) are used to estimate shunt fraction to correct QT.Some studies of the partial CO2 rebreathing approach sug-gest that this technique is not as accurate as thermodilution, the gold standard for measuring QT.42,44 However, other studies sug-gest that the partial CO2 rebreathing method for determination of QT compares favorably to measurements made using a PAC in critically ill patients.45Transesophageal EchocardiographyTransesophageal echocardiography (TEE) has made the transi-tion from operating room to intensive care unit. TEE requires that the patient be sedated and usually intubated for airway pro-tection. Using this powerful technology, global assessments of LV and RV function can be made, including determinations of ventricular volume, EF, and QT. Segmental wall motion abnor-malities, pericardial effusions, and tamponade can be readily identified with TEE. Doppler techniques allow estimation of atrial filling pressures. The technique is somewhat cumbersome and requires considerable training and skill in order to obtain reliable results. Recently, a TEE probe has been introduced into practice that is small enough in diameter that it can be left in place for as long as 72 hours. While only limited data are cur-rently available with this probe, it seems like it will be a useful cardiac monitoring tool for use in selected, complex patients.Assessing Preload ResponsivenessAlthough pulse contour analysis or partial CO2 rebreathing may be able to provide estimates of SV and QT, these approaches alone can offer little or no information about the adequacy of preload. Thus, if QT is low, some other means must be employed to estimate preload. Many clinicians assess the adequacy of car-diac preload by determining CVP or PAOP. However, neither CVP nor PAOP correlate well with the true parameter of inter-est, left ventricular end-diastolic volume (LVEDV).46 Extremely high or low CVP or PAOP results are informative, but readings in a large middle zone (i.e., 5 to 20 mmHg) are less useful. Fur-thermore, changes in CVP or PAOP fail to correlate well with changes in stroke volume.47,48 Echocardiography can be used to estimate LVEDV, but this approach is dependent on the skill and training of the individual using it, and isolated measure-ments of LVEDV fail to predict the hemodynamic response to alterations in preload.49When intrathoracic pressure increases during the appli-cation of positive airway pressure in mechanically ventilated patients, venous return decreases, and as a consequence, left ventricular stroke volume (LVSV) also decreases. Therefore, pulse pressure variation (PPV) during a positive pressure episode can be used to predict the responsiveness of cardiac output to changes in preload.50,51 PPV is defined as the differ-ence between the maximal pulse pressure and the minimum pulse pressure divided by the average of these two pressures (Fig. 13-4). This approach has validated this by comparing PPV, CVP, PAOP, and systolic pressure variation as predictors of pre-load responsiveness in a cohort of critically ill patients. Patients were classified as being “preload responsive” if their cardiac index increased by at least 15% after rapid infusion of a standard volume of intravenous fluid.52 Receiver-operating characteristic (ROC) curves demonstrated that PPV was the best predictor of preload responsiveness. Although atrial arrhythmias can inter-fere with the usefulness of this technique, PPV remains a useful approach for assessing preload responsiveness in most patients because of its simplicity and reliability.49Near-Infrared Spectroscopic Measurement of Tissue Hemoglobin Oxygen SaturationNear-infrared spectroscopy (NIRS) allows continuous, nonin-vasive measurement of tissue hemoglobin oxygen saturation (StO2) using near-infrared wave lengths of light (700–1000 nm). This technology is based on Beer’s law, which states that the transmission of light through a solution with a dissolved Brunicardi_Ch13_p0433-p0452.indd 44422/02/19 2:21 PM 445PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13Figure 13-4. Calculation of pulse pressure variation as it would appear on bedside monitor. This provides a helpful and rapid assessment of fluid responsiveness in the critically ill mechanically ventilated patient.PPmax + PPmin2PPV (%) =PPmax – PPmin× 100InspirationArterial blood pressure (mmHg)ExpirationInspirationInspirationExpirationTimePPminPPmaxsolute decreases exponentially as the concentration of the sol-ute increases. In mammalian tissue, three compounds change their absorption pattern when oxygenated: cytochrome aa3, myoglobin, and hemoglobin. Because of the distinct absorption spectra of oxyhemoglobin and deoxyhemoglobin, Beer’s law can be used to detect their relative concentrations within tissue. Thus, the relative concentrations of the types of hemoglobin can be determined by measuring the change in light inten-sity as it passes through the tissue. Since about 20% of blood volume is intra-arterial and the StO2 measurements are taken without regard to systole or diastole, spectroscopic measure-ments are primarily indicative of the venous oxyhemoglobin concentration.NIRS has been evaluated to assess the severity of traumatic shock in animal models and in trauma patients. Studies have shown that peripheral muscle StO2, as determined by NIRS, is as accurate as other endpoints of resuscitation (i.e., base deficit, mixed venous oxygen saturation) in a porcine model of hemor-rhagic shock.53 Continuously measured StO2 has been evaluated in blunt trauma patients as a predictor of the development of multiple organ dysfunction syndrome (MODS) and mortality.54 383 patients were prospectively studied at seven level I trauma centers. StO2 was monitored for 24 hours after admission along with vital signs and other endpoints of resuscitation such as base deficit (BD). Minimum StO2 (using a minimum StO2 ≤75% as a cutoff) had a similar sensitivity and specificity in predicting the development of MODS as BD ≥6 mEq/L. StO2 and BD were also comparable in predicting mortality. Thus, NIRS-derived muscle StO2 measurements perform similarly to BD in identify-ing poor perfusion and predicting the development of MODS or death after severe torso trauma, yet have the additional advan-tages of being continuous and noninvasive. Ongoing prospec-tive studies will help determine the clinical utility of continuous monitoring of StO2 in clinical scenarios such as trauma, hemor-rhagic shock, sepsis, etc.RESPIRATORY MONITORINGThe ability to monitor various parameters of respiratory func-tion is of utmost importance in critically ill patients. Many of these patients require mechanical ventilation. Monitoring of their respiratory physiology is necessary to assess the adequacy of oxygenation and ventilation, guide weaning and liberation from mechanical ventilation, and detect adverse events associ-ated with respiratory failure and mechanical ventilation. These parameters include gas exchange, neuromuscular activity, respi-ratory mechanics, and patient effort.Arterial Blood GasesBlood gas analysis may provide useful information when caring for patients with respiratory failure. However, even in the absence of respiratory failure or the need for mechanical ventilation, blood gas determinations also can be valuable to detect alterations in acid-base balance due to low QT, sepsis, renal failure, severe trauma, medication or drug overdose, or altered mental status. Arterial blood can be analyzed for pH, Po2, Pco2, HCO3– con-centration and calculated base deficit. When indicated, carboxy-hemoglobin and methemoglobin levels also can be measured. In recent years, efforts have been made to decrease the unnecessary use of arterial blood gas analysis. Serial arterial blood gas deter-minations are not necessary for routine weaning from mechanical ventilation in the majority of postoperative patients.Most bedside blood gas analyses still involve removal of an aliquot of blood from the patient, although continuous bedside arterial blood gas determinations are now possible without sam-pling via an indwelling arterial catheter that contains a biosensor. In studies comparing the accuracy of continuous arterial blood gas and pH monitoring with a conventional laboratory blood gas analyzer, excellent agreement between the two methods has been demonstrated.55 Continuous monitoring can reduce the volume of blood loss due to phlebotomy and dramatically decrease the time necessary to obtain blood gas results. Continuous monitor-ing, however, is expensive and is not widely employed.Determinants of Oxygen DeliveryThe primary goal of the cardiovascular and respiratory systems is to deliver oxygenated blood to the tissues. DO2 is dependent to a greater degree on the oxygen saturation of hemoglobin (Hgb) in arterial blood (Sao2) than on the partial pressure of oxygen in arterial blood (Pao2). DO2 also is dependent on QT and Hgb. As discussed earlier and illustrated mathematically by previous equations, the dissolved oxygen in blood makes only a negligible contribution to DO2. Sao2 in mechanically venti-lated patients depends on the mean airway pressure, the frac-tion of inspired oxygen (Fio2), and SvO2. Thus, when Sao2 is low, the clinician has only a limited number of ways to improve this parameter. The clinician can increase mean airway pres-sure by increasing positive-end expiratory pressure (PEEP) or inspiratory time. Fio2 can be increased to a maximum of 1.0 by decreasing the amount of room air mixed with the oxygen sup-plied to the ventilator. SvO2 can be increased by increasing Hgb Brunicardi_Ch13_p0433-p0452.indd 44522/02/19 2:21 PM 446BASIC CONSIDERATIONSPART Ior QT or decreasing oxygen utilization (e.g., by administering a muscle relaxant and sedation).Peak and Plateau Airway PressureAirway pressures are routinely monitored in mechanically ven-tilated patients. The peak airway pressure measured at the end of inspiration (Ppeak) is a function of the tidal volume, the resistance of the airways, lung/chest wall compliance, and peak inspiratory flow. The airway pressure measured at the end of inspiration when the inhaled volume is held in the lungs by briefly clos-ing the expiratory valve is termed the plateau airway pressure (Pplateau). As a static parameter, plateau airway pressure is indepen-dent of the airway resistance and peak airway flow and is related to the lung/chest wall compliance and delivered tidal volume. Mechanical ventilators monitor Ppeak with each breath and can be set to trigger an alarm if the Ppeak exceeds a predetermined thresh-old. Pplateau is not measured routinely with each delivered tidal vol-ume but rather is measured intermittently by setting the ventilator to close the exhalation circuit briefly at the end of inspiration and record the airway pressure when airflow is zero.If both Ppeak and Pplateau are increased (and tidal volume is not excessive), then the problem is a decrease in the compli-ance in the lung/chest wall unit. Common causes of this problem include pneumothorax, hemothorax, lobar atelectasis, pulmo-nary edema, pneumonia, acute respiratory distress syndrome (ARDS), active contraction of the chest wall or diaphragmatic muscles, abdominal distention, and intrinsic PEEP, such as occurs in patients with bronchospasm and insufficient expira-tory times. When Ppeak is increased but Pplateau is relatively nor-mal, the primary problem is an increase in airway resistance, such as occurs with bronchospasm, use of a small-caliber endo-tracheal tube, or kinking or obstruction of the endotracheal tube. A low Ppeak also should trigger an alarm, as it suggests a discon-tinuity in the airway circuit involving the patient and the ventila-tor. These scenarios are outlined in Table 13-4.Ventilator-induced lung injury (VILI) is now an estab-lished clinical entity of great relevance to the care of critically ill patients. Excessive airway pressure and tidal volume adversely affect pulmonary and possibly systemic responses to critical illness. Subjecting the lung parenchyma to excessive pressure, known as barotrauma, can result in parenchymal lung injury, diffuse alveolar damage similar to ARDS, and pneumothorax, and can impair venous return and therefore limit cardiac output. Lung-protective ventilation strategies have been developed to prevent the development of VILI and improve patient outcomes. Table 13-4Scenarios associated with different combinations of Ppeak and Pplateau in ventilated patientsCONDITIONPpeakPplateauDecreased compliance of the system (ARDS, abdominal distention, intrinsic PEEP)⇑⇑Increase in airway resistance (bronchospasm, endotracheal tube obstruction/kinking, or small-caliber endotracheal tube)⇑normalDisconnected circuit⇓⇓In a large, multicenter, randomized trial of patients with ARDS from a variety of etiologies, limiting plateau airway pressure to less than 30 cm H2O and tidal volume to less than 6 mL/kg of ideal body weight reduced 28-day mortality by 22% relative to a ventilator strategy that used a tidal volume of 12 mL/kg.56 For this reason, monitoring of plateau pressure and using a low tidal volume strategy in patients with ARDS is now the standard of care. Recent data also suggest that a lung-protective ventila-tion strategy is associated with improved clinical outcomes in ventilated patients without ARDS.57 Importantly, this strategy also has been shown to have benefit for high-risk patients under-going general anesthesia for surgical procedures, leading to a reduced overall rate of pulmonary complications in the peri-operative period as well as a reduced length of stay following surgery.58Pulse OximetryThe pulse oximeter is a microprocessor-based device that inte-grates oximetry and plethysmography to provide continuous noninvasive monitoring of the oxygen saturation of arterial blood (Sao2). It is considered one of the most important and useful technologic advances in patient monitoring. Continuous, noninvasive monitoring of arterial oxygen saturation is pos-sible using light-emitting diodes and sensors placed on the skin. Pulse oximetry employs two wavelengths of light (i.e., 660 nm and 940 nm) to analyze the pulsatile component of blood flow between the light source and sensor. Because oxyhemoglobin and deoxyhemoglobin have different absorption spectra, differ-ential absorption of light at these two wavelengths can be used to calculate the fraction of oxygen saturation of hemoglobin. Under normal circumstances, the contributions of carboxyhe-moglobin and methemoglobin are minimal. However, if car-boxyhemoglobin levels are elevated, the pulse oximeter will incorrectly interpret carboxyhemoglobin as oxyhemoglobin and the arterial saturation displayed will be falsely elevated. When the concentration of methemoglobin is markedly increased, the Sao2 will be displayed as 85%, regardless of the true arterial saturation.59 The accuracy of pulse oximetry begins to decline at Sao2 values less than 92% and tends to be unreliable for values less than 85%.60Several studies have assessed the frequency of arterial oxygen desaturation in hospitalized patients and its effect on outcome. Monitoring pulse oximetry in surgical patients is asso-ciated with a reduction in unrecognized deterioration, rescue events, and transfers to the ICU.61 Because of its clinical rel-evance, ease of use, noninvasive nature, and cost-effectiveness, pulse oximetry has become a routine monitoring strategy in patients with respiratory disease, intubated patients, and those undergoing surgical intervention under sedation or general anes-thesia. Pulse oximetry is especially useful in the titration of Fio2 and PEEP for patients receiving mechanical ventilation, and during weaning from mechanical ventilation. The widespread use of pulse oximetry has decreased the need for arterial blood gas determinations in critically ill patients.Pulse CO-OximetryWhile simple pulse oximeters such as those described previ-ously are helpful for determination of the Sao2, extensions of the technology may prove valuable for determination of total hemoglobin concentration as well. Through the use of multiple additional wavelengths of light, clinicians can leverage the dif-ferent spectrophotometric properties of the multiple different Brunicardi_Ch13_p0433-p0452.indd 44622/02/19 2:21 PM 447PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13oxidative states of hemoglobin to get a complete readout of the total hemoglobin present in a given volume, leading to a noninvasive measurement of Hgb. These devices are referred to as pulse CO-Oximeters, as opposed to pulse oximeters, to dif-ferentiate that they are capable of measuring other hemoglobin moieties. Currently, there are two such devices that are com-mercially available for clinical use.Theoretically, the capacity to noninvasively measure Hgb concentration in real time would offer significant clinical ben-efit. These include obviating the need for serial blood draws, the early detection of potential postsurgical hemorrhage, and more judicious usage of blood transfusions. In practice, there are mul-tiple factors that currently affect the accuracy of the technique. Multiple studies have demonstrated that biases with noninvasive Hgb monitoring are inversely correlated with hemoglobin con-centration in a variety of monitoring scenarios; with decreasing hemoglobin values the noninvasive approaches tend to overes-timate the true Hgb.62-64 This poses a significant challenge for monitoring the critically ill patient, as frequently anemia is a common comorbid condition. On the other hand, if the continu-ous monitoring capacity afforded by these monitors can provide usable trend data, that may still provide clinical utility despite less accuracy at low hemoglobin levels. To date, there have been relatively few studies validating the trending capacity of noninvasive Hgb monitoring compared to serial blood draws, with limited agreement due to differences in analysis and study design.65 Further studies are required to evaluate the clinical utility of this potentially useful technology.CapnometryCapnometry is the measurement of carbon dioxide in the airway throughout the respiratory cycle. Capnometry is most commonly measured by infrared light absorption. CO2 absorbs infrared light at a peak wavelength of approximately 4.27 µm. Capnom-etry works by passing infrared light through a sample chamber to a detector on the opposite side. More infrared light passing through the sample chamber (i.e., less CO2) causes a larger sig-nal in the detector relative to the infrared light passing through a reference cell. Capnometric determination of the partial pressure of CO2 in end-tidal exhaled gas (Petco2) is used as a surrogate for the partial pressure of CO2 in arterial blood (Paco2) during mechanical ventilation. In healthy subjects, Petco2 is about 1 to 5 mmHg less than Paco2.66 Thus, Petco2 can be used to estimate Paco2 without the need for blood gas determination. However, changes in Petco2 may not correlate with changes in Paco2 dur-ing a number of pathologic conditions.Capnography allows the confirmation of endotracheal intubation and continuous assessment of ventilation, integrity of the airway, operation of the ventilator, and cardiopulmonary function. Capnometers are configured with either an inline sen-sor or a sidestream sensor. The sidestream systems are lighter and easy to use, but the thin tubing that samples the gas from the ventilator circuit can become clogged with secretions or condensed water, preventing accurate measurements. The inline devices are bulky and heavier but are less likely to become clogged. Continuous monitoring with capnography has become routine during surgery under general anesthesia and for some intensive care patients. A number of situations can be promptly detected with continuous capnography. A sudden reduction in Petco2 suggests either obstruction of the sam-pling tubing with water or secretions, or a catastrophic event such as loss of the airway, airway disconnection or obstruction, ventilator malfunction, or a marked decrease in QT. If the airway is connected and patent and the ventilator is functioning prop-erly, then a sudden decrease in Petco2 should prompt efforts to rule out cardiac arrest, massive pulmonary embolism, or cardio-genic shock. Petco2 can be persistently low during hyperven-tilation or with an increase in dead space such as occurs with pulmonary embolization (even in the absence of a change in QT). Causes of an increase in Petco2 include reduced minute ventilation or increased metabolic rate.RENAL MONITORINGUrine OutputBladder catheterization with an indwelling catheter allows the monitoring of urine output, usually recorded hourly by the nurs-ing staff. With a patent Foley catheter, urine output is a gross indicator of renal perfusion. The generally accepted normal urine output is 0.5 mL/kg per hour for adults and 1 to 2 mL/kg per hour for neonates and infants. Oliguria may reflect inadequate renal artery perfusion due to hypotension, hypovolemia, or low QT. Low urine flow also can be a sign of intrinsic renal dysfunc-tion. It is important to recognize that normal urine output does not exclude the possibility of impending renal failure.Bladder PressureThe triad of oliguria, elevated peak airway pressures, and ele-vated intra-abdominal pressure is known as abdominal com-partment syndrome (ACS). This syndrome, first described in patients after repair of ruptured abdominal aortic aneurysm, is associated with interstitial edema of the abdominal organs, resulting in elevated intra-abdominal pressure (IAP). When IAP exceeds venous or capillary pressures, perfusion of the kidneys and other intra-abdominal viscera is impaired. Oligu-ria is a cardinal sign. While the diagnosis of ACS is a clinical one, measuring IAP is useful to confirm the diagnosis. Ideally, a catheter inserted into the peritoneal cavity could measure IAP to substantiate the diagnosis. In practice, transurethral bladder pressure measurement reflects IAP and is most often used to confirm the presence of ACS. After instilling 50 to 100 mL of sterile saline into the bladder via a Foley catheter, the tubing is connected to a transducing system to measure bladder pressure in the supine position at end-expiration.Intra-abdominal hypertension is defined as an IAP ≥12 mmHg recorded on three standard measurements conducted 4 to 6 hours apart and is separated into several grades. The diag-nosis of ACS is the presence of an IAP ≥20 mmHg recorded by three measurements 1 to 6 hours apart, along with new onset of organ dysfunction (Table 13-5).67-69 Less commonly, gastric or inferior vena cava pressures can be monitored with appropriate catheters to detect elevated intra-abdominal pressures.NEUROLOGIC MONITORINGIntracranial PressureBecause the brain is rigidly confined within the bony skull, cere-bral edema or mass lesions increase intracranial pressure (ICP). Monitoring of ICP is currently recommended in patients with severe traumatic brain injury (TBI), defined as a Glasgow Coma Scale (GCS) score less than or equal to 8 with an abnormal computed tomography (CT) scan, and in patients with severe TBI and a normal CT scan if two or more of the following are present: age >40 years, unilateral or bilateral motor posturing, Brunicardi_Ch13_p0433-p0452.indd 44722/02/19 2:21 PM 448BASIC CONSIDERATIONSPART ITable 13-5Bladder pressure measurements in the assessment of intra-abdominal hypertension or abdominal compartment syndromeRECORDED PRESSURE (mmHg)GRADE OF IAH OR ACS5–7NormalIn the absence of organ dysfunction:12–15Grade I IAH16–20Grade II IAH21–25Grade III IAH>25Grade IV IAHIn the presence of new onset organ dysfunction:>20ACSData from Kirkpatrick AW, Roberts DJ, De Waele J, et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome, Intensive Care Med. 2013 Jul;39(7):1190-1206.or systolic blood pressure <90 mmHg.70 ICP monitoring also is indicated in patients with acute subarachnoid hemorrhage with coma or neurologic deterioration, intracranial hemorrhage with intraventricular blood, ischemic middle cerebral artery stroke, fulminant hepatic failure with coma and cerebral edema on CT scan, and global cerebral ischemia or anoxia with cerebral edema on CT scan. The goal of ICP monitoring is to ensure that cerebral perfusion pressure (CPP) is adequate to support perfu-sion of the brain. CPP is equal to the difference between MAP and ICP: CPP = MAP – ICP.One type of ICP measuring device, the ventriculostomy catheter, consists of a fluid-filled catheter inserted into a cere-bral ventricle and connected to an external pressure transducer. This device permits measurement of ICP but also allows drain-age of cerebrospinal fluid (CSF) as a means to lower ICP and sample CSF for laboratory studies. Other devices locate the pressure transducer within the central nervous system and are used only to monitor ICP. These devices can be placed in the intraventricular, parenchymal, subdural, or epidural spaces. Ventriculostomy catheters are the accepted standard for moni-toring ICP in patients with TBI due to their accuracy, ability to drain CSF, and low complication rate. The associated com-plications include infection (5%), hemorrhage (1.1%), catheter malfunction or obstruction (6.3–10.5%), and malposition with injury to cerebral tissue.71The purpose of ICP monitoring is to detect and treat abnormal elevations of ICP that may be detrimental to cere-bral perfusion and function. In TBI patients, ICP greater than 20 mmHg is associated with unfavorable outcomes.72 However, few studies have shown that treatment of elevated ICP improves clinical outcomes in human trauma patients. In a randomized, controlled, double-blind trial, Eisenberg and colleagues dem-onstrated that maintaining ICP less than 25 mmHg in patients without craniectomy and less than 15 mmHg in patients with craniectomy is associated with improved outcome.73 In patients with low CPP, therapeutic strategies to correct CPP can be directed at increasing MAP or decreasing ICP. While it has been recommended that CPP be maintained between 50 and 70 mmHg, the evidence to support this recommendation are not overly compelling.74 Furthermore, a retrospective cohort study of patients with severe TBI found that ICP/CPP-targeted neurointensive care was associated with prolonged mechanical ventilation and increased therapeutic interventions, without evi-dence for improved outcome in patients who survive beyond 24 hours.75Electroencephalogram and Evoked PotentialsElectroencephalography offers the capacity to monitor global neurologic electrical activity, while evoked potential monitor-ing can assess pathways not detected by the conventional EEG. Continuous EEG (CEEG) monitoring in the intensive care unit permits ongoing evaluation of cerebral cortical activity. It is especially useful in obtunded and comatose patients. CEEG also is useful for monitoring of therapy for status epilepticus and detecting early changes associated with cerebral ischemia. CEEG can be used to adjust the level of sedation, especially if high-dose barbiturate therapy is being used to manage elevated ICP. Somatosensory and brain stem evoked potentials are less affected by the administration of sedatives than is the EEG. Evoked potentials are useful for localizing brain stem lesions or proving the absence of such structural lesions in cases of metabolic or toxic coma. They also can provide prognostic data in posttraumatic coma.An advance in EEG monitoring is the use of the bispectral index (BIS) to titrate the level of sedative medications. While sedative drugs are usually titrated to the clinical neurologic examination, the BIS device has been used in the operating room to continuously monitor the depth of anesthesia. The BIS is an empiric measurement statistically derived from a data-base of over 5000 EEGs.76 The BIS is derived from bifrontal EEG recordings and analyzed for burst suppression ratio, rela-tive alpha to beta ratio, and bicoherence. Using a multivariate regression model, a linear numeric index (BIS) is calculated, ranging from 0 (isoelectric EEG) to 100 (fully awake). Its use has been associated with lower consumption of anesthet-ics during surgery and earlier awakening and faster recovery from anesthesia.77 The BIS also has been validated as a useful approach for monitoring the level of sedation for ICU patients, using the revised Sedation-Agitation Scale as a gold standard.78Transcranial Doppler UltrasonographyThis modality provides a noninvasive method for evaluating cerebral hemodynamics. Transcranial Doppler (TCD) measure-ments of middle and anterior cerebral artery blood flow velocity are useful for the diagnosis of cerebral vasospasm after sub-arachnoid hemorrhage. Qureshi and associates demonstrated that an increase in the middle cerebral artery mean flow velocity as assessed by TCD is an independent predictor of symptom-atic vasospasm in a prospective study of patients with aneurys-mal subarachnoid hemorrhage.79 In addition, while some have proposed using TCD to estimate ICP, studies have shown that TCD is not a reliable method for estimating ICP and CPP and currently cannot be endorsed for this purpose.80 TCD also is useful to confirm the clinical examination for determining brain death in patients with confounding factors such as the presence of CNS depressants or metabolic encephalopathy.Jugular Venous OximetryWhen the arterial oxygen content, hemoglobin concentration, and the oxyhemoglobin dissociation curve are constant, changes in jugular venous oxygen saturation (Sjo2) reflect changes in the difference between cerebral oxygen delivery and demand. Brunicardi_Ch13_p0433-p0452.indd 44822/02/19 2:21 PM 449PHYSIOLOGIC MONITORING OF THE SURGICAL PATIENTCHAPTER 13Generally, a decrease in Sjo2 reflects cerebral hypoperfusion, whereas an increase in Sjo2 indicates the presence of hyperemia. Sjo2 monitoring cannot detect decreases in regional cerebral blood flow if overall perfusion is normal or above normal. This technique requires the placement of a catheter in the jugular bulb, usually via the internal jugular vein. Catheters that permit intermittent aspiration of jugular venous blood for analysis or continuous oximetry catheters are available.Low Sjo2 is associated with poor outcomes after TBI.81 Nevertheless, the value of monitoring Sjo2 remains unproven. If it is employed, it should not be the sole monitoring technique, but rather should be used in conjunction with ICP and CPP monitoring. By monitoring ICP, CPP, and Sjo2, early interven-tion with volume, vasopressors, and hyperventilation has been shown to prevent ischemic events in patients with TBI.82Transcranial Near-Infrared SpectroscopyTranscranial near-infrared spectroscopy (NIRS) is a noninvasive continuous monitoring method to determine cerebral oxygen-ation. It employs technology similar to that of pulse oximetry to determine the concentrations of oxyand deoxyhemoglobin with near-infrared light and sensors and takes advantage of the relative transparency of the skull to light in the near-infrared region of the spectrum. Continuous monitoring of cerebral per-fusion via transcranial NIRS may provide a method to detect early cerebral ischemia in patients with traumatic brain injury.83 Nevertheless, this form of monitoring remains largely a research tool at the present time.Recently, some authors have reported its use as a poten-tial triage tool for prehospital care in the management of TBI, as NIRS allows for rapid screening for intracranial hematoma. Two small EMS studies demonstrated that handheld NIRS devices may be feasible adjunct tools in this setting, particularly when CT scanners may not be readily available.84,85Brain Tissue Oxygen TensionWhile the standard of care for patients with severe TBI includes ICP and CPP monitoring, this strategy does not always prevent secondary brain injury. Growing evidence suggests that moni-toring local brain tissue oxygen tension (PbtO2) may be a useful adjunct to ICP monitoring in these patients. Normal values for PbtO2 are 20 to 40 mmHg, and critical levels are 8 to 10 mmHg. A recent clinical study sought to determine whether the addi-tion of a PbtO2 monitor to guide therapy in severe traumatic brain injury was associated with improved patient outcomes.86 Twenty-eight patients with severe traumatic brain injury (GCS score ≤8) were enrolled in an observational study at a level I trauma center. These patients received invasive ICP and PbtO2 monitoring and were compared with 25 historical controls matched for age, injuries, and admission GCS score that had undergone ICP monitoring alone. Goals of therapy in both groups included maintaining an ICP <20 mmHg and a CPP >60 mmHg. Among patients with PbtO2 monitoring, therapy also was directed at maintaining PbtO2 >25 mmHg. The groups had similar mean daily ICP and CPP levels. The mortality rate in the historical controls treated with standard ICP and CPP management was 44%. Mortality was significantly lower in the patients who had therapy guided by PbtO2 monitoring in addition to ICP and CPP (25%; P <.05). The benefits of PbtO2 monitoring may include the early detection of brain tissue isch-emia despite normal ICP and CPP. In addition, PbtO2-guided management may reduce potential adverse effects associated with therapies to maintain ICP and CPP.CONCLUSIONSModern intensive care is predicated by the need and ability to continuously monitor a wide range of physiologic parameters. This capability has dramatically improved the care of critically ill patients and advanced the development of the specialty of critical care medicine. In some cases, the technological abil-ity to measure such variables has surpassed our understanding of the significance or the knowledge of the appropriate inter-vention to ameliorate such pathophysiologic changes. 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Monitoring during mechanical ventilation. Clin Chest Med. 1996;17(3):453-473. 67. Sugrue M. Abdominal compartment syndrome. Curr Opin Crit Care. 2005;11(4):333-338. 68. Ivatury RR, Porter JM, Simon RJ, Islam S, John R, Stahl WM. Intra-abdominal hypertension after life-threatening penetrat-ing abdominal trauma: prophylaxis, incidence, and clinical relevance to gastric mucosal pH and abdominal compartment syndrome. J Trauma. 1998;44(6):1016-1021; discussion 21-23. 69. Kirkpatrick AW, Roberts DJ, De Waele J, et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intens Care Med. 2013;39(7):1190-1206. 70. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma. 2007;24(suppl 1):S37-S44. 71. Brain Trauma Foundation; American Association of Neurologi-cal Surgeons; Congress of Neurological Surgeons, et al. Guide-lines for the management of severe traumatic brain injury. VII. Intracranial pressure monitoring technology. J Neurotrauma. 2007;24(suppl 1):S45-S54. 72. Juul N, Morris GF, Marshall SB, Marshall LF. Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. J Neurosurg. 2000;92(1):1-6. 73. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracra-nial pressure in patients with severe head injury. J Neurosurg. 1988;69(1):15-23. 74. Brain Trauma Foundation; American Association of Neuro-logical Surgeons; Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. IX. Cerebral perfusion thresholds. J Neurotrauma. 2007;24(suppl 1):S59-S64. 75. Cremer OL, van Dijk GW, van Wensen E, et al. Effect of intra-cranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med. 2005;33(10):2207-2213. 76. Sigl JC, Chamoun NG. An introduction to bispectral analysis for the electroencephalogram. J Clin Monit. 1994;10(6):392-404. 77. Gan TJ, Glass PS, Windsor A, et al. Bispectral index monitoring allows faster emergence and improved recovery from propo-fol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology. 1997;87(4):808-815. 78. Simmons LE, Riker RR, Prato BS, Fraser GL. Assessing seda-tion during intensive care unit mechanical ventilation with the Bispectral Index and the Sedation-Agitation Scale. Crit Care Med. 1999;27(8):1499-1504. 79. Qureshi AI, Sung GY, Razumovsky AY, Lane K, Straw RN, Ulatowski JA. Early identification of patients at risk for symp-tomatic vasospasm after aneurysmal subarachnoid hemorrhage. Crit Care Med. 2000;28(4):984-990. 80. Czosnyka M, Matta BF, Smielewski P, Kirkpatrick PJ, Pickard JD. Cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial Doppler ultrasonography. J Neurosurg. 1998;88(5):802-808. 81. Feldman Z, Robertson CS. Monitoring of cerebral hemody-namics with jugular bulb catheters. Crit Care Clin. 1997;13(1): 51-77. 82. Vigue B, Ract C, Benayed M, et al. Early SjvO2 monitoring in patients with severe brain trauma. Intensive Care Med. 1999;25(5):445-451. 83. Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth. 2009;103(suppl 1):i3-i13. 84. Peters J, Van Wageningen B, Hoogerwerf N, Tan E. Near-infrared spectroscopy: a promising prehospital tool for man-agement of traumatic brain injury. Prehosp Disaster Med. 2017;32(4):414-418. 85. Schober P, Bossers SM, Schwarte LA. Intracranial hematoma detection by near infrared spectroscopy in a helicopter emer-gency medical service: practical experience. Biomed Res Int. 2017;2017:1846830. 86. Stiefel MF, Spiotta A, Gracias VH, et al. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg. 2005;103(5):805-811.Brunicardi_Ch13_p0433-p0452.indd 45122/02/19 2:21 PM

Brunicardi_Ch13_p0433-p0452.indd 45222/02/19 2:21 PMThis page intentionally left blankMinimally Invasive Surgery, Robotics, Natural Orifice Transluminal Endoscopic Surgery, and Single-Incision Laparoscopic SurgeryDonn H. Spight, Blair A. Jobe, and John G. Hunter 14chapterINTRODUCTIONMinimally invasive surgery describes an area of surgery that crosses all traditional disciplines, from general surgery to neu-rosurgery. It is not a discipline unto itself, but more a philosophy of surgery, a way of thinking. Minimally invasive surgery is a means of performing major operations through small inci-sions, often using miniaturized, high-tech imaging sys-tems, to minimize the trauma of surgical exposure. Some believe that the term minimal access surgery more accurately describes the small incisions generally necessary to gain access to surgical sites in high-tech surgery, but John Wickham’s term minimally invasive surgery (MIS) is widely used because it describes the paradox of postmodern high-tech surgery—small holes, big operations.Robotic surgery today is practiced using a single platform (Intuitive, Inc, Sunnyvale, CA) and should better be termed computer-enhanced surgery because the term robotics assumes autonomous action that is not a feature of the da Vinci robotic system. Instead, the da Vinci robot couples an ergonomic work-station that features stereoptic video imaging and intuitive micromanipulators (surgeon side) with a set of arms deliver-ing specialized laparoscopic instruments enhanced with more degrees of freedom than are allowed by laparoscopic surgery alone (patient side). A computer between the surgeon side and patient side removes surgical tremor and scales motion to allow 1precise microsurgery, which is helpful for microdissection and difficult anastomoses.Single-incision laparoscopic surgery (SILS), also called laparoendoscopic single-site surgery (LESS), is a recent addi-tion to the armamentarium of the minimally invasive surgeon. As public awareness has grown, so too has its spread outside of larger institutions. SILS challenges the well-established paradigm of standard laparoscopic surgery by placing multiple trocars within the fascia at the umbilicus or through a single multichannel trocar at the umbilicus. The manipulation of tightly spaced instruments across the fulcrum of the abdomi-nal wall requires that the surgeon either operate in a crossed hands fashion or use specialized curved instruments to avoid clashing outside the body while working intra-abdominally. The primary advantage of SILS is the reduction to one surgical scar. Greater efficacy, safety, and cost savings have yet to be fully elucidated in the increasing number of procedures that are being attempted in this manner. The advent of a robotic SILS platform now enables the computer reassignment of the surgeon’s hands, thus eliminating the difficult ergonomic challenges making the technique far more accessible.Natural orifice transluminal endoscopic surgery (NOTES) is an extension of interventional endoscopy. Using the mouth, anus, vagina, and urethra (natural orifices), flexible endoscopes are passed through the wall of the esophagus, stomach, colon, Introduction 453Historical Background 454Physiology and Pathophysiology  of Minimally Invasive Surgery 455Laparoscopy / 455Thoracoscopy / 457Extracavitary Minimally Invasive Surgery / 457Anesthesia / 457The Minimally Invasive Team / 458Room Setup and the Minimally Invasive Suite / 458Patient Positioning / 458General Principles of Access / 459Laparoscopic Access / 459Access for Subcutaneous and Extraperitoneal Surgery / 460Hand-Assisted Laparoscopic Access / 461Natural Orifice Transluminal Endoscopic Surgery Access / 461Single-Incision Laparoscopic Surgery Access / 462Port Placement / 462Imaging Systems / 463Energy Sources for Endoscopic and Endoluminal Surgery / 465Instrumentation / 467Robotic Surgery / 467Endoluminal and Endovascular Surgery / 469Natural Orifice Transluminal Endoscopic Surgery / 470Single-Incision Laparoscopic Surgery / 471Special Considerations 473Pediatric Laparoscopy / 473Laparoscopy During Pregnancy / 473Minimally Invasive Surgery and Cancer Treatment / 474Considerations in the Elderly and Infirm / 474Cirrhosis and Portal Hypertension / 474Economics of Minimally Invasive Surgery / 474Education and Skill Acquisition / 474Telementoring / 475Innovation and Introduction of New Procedures / 475Brunicardi_Ch14_p0453-p0478.indd 45301/03/19 4:58 PM 454bladder, or vagina entering the mediastinum, the pleural space, or the peritoneal cavity. The advantage of this method of mini-mal access is principally the elimination of the scar associated with laparoscopy or thoracoscopy. Other advantages have yet to be elucidated, including pain reduction, need for hospitalization, and cost savings.HISTORICAL BACKGROUNDAlthough the term minimally invasive surgery is relatively recent, the history of its component parts is nearly 100 years old. What is considered the newest and most popular variety of MIS, laparoscopy, is in fact the oldest. Primitive laparos-copy, placing a cystoscope within an inflated abdomen, was first performed by Kelling in 1901.1 Illumination of the abdomen required hot elements at the tip of the scope and was danger-ous. In the late 1950s, Hopkins described the rod lens, a method of transmitting light through a solid quartz rod with no heat and little light loss.1 Around the same time, thin quartz fibers were discovered to be capable of trapping light internally and conducting it around corners, opening the field of fiber optics and allowing the rapid development of flexible endoscopes.2,3 In the 1970s, the application of flexible endoscopy grew faster than that of rigid endoscopy except in a few fields such as gyne-cology and orthopedics.4 By the mid-1970s, rigid and flexible endoscopes made a rapid transition from diagnostic instruments to therapeutic ones. The explosion of video-assisted surgery in the past 20 years was a result of the development of compact, high-resolution, charge-coupled devices (CCDs) that could be mounted on the internal end of flexible endoscopes or on the external end of a Hopkins telescope. Coupled with bright light sources, fiber-optic cables, and high-definition video monitors, the videoendoscope has changed our understanding of surgical anatomy and reshaped surgical practice.Flexible endoscopic imaging started in the 1960s with the first bundling of many quartz fibers into bundles, one for illu-mination and one for imaging. The earliest upper endoscopes revolutionized the diagnosis and treatment of gastroesophageal reflux and peptic ulcer disease and made possible early detec-tion of upper and lower gastrointestinal (GI) cancer at a stage that could be cured. The first endoscopic surgical procedure was the colonoscopic polypectomy, developed by Shinya and Wolfe, two surgeons from New York City. The percutane-ous endoscopic gastrostomy (PEG) invented by Gauderer and Ponsky may have been the first NOTES procedure, reported in 1981.5 Endoscopic pancreatic pseudocyst drainage is thought to be the next NOTES procedure developed; however, there was little energy and money put into the development of NOTES until a number of gastroenterologists claimed the ability to remove the gallbladder with a flexible endoscope, using a transgastric technique. With this pronouncement, the surgical community took notice and seized the momentum for NOTES research and development. Today most intra-abdominal NOTES procedures remain within the realm of research or incorporate a hybrid laparoscopic technique outside of highly specialized centers. Clinically the transvaginal approach has been studied the most extensively. Evaluation of 551 female patients from the German NOTES registry has shown conversion and compli-cation rates similar to conventional laparoscopic surgery for cholecystectomy and appendectomy procedures.6 Endoscopic mucosal resection (EMR) of early-stage esophageal and gastric lesions has revolutionized the management of these malignan-cies. The peroral endoscopic myotomy (POEM) procedure for achalasia is showing clinical efficacy and gaining popularity.As the race to minimize the size and increase the function-ality of laparoscopic instruments progressed, the notion of using fewer access points to accomplish the same operations resulted in the development of single-incision laparoscopic surgery (SILS), synonymously termed laparoendoscopic single-site surgery (LESS). Viewed as a progression of laparoscopic surgery, SILS has recently garnered greater enthusiasm over its transvisceral NOTES counterpart.7 Currently the single-incision technique is used regularly across a wide variety of surgical areas including general, urologic, gynecologic, colorectal, and bariatric surgery.8 Although optical imaging produced the majority of MIS pro-cedures, other (traditionally radiologic) imaging technologies allowed the development of innovative procedures in the 1970s. Fluoroscopic imaging allowed the adoption of percutaneous vas-cular procedures, the most revolutionary of which was balloon angioplasty. Balloon-based procedures spread into all fields of medicine used to open up clogged lumens with minimal access. Stents were then developed that were used in many disciplines to keep the newly ballooned segment open. The culmination of fluoroscopic balloon and stent proficiency is exemplified by the transvenous intrahepatic portosystemic shunt and by the aortic stent graft, which has nearly replaced open elective abdominal aortic aneurysm repair.MIS procedures using ultrasound imaging have been limited to fairly crude exercises, such as fragmenting kidney stones and freezing liver tumors, because of the relatively low Key Points1 Minimally invasive surgery describes a philosophical approach to surgery in which access trauma is minimized without compromising the quality of the surgical procedure.2 The carbon dioxide pneumoperitoneum used for laparoscopy induces some unique pathophysiologic consequences.3 Robotic surgery has been most valuable in the performance of minimally invasive urologic, gynecologic, colorectal, and complex abdominal wall reconstruction procedures.4 Natural orifice transluminal endoscopic surgery represents an opportunity to perform truly scar-free surgery.5 Single-incision laparoscopic surgery reduces the amount of abdominal wall trauma but presents unique challenges to the traditional tenets of laparoscopic ergonomics.6 Laparoscopy during pregnancy is best performed in the sec-ond trimester and is safe if appropriate monitoring is performed.7 Laparoscopic surgery for cancer is also appropriate if good tissue handling techniques are maintained.8 Training for laparoscopy requires practice outside of the operating room in a simulation laboratory.Brunicardi_Ch14_p0453-p0478.indd 45401/03/19 4:58 PM 455MINIMALLY INVASIVE SURGERYCHAPTER 14resolution of ultrasound devices. Newer, high-resolution ultra-sound methods with high-frequency crystals may act as a guide while performing minimally invasive resections of individual layers of the intestinal wall.Axial imaging, such as computed tomography (CT), has allowed the development of an area of MIS that often is not recognized because it requires only a CT scanner and a long needle. CT-guided drainage of abdominal fluid collections and percutaneous biopsy of abnormal tissues are minimally invasive means of performing procedures that previously required a celi-otomy. CT-guided percutaneous radiofrequency (RF) ablation has emerged as a useful treatment for primary and metastatic liver tumors. This procedure also is performed laparoscopically under ultrasound guidance.9A powerful, noninvasive method of imaging that will allow the development of the least invasive—and potentially noninvasive—surgery is magnetic resonance imaging (MRI). MRI is an extremely valuable diagnostic tool, but it is only slowly coming to be of therapeutic value. One obstacle to the use of MRI for MIS is that image production and refreshment of the image as a procedure progresses are slow. Another is that all instrumentation must be nonmetallic when working with the powerful magnets of an MRI scanner. Moreover, MRI magnets are bulky and limit the surgeon’s access to the patient. Open magnets have been developed that allow the surgeon to stand between two large MRI coils, obtaining access to the portion of the patient being scanned. The advantage of MRI, in addition to the superb images produced, is that there is no radiation expo-sure to patient or surgeon. Some neurosurgeons are accumu-lating experience using MRI to perform frameless stereotactic surgery.Robotic surgery has been dreamed about for some time, and many science fiction–like devices have been developed over the years to provide mechanical assistance for the surgeon. The first computer-assisted robot was designed to accurately drill femoral shaft bone for wobble-free placement of hip prostheses. Although the concept was appealing, the robot proved no better than a skilled orthopedic surgeon and was a good deal slower. Following this, the first and only two commercially successful robots for laparoscopic surgery were developed in California. Computer Motion, founded by Yulun Wang in Santa Barbara, used National Science Foundation funds to create a mechanical arm, the Aesop robot, which held and moved the laparoscope with voice, foot, or hand control. In Northern California, a master-slave system first developed for surgery on the multina-tional space station by Philip Green was purchased by Fred Moll and Lonnie Smith, and then reengineered with the surgeon in mind to create a remarkably intuitive computer-enhanced surgi-cal platform. The company, Intuitive Surgical, was aptly named, and their primary product, the da Vinci robot, is currently the only major robotic platform on the market, although competi-tors are rapidly emerging in the horizon. Although eschewed by many experienced laparoscopists, the da Vinci achieved a toehold among many skilled surgeons who found that the robot could facilitate MIS procedures that were difficult with standard laparoscopic procedures. The latest iteration of the da Vinci Xi platform released in 2014 features high-defini-tion, three-dimensional vision and a dual-console capability allowing greater visualization, assistance, and instruction capa-bilities. Additionally, the new overhead boom design facilitates anatomical access from virtually any position enabling complex multiquadrant surgeries.PHYSIOLOGY AND PATHOPHYSIOLOGY OF MINIMALLY INVASIVE SURGERYEven with the least invasive of the MIS procedures, physiologic changes occur. Many minimally invasive procedures require minimal or no sedation, and there are few adverse consequences to the cardiovascular, endocrinologic, or immunologic systems. The least invasive of such procedures include stereotactic biopsy of breast lesions and flexible GI endoscopy. Minimally invasive procedures that require general anesthesia have a greater physi-ologic impact because of the anesthetic agent, the incision (even if small), and the induced pneumoperitoneum.LaparoscopyThe unique feature of laparoscopic surgery is the need to lift the abdominal wall from the abdominal organs. Two methods have been devised for achieving this.10 The first, used by most sur-geons, is a pneumoperitoneum. Throughout the early 20th century, intraperitoneal visualization was achieved by inflating the abdominal cavity with air, using a sphygmomanometer bulb.11 The problem with using air insufflation is that nitrogen is poorly soluble in blood and is slowly absorbed across the peritoneal surfaces. Air pneumoperitoneum was believed to be more pain-ful than nitrous oxide (N2O) pneumoperitoneum, but less pain-ful than carbon dioxide (CO2) pneumoperitoneum. Subsequently, CO2 and N2O were used for inflating the abdomen. N2O had the advantage of being physiologically inert and rap-idly absorbed. It also provided better analgesia for laparoscopy performed under local anesthesia when compared with CO2 or air.12 Despite initial concerns that N2O would not suppress combustion, controlled clinical trials have established its safety within the peritoneal cavity.13 In addition, N2O has been shown to reduce the intraoperative end-tidal CO2 and minute ventila-tion required to maintain homeostasis when compared to CO2 pneumoperitoneum.13 The effect of N2O on tumor biology and the development of port site metastasis are unknown. As such, caution should be exercised when performing laparoscopic can-cer surgery with this agent. Finally, the safety of N2O pneumo-peritoneum in pregnancy has yet to be elucidated.The physiologic effects of CO2 pneumoperitoneum can be divided into two areas: (a) gas-specific effects and (b) pressure-specific effects (Fig. 14-1). CO2 is rapidly absorbed across the peritoneal membrane into the circulation. In the circulation, 2Local effectsPeritoneal distentionVagal reactionElevated diaphragmAltered venous returnPainSystemic effectsHypercarbiaAcidosisIncreased afterloadIncreased catecholaminesMyocardial stressCO2Figure 14-1. Carbon dioxide gas insufflated into the peritoneal cavity has both local and systemic effects that cause a complex set of hemodynamic and metabolic alterations. (Reproduced with permission from Hunter JG: Bailliere’s Clinical Gastroen-terology Laparoscopic Surgery. London/Philadelphia: Bailliere Tindall; 1993.)Brunicardi_Ch14_p0453-p0478.indd 45501/03/19 4:58 PM 456BASIC CONSIDERATIONSPART ICO2 creates a respiratory acidosis by the generation of carbonic acid.14 Body buffers, the largest reserve of which lies in bone, absorb CO2 (up to 120 L) and minimize the development of hypercarbia or respiratory acidosis during brief endoscopic pro-cedures.14 Once the body buffers are saturated, respiratory aci-dosis develops rapidly, and the respiratory system assumes the burden of keeping up with the absorption of CO2 and its release from these buffers.In patients with normal respiratory function, this is not difficult; the anesthesiologist increases the ventilatory rate or vital capacity on the ventilator. If the respiratory rate required exceeds 20 breaths per minute, there may be less efficient gas exchange and increasing hypercarbia.15 Conversely, if vital capacity is increased substantially, there is a greater opportunity for barotrauma and greater respiratory motion–induced disrup-tion of the upper abdominal operative field. In some situations, it is advisable to evacuate the pneumoperitoneum or reduce the intra-abdominal pressure to allow time for the anesthesiologist to adjust for hypercarbia.16 Although mild respiratory acidosis probably is an insignificant problem, more severe respiratory acidosis leading to cardiac arrhythmias has been reported.17 Hypercarbia also causes tachycardia and increased systemic vascular resistance, which elevates blood pressure and increases myocardial oxygen demand.14,17The pressure effects of the pneumoperitoneum on cardio-vascular physiology also have been studied. In the hypovolemic individual, excessive pressure on the inferior vena cava and a reverse Trendelenburg position with loss of lower extremity muscle tone may cause decreased venous return and decreased cardiac output.14,18 This is not seen in the normovolemic patient. The most common arrhythmia created by laparoscopy is brady-cardia. A rapid stretch of the peritoneal membrane often causes a vagovagal response with bradycardia and, occasionally, hypo-tension.19 The appropriate management of this event is desuf-flation of the abdomen, administration of vagolytic agents (e.g., atropine), and adequate volume replacement.20With the increased intra-abdominal pressure compressing the inferior vena cava, there is diminished venous return from the lower extremities. This has been well documented in the patient placed in the reverse Trendelenburg position for upper abdominal operations. Venous engorgement and decreased venous return promote venous thrombosis.21,22 Many series of advanced laparoscopic procedures in which deep venous thrombosis (DVT) prophylaxis was not used demonstrate the frequency of pulmonary embolus. This usually is an avoidable complication with the use of sequential compression stockings, subcutaneous heparin, or low molecular weight heparin.20,23 In short-duration laparoscopic procedures, such as appendectomy, hernia repair, or cholecystectomy, the risk of DVT may not be sufficient to warrant extensive DVT prophylaxis.The increased pressure of the pneumoperitoneum is trans-mitted directly across the paralyzed diaphragm to the thoracic cavity, creating increased central venous pressure and increased filling pressures of the right and left sides of the heart. If the intra-abdominal pressures are kept under 20 mmHg, the car-diac output usually is well maintained.22-24 The direct effect of the pneumoperitoneum on increasing intrathoracic pressure increases peak inspiratory pressure, pressure across the chest wall, and also, the likelihood of barotrauma. Despite these concerns, disruption of blebs and consequent pneumothoraces are rare after uncomplicated laparoscopic surgery.24 Pneumo-thoraces occurring with laparoscopic esophageal surgery may be very significant. The pathophysiology and management are discussed at the end of this section. Increased intra-abdominal pressure decreases renal blood flow, glomerular filtration rate, and urine output. These effects may be mediated by direct pressure on the kidney and the renal vein.25,26 The secondary effect of decreased renal blood flow is to increase plasma renin release, thereby increasing sodium retention. Increased circu-lating antidiuretic hormone levels also are found during the pneumoperitoneum, increasing free water reabsorption in the distal tubules.27 Although the effects of the pneumoperitoneum on renal blood flow are immediately reversible, the hormonally mediated changes such as elevated antidiuretic hormone levels decrease urine output for up to 1 hour after the procedure has ended. Intraoperative oliguria is common during laparoscopy, but the urine output is not a reflection of intravascular volume status; intravenous (IV) fluid administration during an uncom-plicated laparoscopic procedure should not be linked to urine output. Because insensible fluid losses through the open abdo-men are eliminated with laparoscopy, the need for supplemen-tal fluid during a laparoscopic surgical procedure should only keep up with venous pooling in the lower limbs, third-space losses into the bowel, and blood loss, which is generally less than occurs with an equivalent open operation.The hemodynamic and metabolic consequences of pneu-moperitoneum are well tolerated by healthy individuals for a prolonged period and by most individuals for at least a short period. Difficulties can occur when a patient with compromised cardiovascular function is subjected to a long laparoscopic pro-cedure. It is during these procedures that alternative approaches should be considered or insufflation pressure reduced. Alterna-tive gases that have been suggested for laparoscopy include the inert gases helium, neon, and argon. These gases are appeal-ing because they cause no metabolic effects, but are poorly soluble in blood (unlike CO2 and N2O) and are prone to create gas emboli if the gas has direct access to the venous system.22 Gas emboli are rare but serious complications of laparoscopic surgery.23,28 They should be suspected if hypotension develops during insufflation. Diagnosis may be made by listening (with an esophageal stethoscope) for the characteristic “mill wheel” murmur. The treatment of gas embolism is to place the patient in a left lateral decubitus position with the head down to trap the gas in the apex of the right ventricle.23 A rapidly placed central venous catheter then can be used to aspirate the gas out of the right ventricle.In some situations, minimally invasive abdominal surgery can be performed without insufflation. This is possible with the assistance of an abdominal lift device that can be placed through a 10to 12-mm trocar at the umbilicus.29 These devices have the advantage of creating little physiologic derangement, but they are bulky and intrusive. The exposure and working room offered by lift devices also are inferior to those accomplished by pneumoperitoneum. Lifting the anterior abdominal wall reduces space available laterally and thereby displaces the bowel medi-ally and anteriorly into the operative field. A pneumoperi-toneum, with its well-distributed intra-abdominal pressure, provides better exposure. Abdominal lift devices also cause more postoperative pain, but they do allow the performance of MIS with standard (nonlaparoscopic) surgical instruments.Endocrine responses to laparoscopic surgery are not always intuitive. Serum cortisol levels after laparoscopic opera-tions are often higher than after the equivalent operation per-formed through an open incision.30 The greatest difference Brunicardi_Ch14_p0453-p0478.indd 45601/03/19 4:58 PM 457MINIMALLY INVASIVE SURGERYCHAPTER 14between the endocrine response of open and laparoscopic sur-gery is the more rapid equilibration of most stress-mediated hormone levels after laparoscopic surgery. Immune suppression also is less after laparoscopy than after open surgery. There is a trend toward more rapid normalization of cytokine levels after a laparoscopic procedure than after the equivalent procedure performed by celiotomy.31Transhiatal mobilization of the distal esophagus is com-monly performed as a component of many laparoscopic upper abdominal procedures. If there is compromise of the mediastinal pleura with resultant CO2 pneumothorax, the defect should be enlarged so as to prevent a tension pneumothorax. Even with such a strategy, tension pneumothorax may develop, as medi-astinal structures may seal the hole during inspiration, allowing the chest to fill during expiration. In addition to enlargement of the hole, a thoracostomy tube (chest tube) should be placed across the breach into the abdomen with intra-abdominal pres-sures reduced below 8 mmHg, or a standard chest tube may be placed. When a pneumothorax occurs with laparoscopic Nissen fundoplication or Heller myotomy, it is preferable to place an 18-French red rubber catheter with multiple side holes cut out of the distal end across the defect. At the end of the procedure, the distal end of the tube is pulled out a 10-mm port site (as the port is removed), and the pneumothorax is evacuated to a primitive water seal using a bowl of sterile water or saline. During laparo-scopic esophagectomy, it is preferable to leave a standard chest tube, as residual intra-abdominal fluid will tend to be siphoned through the defect postoperatively if the tube is removed at the end of the case.ThoracoscopyThe physiology of thoracic MIS (thoracoscopy) is different from that of laparoscopy. Because of the bony confines of the thorax, it is unnecessary to use positive pressure when working in the thorax.32 The disadvantages of positive pressure in the chest include decreased venous return, mediastinal shift, and the need to keep a firm seal at all trocar sites. Without positive pressure, it is necessary to place a double-lumen endotracheal tube so that the ipsilateral lung can be deflated when the opera-tion starts. By collapsing the ipsilateral lung, working space within the thorax is obtained. Because insufflation is unneces-sary in thoracoscopic surgery, it can be beneficial to use stan-dard instruments via extended port sites in conjunction with thoracoscopic instruments. This approach is particularly useful when performing advanced procedures such as thoracoscopic anatomic pulmonary resection.Extracavitary Minimally Invasive SurgeryMany MIS procedures create working spaces in extrathoracic and extraperitoneal locations. Laparoscopic inguinal her-nia repair usually is performed in the anterior extraperitoneal Retzius space.33,34 Laparoscopic nephrectomy often is per-formed with retroperitoneal laparoscopy. Endoscopic retro-peritoneal approaches to pancreatic necrosectomy have seen some limited use.35 Lower extremity vascular procedures and plastic surgical endoscopic procedures require the development of working space in unconventional planes, often at the level of the fascia, sometimes below the fascia, and occasionally in nonanatomic regions.36 Some of these techniques use insuffla-tion of gas, but many use balloon inflation to develop the space, followed by low-pressure gas insufflation or lift devices to maintain the space (Fig. 14-2). These techniques produce fewer and less severe adverse physiologic consequences than does the ABCFigure 14-2. Balloons are used to create extra-anatomic working spaces. In this example (A through C), a balloon is introduced into the space between the posterior rectus sheath and the rectus abdom-inal muscle. The balloon is inflated in the preperitoneal space to create working room for extraperitoneal endoscopic hernia repair.pneumoperitoneum, but the insufflation of carbon dioxide into extraperitoneal locations can spread widely, causing subcutane-ous emphysema and metabolic acidosis.AnesthesiaProper anesthesia management during laparoscopic surgery requires a thorough knowledge of the pathophysiology of the CO2 pneumoperitoneum.20 The laparoscopic surgeon can influ-ence cardiovascular performance by reducing or removing the CO2 pneumoperitoneum. Insensible fluid losses are negligible, and therefore, IV fluid administration should not exceed that necessary to maintain circulating volume. MIS procedures are often outpatient procedures, so short-acting anesthetic agents are preferable. Because the factors that require hospitaliza-tion after laparoscopic procedures include the management of nausea, pain, and urinary retention, the anesthesiologist should minimize the use of agents that provoke these conditions and maximize the use of medications that prevent such problems. Critical to the anesthesia management of these patients is the use of nonnarcotic analgesics (e.g., ketorolac) when hemosta-sis allows it and the liberal use of antiemetic agents, including ondansetron and steroids.The Minimally Invasive TeamFrom the beginning, the tremendous success of MIS was founded on the understanding that a team approach was Brunicardi_Ch14_p0453-p0478.indd 45701/03/19 4:58 PM 458BASIC CONSIDERATIONSPART ITable 14-1Laparoscopic surgical proceduresBASICADVANCEDAppendectomyNissen fundoplicationLymph node dissectionCholecystectomyHeller myotomyRoboticsInguinal hernia repairParaesophageal herniaBariatricEnteral accessGastrectomyComplex abdominal wall reconstruction Lysis of adhesionsEsophagectomy Bile duct explorationHepatectomy ColectomyPancreatectomy SplenectomyProstatectomy AdrenalectomyHysterectomy Nephrectomy Figure 14-3. An example of a typical minimally invasive surgery suite. All core equipment is located on easily movable consoles.necessary. The many laparoscopic procedures performed daily range from basic to advanced complexity, and require that the surgical team have an intimate understanding of the operative conduct (Table 14-1). Minimally invasive procedures require complicated and fragile equipment that demands constant main-tenance. In addition, multiple intraoperative adjustments to the equipment, camera, insufflator, monitors, and patient/surgeon position are made during these procedures. As such, a coordi-nated team approach is mandated to ensure patient safety and excellent outcomes. More and more, flexible endoscopes are used to guide or provide quality control for laparoscopic pro-cedures. As NOTES, SILS, and robotic surgery become more common, hybrid procedures (laparoscopy and endoscopy) and complicated robotics cases will require a nursing staff capable of maintaining flexible endoscopes and understanding the oper-ation of sophisticated technology.A typical MIS team may consist of a laparoscopic surgeon and an operating room (OR) nurse with an interest in laparo-scopic and endoscopic surgery. Adding dedicated assistants and circulating staff with an intimate knowledge of the equipment will add to and enhance team competency. Studies have dem-onstrated that having a designated laparoscopic team increases the efficiency and safety of laparoscopic surgery, which is trans-lated into a benefit for the patient and the hospital.37Room Setup and the Minimally Invasive SuiteNearly all MIS, whether using fluoroscopic, ultrasound, or opti-cal imaging, incorporates a video monitor as a guide. Occasion-ally, two images are necessary to adequately guide the operation, as in procedures such as endoscopic retrograde cholangiopan-creatography, laparoscopic common bile duct exploration, and laparoscopic ultrasonography. When two images are necessary, the images should be displayed on two adjacent video monitors or projected on a single screen with a picture-in-picture effect. The video monitor(s) should be set across the operating table from the surgeon. The patient should be interposed between the surgeon and the video monitor; ideally, the operative field also lies between the surgeon and the monitor. In pelviscopic sur-gery, it is best to place the video monitor at the patient’s feet, and in laparoscopic cholecystectomy, the monitor is placed at the 10 o’clock position (relative to the patient) while the surgeon stands on the patient’s left at the 4 o’clock position. The insuf-flating and patient-monitoring equipment ideally also is placed across the table from the surgeon so that the insufflating pres-sure and the patient’s vital signs and end-tidal CO2 tension can be monitored.The development of the minimally invasive surgical suite has been a tremendous contribution to the field of laparoscopy in that it has facilitated the performance of advanced proce-dures and techniques (Fig. 14-3). By having the core equipment (monitors, insufflators, and imaging equipment) located within mobile, ceiling-mounted consoles, the surgery team is able to accommodate and make small adjustments rapidly and con-tinuously throughout the procedure. The specifically designed minimally invasive surgical suite serves to decrease equipment and cable disorganization, ease the movements of operative per-sonnel around the room, improve ergonomics, and facilitate the use of advanced imaging equipment such as laparoscopic ultra-sound.38 Although having a minimally invasive surgical suite available is very useful, it is not essential to successfully carry out advanced laparoscopic procedures.Patient PositioningPatients usually are placed in the supine position for laparo-scopic surgery. When the operative field is the gastroesophageal junction or the left lobe of the liver, it is easiest to operate from between the legs. The legs may be elevated in Allen stirrups or abducted on leg boards to achieve this position. When pel-vic procedures are performed, it usually is necessary to place the legs in Allen stirrups to gain access to the perineum. A lat-eral decubitus position with the table flexed provides the best access to the retroperitoneum when performing nephrectomy or adrenalectomy. For laparoscopic splenectomy, a 45° tilt of the patient provides excellent access to the lesser sac and the lateral peritoneal attachments to the spleen. For thoracoscopic surgery, the patient is placed in the lateral position with table flexion to open the intercostal spaces and the distance between the iliac crest and costal margin (Fig. 14-4). Additional con-sideration must be made in robotic operations to position the Brunicardi_Ch14_p0453-p0478.indd 45801/03/19 4:58 PM 459MINIMALLY INVASIVE SURGERYCHAPTER 14Figure 14-4. Proper padding and protection of pressure points is an essential consideration in laparoscopic and thoracoscopic approaches. In preparation for thoracoscopy, this patient is placed in left lateral decubitus position with the table flexed, which serves to open the intercostal spaces and increase the distance between the iliac crest and the inferior costal margin.patient appropriately before starting. Clashing of the robotic arms with surrounding equipment or each other can occur if not positioned correctly. This is more common in predecessors of the da Vinci Xi platform. Unless an operative table with inte-grated table motion is available, once the robot is docked to the patient the bed cannot be moved without undocking.When the patient’s knees are to be bent for extended peri-ods or the patient is going to be placed in a reverse Trendelen-burg position for more than a few minutes, DVT prophylaxis should be used. Sequential compression devices should be placed on the lower extremities during laparoscopic procedures to increase venous return and provides inhibition of thrombo-plastin activation.General Principles of AccessThe most natural ports of access for MIS and NOTES are the anatomic portals of entry and exit. The nares, mouth, anus, vagina, and urethra are used to access the respiratory, GI, and urinary systems. The advantage of using these points of access is that no incision is required. The disadvantages lie in the long distances between the orifice and the region of interest. For NOTES procedures, the vagina may serve as point of access, entering the abdomen via the posterior cul-de-sac of the pelvis. Similarly, the peritoneal cavity may be reached through the side wall of the stomach or colon.Access to the vascular system may be accomplished under local anesthesia by cutting down and exposing the desired vessel, usually in the groin. Increasingly, vascular access is obtained with percutaneous techniques using a small incision, a needle, and a guidewire, over which are passed a variety of different-sized access devices. This approach, known as the Seldinger technique, is most frequently used by general sur-geons for placement of Hickman catheters, but it also is used to gain access to the arterial and venous system for performance of minimally invasive procedures. Guidewire-assisted, Seldinger-type techniques also are helpful for gaining access to the gut for procedures such as PEG, for gaining access to the biliary system through the liver, and for gaining access to the upper urinary tract.In thoracoscopic surgery, the access technique is similar to that used for placement of a chest tube. In these procedures, general anesthesia and single lung ventilation are essential. A small incision is made over the top of a rib and, under direct vision, carried down through the pleura. The lung is collapsed, and a trocar is inserted across the chest wall to allow access with a telescope. Once the lung is completely collapsed, subse-quent access may be obtained with direct puncture, viewing all entry sites through the videoendoscope. Because insufflation of the chest is unnecessary, simple ports that keep the small inci-sions open are all that is required to allow repeated access to the thorax.Laparoscopic AccessThe requirements for laparoscopy are more involved because the creation of a pneumoperitoneum requires that instruments of access (trocars) contain valves to maintain abdominal inflation.Two methods are used for establishing abdominal access during laparoscopic procedures.39,40 The first, direct puncture laparoscopy, begins with the elevation of the relaxed abdominal wall with two towel clips or a well-placed hand. A small inci-sion is made in the umbilicus, and a specialized spring-loaded (Veress) needle is placed in the abdominal cavity (Fig. 14-5). Figure 14-5. A. Tip of spring loaded (Veress) needle. B. Veress needle held at its serrated collar with a thumb and forefinger. At the umbilicus, the abdominal wall is grasped with fingers or penetrating towel clip to elevate the abdominal wall away from the underlying structures.ABBrunicardi_Ch14_p0453-p0478.indd 45901/03/19 4:58 PM 460BASIC CONSIDERATIONSPART IFigure 14-6. It is essential to be able to interpret the insufflator pressure readings and flow rates. These readings indicate proper intraperitoneal placement of the Veress needle.Figure 14-7. The open laparoscopy technique involves identifica-tion and incision of the peritoneum, followed by the placement of a specialized trocar with a conical sleeve to maintain a gas seal. Spe-cialized wings on the trocar are attached to sutures placed through the fascia to prevent loss of the gas seal.With the Veress needle, two distinct pops are felt as the surgeon passes the needle through the abdominal wall fascia and the peritoneum. The umbilicus usually is selected as the preferred point of access because, in this location, the abdominal wall is quite thin, even in obese patients. The abdomen is inflated with a pressure-limited insufflator. CO2 gas usually is used, with maximal pressures in the range of 14 to 15 mmHg. During the process of insufflation, it is essential that the surgeon observe the pressure and flow readings on the monitor to confirm an intraperitoneal location of the Veress needle tip (Fig. 14-6). Laparoscopic surgery can be performed under local anesthesia, but general anesthesia is preferable. Under local anesthesia, N2O is used as the insufflating agent, and insufflation is stopped after 2 L of gas is insufflated or when a pressure of 10 mmHg is reached.After peritoneal insufflation, direct access to the abdomen is obtained with a 5or 10-mm trocar. This can be performed through a radially dilating sheath placed over the Veress needle or an optical viewing trocar. In the latter technique, a camera is placed inside of a clear pyramidal trocar. Direct puncture entry is observed as the trocar is passed through the abdominal wall. The critical issues for safe direct-puncture laparoscopy include the use of a vented stylet for the trocar, or a trocar with a safety shield or dilating tip. An optical viewing trocar can be used without prior insufflation; however, proper recognition of the abdominal wall layers is critical to avoid entry into the mes-entery or underlying structures. In all direct puncture entry the trocar must be pointed away from the sacral promontory and the great vessels.41 Patient position should be surveyed before trocar placement to ensure a proper trajectory.Occasionally, the direct peritoneal access (Hasson) tech-nique is advisable.42 With this technique, the surgeon makes a small incision just below the umbilicus and under direct vision locates the abdominal fascia. Two Kocher clamps are placed on the fascia, and with curved Mayo scissors, a small incision is made through the fascia and underlying peritoneum. A fin-ger is placed into the abdomen to make sure that there is no adherent bowel. A sturdy suture is placed on each side of the fascia and secured to the wings of a specialized trocar, which is then passed directly into the abdominal cavity (Fig. 14-7). Rapid insufflation can make up for some of the time lost with the initial dissection. This technique is preferable for the abdo-men of patients who have undergone previous operations in which small bowel may be adherent to the undersurface of the abdominal wound. The close adherence of bowel to the perito-neum in the previously operated abdomen does not eliminate the possibility of intestinal injury but should make great vessel injury extremely unlikely. Because of the difficulties in visual-izing the abdominal region immediately adjacent to the primary trocar, it is recommended that the telescope be passed through a secondary trocar to inspect the site of initial abdominal access.40 Secondary punctures are made with 5and 10-mm trocars. For safe access to the abdominal cavity, it is critical to visualize all sites of trocar entry.41,42 At the completion of the operation, all trocars are removed under direct vision, and the insertion sites are inspected for bleeding. If bleeding occurs, direct pres-sure with an instrument from another trocar site or balloon tamponade with a Foley catheter placed through the trocar site generally stops the bleeding within 3 to 5 minutes. When this is not successful, a full-thickness abdominal wall suture has been used successfully to tamponade trocar site bleeding.It is generally agreed that 5-mm trocars need no site sutur-ing. Ten-millimeter trocars placed off the midline, through a radially dilating sheath or above the transverse mesocolon do not typically require repair. Conversely, if the fascia has been dilated to allow the passage of the gallbladder or other organ, it should be repaired at the fascial level with interrupted sutures. The port site may be closed with suture delivery systems simi-lar to crochet needles enabling mass closure of the abdominal wall. This is especially helpful in obese patients where direct fascial closure may be challenging, through a small skin inci-sion. Failure to close lower abdominal trocar sites that are 10 mm in diameter or larger can lead to an incarcerated hernia.Access for Subcutaneous and Extraperitoneal SurgeryThere are two methods for gaining access to nonanatomic spaces. For retroperitoneal locations, balloon dissection is effec-tive. This access technique is appropriate for the extraperitoneal repair of inguinal hernias and for retroperitoneal surgery for adrenalectomy, nephrectomy, lumbar discectomy, pancreatic necrosectomy, or para-aortic lymph node dissection.43,44 The Brunicardi_Ch14_p0453-p0478.indd 46001/03/19 4:58 PM 461MINIMALLY INVASIVE SURGERYCHAPTER 14initial access to the extraperitoneal space is performed in a way similar to direct puncture laparoscopy, except that the last layer (the peritoneum) is not traversed. Once the transversalis fascia has been punctured, a specialized trocar with a balloon on the end is introduced. The balloon is inflated in the extraperitoneal space to create a working chamber. The balloon then is deflated, and a Hasson trocar is placed. An insufflation pressure of 10 mmHg usually is adequate to keep the extraperitoneal space open for dissection and will limit subcutaneous emphysema. Higher gas pressures force CO2 into the soft tissues and may contribute to hypercarbia. Extraperitoneal endosurgery provides less working space than laparoscopy but eliminates the possibil-ity of intestinal injury, intestinal adhesion, herniation at the tro-car sites, and ileus. These issues are important for laparoscopic hernia repair because extraperitoneal approaches prevent the small bowel from sticking to the prosthetic mesh.34Subcutaneous surgery has been most widely used in car-diac, vascular, and plastic surgery.36 In cardiac surgery, subcu-taneous access has been used for saphenous vein harvesting, and in vascular surgery for ligation of subfascial perforating veins (Linton procedure). With minimally invasive techniques, the entire saphenous vein above the knee may be harvested through a single incision (Fig. 14-8).45,46 Once the saphenous vein is located, a long retractor that holds a 5-mm laparoscope allows the coaxial dissection of the vein and coagulation or clipping of Figure 14-8. With two small incisions, virtually the entire saphe-nous vein can be harvested for bypass grafting.each side branch. A small incision above the knee also can be used to ligate perforating veins in the lower leg.Subcutaneous access also is used for plastic surgery pro-cedures.46 Minimally invasive approaches are especially well suited to cosmetic surgery, in which attempts are made to hide the incision. It is easier to hide several 5-mm incisions than one long incision. The technique of blunt dissection along fascial planes combined with lighted retractors and endoscope-holding retractors is most successful for extensive subcutaneous surgery. Some prefer gas insufflation of these soft tissue planes. The pri-mary disadvantage of soft tissue insufflation is that subcutane-ous emphysema can be created.Hand-Assisted Laparoscopic AccessHand-assisted laparoscopic surgery is thought to combine the tactile advantages of open surgery with the minimal access of laparoscopy and thoracoscopy. This approach commonly is used to assist with difficult cases before conversion to celiotomy is necessary. Additionally, hand-assisted laparoscopic surgery is used to help surgeons negotiate the steep learning curve associ-ated with advanced laparoscopic procedures.47 This technology uses an entryway for the hand that preserves the pneumoperi-toneum and enables laparoscopic visualization in combination with the use of minimally invasive instruments (Fig. 14-9). For-mal investigation of this modality has been limited primarily to case reports and small series and has focused primarily on solid organ and colon surgery.Intraperitoneal, intrathoracic, and retroperitoneal access for robotic surgery adheres to the principles of laparoscopic and thoracoscopic access; however, the port size for the primary puncture is 12 mm to allow placement of the stereo laparoscope. Remaining trocars are 8 mm.Natural Orifice Transluminal Endoscopic Surgery AccessMultiple studies have shown safety in the performance of NOTES procedures. Transvaginal, transvesicle, transanal, transcolonic, transgastric, and transoral approaches have all been attempted with varying success. The ease of decontamina-tion, entry, and closure of these structures create variable chal-lenges. The transvaginal approach for resection of the uterus has been employed for many years by gynecologists and has been modified by laparoscopists with great success. Extraction of the gallbladder, kidney, bladder, large bowel, and stomach can be Figure 14-9. This is an example of hand-assisted laparoscopic surgery during left colectomy. The surgeon uses a hand to provide retraction and counter tension during mobilization of the colon from its retroperitoneal attachments, as well as during division of the mesocolon. This technique is particularly useful in the region of the transverse colon.Brunicardi_Ch14_p0453-p0478.indd 46101/03/19 4:58 PM 462BASIC CONSIDERATIONSPART IFigure 14-10. Submucosal tunnel technique for transesophageal mediastinoscopy. (Reproduced with permission from Khashab MA, Kalloo AN. NOTES: current status and new horizons, Gastroenterology. 2012 Apr;142(4):704-710.e1.)performed via the vagina. The esophagus can be traversed to enter the mediastinum. Leaving the orifice or organ of entry with an endoscope requires the use of an endoscopic needle knife followed by submucosal tunneling or direct puncture and balloon dilation (Fig. 14-10). Closure has been performed using endoscopic clips or sutures with advanced endoscopic platforms.Single-Incision Laparoscopic Surgery AccessThere is no standardized approach for SILS, and access tech-niques vary by surgeon preference. Traditionally, a single skin incision is made directly through the umbilical scar ranging from 1 to 3 cm. Through this single incision, multiple low-profile trocars can be placed separately into the fascia to allow insufflation, camera, and working instruments. The advantage of this technique is that conventional laparoscopic tools can be employed. The disadvantage becomes apparent when an extrac-tion site is needed. A variety of specialized multilumen trocars are on the market that can be placed through the umbilical ring48 (Fig. 14-11A,B). The advantages of these devices include faster access, improved safety, minimization of air leaks, and plat-form-derived instrument triangulation. The major disadvantage is cost.Port PlacementTrocars for the surgeon’s left and right hand should be placed at least 10 cm apart. For most operations, it is possible to orient ABCDEthe telescope between these two trocars and slightly back from them. The ideal trocar orientation creates an equilateral triangle between the surgeon’s right hand, left hand, and the telescope, with 10 to 15 cm on each leg. If one imagines the target of the operation (e.g., the gallbladder or gastroesophageal junc-tion) oriented at the apex of a second equilateral triangle built on the first, these four points of reference create a diamond (Fig. 14-12). The surgeon stands behind the telescope, which provides optimal ergonomic orientation but frequently requires that a camera operator (or mechanical camera holder) reach between the surgeon’s hands to guide the telescope. SILS is challenging for even the experienced laparoscopist because it violates most of the aforementioned ergonomic principles. Hav-ing only a single point of entry into the abdominal cavity creates an inherently crowded port and hand position. The inability to space trocars severely limits the ability to triangulate the leftand right-hand instruments. As a result, the surgeon must often work in a crossed hands fashion (Fig. 14-13). Additionally, the axis of the camera view is often in line with the working instru-ments, making visualization difficult without a deflectable tip laparoscope.The position of the operating table should permit the sur-geon to work with both elbows in at the sides, with arms bent 90° at the elbow.49 It usually is necessary to alter the operating table position with left or right tilt with the patient in the Tren-delenburg or reverse Trendelenburg position, depending on the operative field.50,51Brunicardi_Ch14_p0453-p0478.indd 46201/03/19 4:58 PM 463MINIMALLY INVASIVE SURGERYCHAPTER 14Figure 14-11. A. Specialized multilumen trocars can facilitate instrument placement. B. For single-incision laparoscopic surgery, multiple fascial punctures can be performed via a single skin incision. (Reproduced with permission from The Johns Hopkins University School of Medicine, Baltimore, MD; 2014. Illustration by Corinne Sandone.)Multiple trocarsthrough singleskin incision Single portaccommodatesmultiple trocarsABTHE DIAMOND OF SUCCESS"Home plate"(telescope)"First base"(R hand)"Third base"(L hand)"Second base"(hiatal hernia)15 cmFigure 14-12. The diamond configuration created by placing the telescope between the left and the right hand, recessed from the target by about 15 cm. The distance between the left and the right hand is also ideally 10 to 15 cm. In this “baseball diamond” con-figuration, the surgical target occupies the second base position.Figure 14-13. The single point of abdominal entry for trocars often requires that the surgeon work in a crossed hands fashion. (Reproduced with permission from The Johns Hopkins University School of Medi-cine, Baltimore, MD; 2014. Illustration by Corinne Sandone.)Imaging SystemsTwo methods of videoendoscopic imaging are widely used. Both methods use a camera with a charge-coupled device (CCD), which is an array of photosensitive sensor elements (pixels) that convert the incoming light intensity to an electric charge. The electric charge is subsequently converted into a color image.52With videoendoscopy, the CCD chip is placed on the inter-nal end of a long, flexible endoscope. With older flexible endo-scopes, thin quartz fibers are packed together in a bundle, and the CCD camera is mounted on the external end of the endoscope. Most standard GI endoscopes have the CCD chip at the distal end, but small, delicate choledochoscopes and nephroscopes are equipped with fiber-optic bundles.53 Distally mounted CCD chips have been developed for laparoscopy but remain very expensive and therefore have not become as widely used.Video cameras come in two basic designs. Nearly all lapa-roscopic cameras contain a red, green, and blue input, and are identical to the color cameras used for television production.52 An additional feature of many video cameras is digital enhance-ment. Digital enhancement detects edges, areas where there are drastic color or light changes between two adjacent pixels.54 By enhancing this difference, the image appears sharper and surgi-cal resolution is improved. New laparoscopic cameras contain a high-definition (HD) chip, which increases the lines of resolu-tion from 480 to 1080 lines. To enjoy the benefit of the clarity of HD video imaging, HD monitors also are necessary.Priorities in a video imaging system for MIS are illumina-tion first, resolution second, and color third. Without the first two attributes, video surgery is unsafe. Illumination and resolu-tion are as dependent on the telescope, light source, and light cable as on the video camera used. Imaging for laparoscopy, thoracoscopy, and subcutaneous surgery uses a rigid metal telescope, usually 30 cm in length. Longer telescopes are avail-able for obese patients and for reaching the mediastinum and deep in the pelvis from a periumbilical entry site. The standard Brunicardi_Ch14_p0453-p0478.indd 46301/03/19 4:58 PM 464BASIC CONSIDERATIONSPART IFigure 14-14. The laparoscope tips come in a variety of angled configurations. All laparoscopes have a 70° field of view. A 30°-angled scope enables the surgeon to view this field at a 30° angle to the long axis of the scope.Figure 14-15. The Hopkins rod lens telescope includes a series of optical rods that effectively transmit light to the eyepiece. The video camera is placed on the eyepiece to provide the working image. The image is only as clear as the weakest link in the image chain. CCD = charge-coupled device. (Reproduced with permission from Toouli JG, Gossot D, Hunter JG: Endosurgery. New York/London: Churchill-Livingstone/Elsevier; 1996.)telescope contains a series of quartz optical rods and focusing lenses.55 Telescopes vary in size from 2 to 12 mm in diameter. Because light transmission is dependent on the cross-sectional area of the quartz rod, when the diameter of a rod/lens system is doubled, the illumination is quadrupled. Little illumination is needed in highly reflective, small spaces such as the knee, and a very small telescope will suffice. When working in the abdomi-nal cavity, especially if blood is present, the full illumination of a 10-mm telescope usually is necessary.Rigid telescopes may have a flat or angled end. The flat end provides a straight view (0°), and the angled end provides an oblique view (30° or 45°).52 Angled telescopes allow greater flexibility in viewing a wider operative field through a single trocar site (Fig. 14-14A); rotating an angled telescope changes LampLight sourceCameracontrollerCameraobjectivelensRelayedimageIlluminationlight guideImage formedby objective lensObservationpositionAdaption opticObjectivelens sectionRelaylens sectionEyepiecelens sectionFocus ringCCD chipMonitorCondensor lensLight guide cablethe field of view. The use of an angled telescope has distinct advantages for most videoendoscopic procedures, particularly in visualizing the common bile duct during laparoscopic cho-lecystectomy or visualizing the posterior esophagus or the tip of the spleen during laparoscopic fundoplication. Flexible tip laparoscopes offer even greater optical freedom.Light is delivered to the endoscope through a fiber-optic light cable. These light cables are highly inefficient, losing >90% of the light delivered from the light source. Extremely bright light sources (300 watts) are necessary to provide ade-quate illumination for laparoscopic surgery.The quality of the videoendoscopic image is only as good as the weakest component in the imaging chain (Fig. 14-15). Therefore, it is important to use a video monitor that has a reso-lution equal to or greater than the camera being used.55 Resolu-tion is the ability of the optical system to distinguish between line pairs. The larger the number of line pairs per millimeter, the sharper and more detailed the image. Most high-resolution monitors have up to 700 horizontal lines. HD television can deliver up to eight times more resolution than standard moni-tors; when combined with digital enhancement, a very sharp and well-defined image can be achieved.52,55 A heads-up display is a high-resolution liquid crystal monitor that is built into eyewear worn by the surgeon.56 This technology allows the surgeon to view the endoscopic image and operative field simultaneously. The proposed advantages of heads-up display include a high-resolution monocular image, which affords the surgeon mobility and reduces vertigo and eyestrain. However, this technology has not yet been widely adopted.Interest in three-dimensional (3-D) laparoscopy has waxed and waned. 3-D laparoscopy provides the additional depth of field that is lost with two-dimensional endosurgery and improves performance of novice laparoscopists performing complex tasks of dexterity, including suturing and knot tying.57 The advantages of 3-D systems are less obvious to experienced Brunicardi_Ch14_p0453-p0478.indd 46401/03/19 4:58 PM 465MINIMALLY INVASIVE SURGERYCHAPTER 14laparoscopists. Additionally, because 3-D systems require the flickering of two similar images, which are resolved with spe-cial glasses, the images’ edges become fuzzy and resolution is lost. The optical accommodation necessary to rectify these slightly differing images is tiring and may induce headaches when one uses these systems for a long period of time. The da Vinci robot uses a specialized laparoscope with two optical bundles on opposite sides of the telescope. A specialized bin-ocular eyepiece receives input from two CCD chips, each cap-turing the image from one of the two quartz rod lens systems, thereby creating true 3-D imaging without needing to employ active or passive technologies that have made 3-D laparoscopy so disappointing.Single-incision laparoscopy presents new challenges to visualization of the operative field. In the traditional laparo-scope, the light source enters the scope at a 90° angle. That position coupled with a bulky scope handle creates crowding in an already limited space. Additionally, because the scope and instruments enter the abdomen at the same point, an adequate perspective is often unobtainable even with a 30° scope. The advent of increased length laparoscopes with lighting coming from the end and a deflectable tip now allows the surgeon to recreate a sense of internal triangulation with little compromise externally. The ability to move the shaft of the scope off line while maintaining the same image provides a greater degree of freedom for the working ports.Energy Sources for Endoscopic and Endoluminal SurgeryMany MIS procedures use conventional energy sources, but the benefits of bloodless surgery to maintain optimal visualization have spawned new ways of applying energy. The most common energy source is RF electrosurgery using an alternating current with a frequency of 500,000 cycles/s (Hz). Tissue heating pro-gresses through the well-known phases of coagulation (60°C [140°F]), vaporization and desiccation (100°C [212°F]), and carbonization (>200°C [392°F]).58The two most common methods of delivering RF electro-surgery are with monopolar and bipolar electrodes. With mono-polar electrosurgery, a remote ground plate on the patient’s leg or back receives the flow of electrons that originate at a point source, the surgical electrode. A fine-tipped electrode causes a high current density at the site of application and rapid tissue heating. Monopolar electrosurgery is inexpensive and easy to modulate to achieve different tissue effects.59 A short-duration, high-voltage discharge of current (coagulation current) provides extremely rapid tissue heating. Lower-voltage, higher-wattage current (cutting current) is better for tissue desiccation and vaporization. When the surgeon desires tissue division with the least amount of thermal injury and least coagulation necrosis, a cutting current is used.With bipolar electrosurgery, the electrons flow between two adjacent electrodes. The tissue between the two electrodes is heated and desiccated. There is little opportunity for tissue cutting when bipolar current is used alone, but the ability to coapt the electrodes across a vessel provides the best method of small-vessel coagulation without thermal injury to adjacent tissues.60 Advanced laparoscopic device manufacturers have leveraged the ability to selectively use bipolar energy and combined it with compressive force and a controllable blade to create a number of highly functional dissection and vessel-sealing tools (Fig. 14-16).Figure 14-16. Examples of advanced bipolar devices. The flow of electrons passes from one electrode to the other heating and desic-cating tissue. A controllable blade travels the length of the jaw to divide intervening tissue.To avoid thermal injury to adjacent structures, the lapa-roscopic field of view must include all uninsulated portions of the electrosurgical electrode. In addition, the integrity of the insulation must be maintained and assured. Capacitive coupling occurs when a plastic trocar insulates the abdominal wall from the current; in turn, the current is bled off of a metal sleeve or laparoscope into the viscera54 (Fig. 14-17A). This may result in thermal necrosis and a delayed fecal fistula. Another potential mechanism for unrecognized visceral injury may occur with the direct coupling of current to the laparoscope and adjacent bowel58 (Fig. 14-17B).Another method of delivering RF electrosurgery is argon beam coagulation. This is a type of monopolar electrosurgery in which a uniform field of electrons is distributed across a tissue surface by the use of a jet of argon gas. The argon gas jet distrib-utes electrons more evenly across the surface than does spray electrofulguration. This technology has its greatest application for coagulation of diffusely bleeding surfaces such as the cut edge of liver or spleen. It is of less value in laparoscopic proce-dures because the increased intra-abdominal pressures created by the argon gas jet can increase the chances of a gas embolus. It is paramount to vent the ports and closely monitor insufflation pressure when using this source of energy within the context of laparoscopy.With endoscopic endoluminal surgery, RF alternating cur-rent in the form of a monopolar circuit represents the mainstay for procedures such as snare polypectomy, sphincterotomy, lower esophageal sphincter ablation, and biopsy.61,62 A ground-ing (return) electrode is necessary for this form of energy. Bipo-lar electrocoagulation is used primarily for thermal hemostasis. The electrosurgical generator is activated by a foot pedal so the endoscopist may keep both hands free during the endoscopic procedure.Gas, liquid, and solid-state lasers have been available for medical application since the mid-1960s.63 The CO2 laser (wavelength 10.6 µm) is most appropriately used for cutting Brunicardi_Ch14_p0453-p0478.indd 46501/03/19 4:58 PM 466BASIC CONSIDERATIONSPART IFigure 14-17. A. Capacitive coupling occurs as a result of high current density bleeding from a port sleeve or laparoscope into adjacent bowel. B. Direct coupling occurs when current is transmitted directly from the electrode to a metal instrument or laparoscope, and then into adjacent tissue. (Reproduced with permission from Hunter JG, Sackier JM: Minimally Invasive Surgery. New York, NY: McGraw-Hill Education; 1993.)Figure 14-18. This graph shows the absorption of light by various tissue compounds (water, melanin, and oxyhemoglobin) as a func-tion of the wavelength of the light. The nadir of the oxyhemoglo-bin and melanin curves is close to 1064 nm, the wavelength of the neodymium yttrium-aluminum garnet laser. (Reproduced with per-mission from Hunter JG, Sackier JM: Minimally Invasive Surgery. New York, NY: McGraw-Hill Education; 1993.)Conduction through ungrounded telescopeCannulaPlastic cannulaTelescopeBCapacitive coupled fault conditionCapacitivelycoupled energyto metalcannulaPlastic collarover metaltrocarAand superficial ablation of tissues. It is most helpful in locations unreachable with a scalpel such as excision of vocal cord granu-lomas. The CO2 laser beam must be delivered with a series of mirrors and is therefore somewhat cumbersome to use. The next most popular laser is the neodymium yttrium-aluminum garnet (Nd:YAG) laser. Nd:YAG laser light is 1.064 µm (1064 nm) in wavelength. It is in the near-infrared portion of the spectrum and, like CO2 laser light, is invisible to the naked eye. A unique feature of the Nd:YAG laser is that 1064-nm light is poorly absorbed by most tissue pigments and therefore travels deep into tissue.64 Deep tissue penetration provides deep tissue heating (Fig. 14-18). For this reason, the Nd:YAG laser is capable of the greatest amount of tissue destruction with a single application.63 Absorption coefficientWavelength (nm)10610510410310210110–110–211001000 10,000UV Visible InfaredHbO2H2OH2O1064 nmMelanin Such capabilities make it the ideal laser for destruction of large fungating tumors of the rectosigmoid, tracheobronchial tree, or esophagus. A disadvantage is that the deep tissue heating may cause perforation of a hollow viscus.When it is desirable to coagulate flat lesions in the cecum, a different laser should be chosen. The frequency-doubled Nd:YAG laser, also known as the KTP laser (potassium thionyl phosphate crystal is used to double the Nd:YAG frequency), pro-vides 532-nm light. This is in the green portion of the spectrum, and at this wavelength, selective absorption by red pigments in tissue (such as hemangiomas and arteriovenous malformations) is optimal. The depth of tissue heating is intermediate, between those of the CO2 and the Nd:YAG lasers. Coagulation (without vaporization) of superficial vascular lesions can be obtained without intestinal perforation.64In flexible GI endoscopy, the CO2 and Nd:YAG lasers have largely been replaced by heater probes and endoluminal stents. The heater probe is a metal ball that is heated to a tem-perature (60–100°C [140°–212°F]) that allows coagulation of bleeding lesions without perforation.Photodynamic therapy is a palliative treatment for obstruct-ing cancers of the GI tract.65 Patients are given an IV dose of porfimer sodium, which is a photosensitizing agent that is taken up by malignant cells. Two days after administration, the drug is endoscopically activated using a laser. The activated porfimer sodium generates oxygen free radicals, which kill the tumor cells. The tumor is later endoscopically debrided. The use of this modality for definitive treatment of early cancers is limited.A unique application of laser technology provides extremely rapid discharge (<10–6 s) of large amounts of energy (>103 volts). These high-energy lasers, of which the pulsed dye laser has seen the most clinical use, allow the conversion of light energy to mechanical disruptive energy in the form of a shock wave. Such energy can be delivered through a quartz fiber, and with rapid repetitive discharges, can provide sufficient shock-wave energy to fragment kidney stones and gallstones.66 Shock waves also may be created with miniature electric spark-plug discharge systems known as electrohydraulic lithotriptors. These devices Brunicardi_Ch14_p0453-p0478.indd 46601/03/19 4:58 PM 467MINIMALLY INVASIVE SURGERYCHAPTER 14also are inserted through thin probes for endoscopic application. Lasers have the advantage of pigment selectivity, but electrohy-draulic lithotriptors are more popular because they are substan-tially less expensive and are more compact.Methods of producing shock waves or heat with ultrasonic energy are also of interest. Extracorporeal shockwave lithotripsy creates focused shock waves that intensify as the focal point of the discharge is approached. When the focal point is within the body, large amounts of energy are capable of fragmenting stones. Slightly different configurations of this energy can be used to provide focused internal heating of tissues. Potential applications of this technology include the ability to noninvasively produce sufficient internal heating to destroy tissue without an incision.A third means of using ultrasonic energy is to create rap-idly oscillating instruments that are capable of heating tissue with friction; this technology represents a major step forward in energy technology.67 An example of its application is the lapa-roscopic coagulation shears device (Harmonic Scalpel), which is capable of coagulating and dividing blood vessels by first occluding them and then providing sufficient heat to weld the blood vessel walls together and to divide the vessel (Fig. 14-19). This nonelectric method of coagulating and dividing tissue with a minimal amount of collateral damage has facilitated the performance of numerous endosurgical procedures.68 It is espe-cially useful in the control of bleeding from medium-sized ves-sels that are too big to manage with monopolar electrocautery. The ability to clamp tissue between an active blade and passive blade allows annealing of tissues followed by cutting.InstrumentationHand instruments for MIS usually are duplications of conven-tional surgical instruments made longer, thinner, and smaller at the tip. It is important to remember that when grasping tissue with laparoscopic instruments, a greater force is applied over a smaller surface area, which increases the risk for perforation or injury.69Certain conventional instruments such as scissors are easy to reproduce with a diameter of 3 to 5 mm and a length of 20 to 45 cm, but other instruments such as forceps and clamps can-not provide remote access. Different configurations of grasp-ers were developed to replace the various configurations of surgical forceps and clamps. Standard hand instruments are 5 mm in diameter and 30 cm in length, but smaller and shorter hand instruments are now available for pediatric surgery, for microlaparoscopic surgery, and for arthroscopic procedures.69 A unique laparoscopic hand instrument is the monopolar electrical hook. This device usually is configured with a suction and irriga-tion apparatus to eliminate smoke and blood from the operative Figure 14-19. Ultrasonic shear. When closed vibration of black (active blade) against white (passive blade) cuts and cauterizes intervening tissue.field. The monopolar hook allows tenting of tissue over a bare metal wire with subsequent coagulation and division of the tissue.Instrumentation for NOTES is still evolving, but many long micrograspers, microscissors, electrocautery adapters, suturing devices, clip appliers, and visceral closure devices are in design and application. These instruments often require an entirely different endoscopic platform requiring manipula-tion by a surgeon and assistant to accomplish complex maneu-vers. Techniques such as mucosotomy, hydrodissection, and clip application require specialized training. The sheer size of the instrumentation often requires an overtube to allow easy exchange throughout the procedure. Instrumentation for SILS seeks to restore the surgeon’s ability to triangulate the left and right hands through variation in length, mechanical articulation, or curved design. Additionally, a lower profile camera head helps reduce the instrument crowding that occurs at the single point of abdominal entry.Robotic SurgeryThe term robot defines a device that has been programmed to perform specific tasks in place of those usually performed by people. The devices that have earned the title “surgical robots” would be more aptly termed computer-enhanced surgical devices, as they are controlled entirely by the surgeon for the purpose of improving performance. The first computer-assisted surgical device was the laparoscopic camera holder (Aesop, Computer Motion, Goleta, CA), which enabled the surgeon to maneuver the laparoscope either with a hand control, foot con-trol, or voice activation. Randomized studies with such camera holders demonstrated a reduction in operative time, steadier image, and a reduction in the number of required laparoscope cleanings.70 This device had the advantage of eliminating the need for a human camera holder, which served to free valuable OR personnel for other duties. This technology has now been eclipsed by simpler systems using passive positioning of the camera with a mechanical arm, but the benefits of a steadier image and fewer members of the OR team remain.The major revolution in robotic surgery was the develop-ment of a master-slave surgical platform that returned the wrist to laparoscopic surgery and improved manual dexterity by developing an ergonomically comfortable work station, with 3-D imaging, tremor elimination, and scaling of movement (e.g., large, gross hand movements can be scaled down to allow suturing with microsurgical precision) (Fig. 14-20). The most recent iteration of the robotic platform features a second surgi-cal console enabling greater assisting and teaching opportuni-ties. The surgeon is physically separated from the operating table, and the working arms of the device are placed over the patient (Fig. 14-21). An assistant remains at the bedside and changes the instruments as needed, providing retraction as needed to facilitate the procedure. The robotic platform (da Vinci, Intuitive Surgical, Sunnyvale, CA) was initially greeted with some skepticism by expert laparoscopists, as it was difficult to prove additional value for operations performed with the da Vinci robot. Not only were the operations longer and the equip-ment more expensive, but additional quality could not be dem-onstrated. Two randomized controlled trials compared robotic and conventional laparoscopic approaches to Nissen fundoplica-tion.71,72 In both of these trials, the operative time was longer for robotic surgery, and there was no difference in ultimate outcome. Similar results were achieved for laparoscopic cholecystec-tomy.73 Nevertheless, the increased dexterity provided by the da Brunicardi_Ch14_p0453-p0478.indd 46701/03/19 4:58 PM 468BASIC CONSIDERATIONSPART IFigure 14-21. Room setup and position of surgeon and assistant for robotic surgery. (© 2013 Intuitive Surgical, Inc. Reprinted with permission.)Vinci robot convinced many surgeons and health administrators that robotic platforms were worthy of investment, for marketing purposes if for no other reason. The success story for computer-enhanced surgery with the da Vinci started with cardiac surgery and migrated to the pelvis. Mitral valve surgery, performed with right thoracoscopic access, became one of the more popular procedures performed with the robot.74To date, a myriad of publications have demonstrated suc-cess performing procedures from thyroidectomies to colec-tomies with total mesorectal excision. Almost any procedure performed laparoscopically has been attempted robotically, although true advantage is demonstrated only very sparingly. In most cases, increased cost and operative time challenge the notion of “better.”The tidal wave of enthusiasm for robotic surgery came when most minimally invasive urologists declared robotic prostatectomy to be preferable to laparoscopic and open pros-tatectomy.75 The great advantage—it would appear—of robotic prostatectomy is the ability to visualize and spare the pelvic nerves responsible for erectile function. In addition, the cre-ation of the neocystourethrotomy, following prostatectomy, was greatly facilitated by needle holders and graspers with a wrist in them. Female pelvic surgery with the da Vinci robot is also reaching wide appeal. The magnified imaging provided makes this approach ideal for microsurgical tasks such as reanastomo-sis of the Fallopian tubes. In general surgery, there is emerging 3Figure 14-20. Robotic instruments and hand controls. The sur-geon is in a sitting position, and the arms and wrists are in an ergo-nomic and relaxed position.Brunicardi_Ch14_p0453-p0478.indd 46801/03/19 4:58 PM 469MINIMALLY INVASIVE SURGERYCHAPTER 14popularity for the use of the robotic platform for revisional bar-iatric surgery and complex abdominal wall reconstruction. The ability to close the defect before placement of mesh in ventral hernia repairs or to perform complex transversus abdominus release herniorrhaphy is revolutionizing MIS hernia repair.The final frontier for computer-enhanced surgery is the promise of telesurgery, in which the surgeon is a great distance from the patient (e.g., combat or space). This application has rarely been used, as the safety provided by having the surgeon at bedside cannot be sacrificed to prove the concept. However, remote laparoscopic cholecystectomy has been performed when a team of surgeons located in New York performed a cholecys-tectomy on a patient located in France.76Endoluminal and Endovascular SurgeryThe fields of vascular surgery, interventional radiology, neu-roradiology, gastroenterology, general surgery, pulmonology, and urology all encounter clinical scenarios that require the urgent restoration of luminal patency. Based on this need, fun-damental techniques have been pioneered that are applicable to all specialties and virtually every organ system. As a result, all minimally invasive surgical procedures, from coronary artery angioplasty to palliation of pancreatic malignancy, involve the use of access devices, catheters, guidewires, balloon dilators, stents, and other devices (e.g., lasers, atherectomy catheters) that are capable of opening up the occluded biologic cylinder77 (Table 14-2). Endoluminal balloon dilators may be inserted through an endoscope, or they may be fluoroscopically guided. Balloon dilators all have low compliance—that is, the balloons do not stretch as the pressure within the balloon is increased. The high pressures achievable in the balloon create radial expansion of the narrowed vessel or orifice, usually disrupting the atherosclerotic plaque, the fibrotic stricture, or the muscular band (e.g., esophageal achalasia).78Once the dilation has been attained, it is frequently ben-eficial to hold the lumen open with a stent.79 Stenting is particu-larly valuable in treating malignant lesions and atherosclerotic Figure 14-22. The deployment of a metal stent across an isolated vessel stenosis is illustrated. (Reproduced with permission from Hunter JG, Sackier JM, eds. Minimally Invasive Surgery. New York: McGraw-Hill; 1993:235.)GuidewireBalloonSheathBalloon with stentStent expandedStent in placeTable 14-2Modalities and techniques of restoring luminal patencyMODALITYTECHNIQUECore outPhotodynamic therapyLaserCoagulationEndoscopic biopsy forcepsChemicalUltrasoundFractureUltrasoundEndoscopic biopsyBalloonDilateBalloonBougieAngioplastyEndoscopeBypassTransvenous intrahepatic portosystemic shuntSurgical (synthetic or autologous conduit)StentSelf-expanding metal stentPlastic stentocclusions or aneurysmal disease (Fig. 14-22). Stenting is also of value to seal leaky cylinders, including aortic dissections, traumatic vascular injuries, leaking GI anastomoses, and fistu-las. Stenting usually is not applicable for long-term manage-ment of benign GI strictures except in patients with limited life expectancy (Fig. 14-23).79–81A variety of stents are available that are divided into six basic categories: plastic stents, metal stents, drug-eluting stents (to decrease fibrovascular hyperplasia), covered metal stents, anchored stent grafts, and removable covered plastic stents80 (Fig. 14-24). Plastic stents came first and are used widely as endoprostheses for temporary bypass of obstructions in the biliary or urinary systems. Metal stents generally are delivered over a balloon and expanded with the balloon to the desired size. These metal stents usually are made of titanium or niti-nol and are still used in coronary stenting. A chemotherapeutic agent was added to coronary stents several years ago to decrease endothelial proliferation. These drug-eluting stents provide greater long-term patency but require long-term anticoagula-tion with antiplatelet agents to prevent thrombosis.82 Coated metal stents are used to prevent tissue ingrowth. Ingrowth may Brunicardi_Ch14_p0453-p0478.indd 46901/03/19 4:59 PM 470BASIC CONSIDERATIONSPART IFigure 14-23. This is an esophagram in a patient with severe dys-phagia secondary to advanced esophageal cancer (A) before and (B) after placement of a covered self-expanding metal stent.ABFigure 14-24. Covered self-expanding metal stents. These devices can be placed fluoroscopically or endoscopically.be an advantage in preventing stent migration, but such tissue ingrowth may occlude the lumen and cause obstruction anew. This is a particular problem when stents are used for palliation of GI malignant growth and may be a problem for the long-term use of stents in vascular disease. Filling the interstices with Silastic or other materials may prevent tumor ingrowth but also makes stent migration more likely. In an effort to minimize stent migration, stents have been incorporated with hooks and barbs at the proximal end of the stent to anchor it to the wall of the vessel. Endovascular stenting of aortic aneurysms has nearly replaced open surgery for this condition. Lastly, self-expanding plastic stents have been developed as temporary devices to be used in the GI tract to close internal fistulas and bridge leaking anastomoses.Natural Orifice Transluminal Endoscopic SurgeryThe use of the flexible endoscope to enter the GI, urinary, or reproductive tracts and then traverse the wall of the structure to enter the peritoneal cavity, the mediastinum, or the chest has strong appeal to patients wishing to avoid scars and pain caused by abdominal wall trauma. In truth, transluminal surgery has been performed in the stomach for a long time, either from the inside out (e.g., percutaneous, PEG, and transgastric pseudocyst drainage) or from the outside in (e.g., laparoscopic-assisted intragastric tumor resection). The catalyz-ing events for NOTES were the demonstration that a porcine gallbladder could be removed with a flexible endoscope passed through the wall of the stomach and then removed through the mouth and the demonstration in a series of 10 human cases from India of the ability to perform transgastric appendectomy. Since that time, a great deal of money has been invested by endo-scopic and MIS companies to help surgeons and gastroenterolo-gists explore this new territory. Systemic inflammatory markers such as C-reactive protein, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 have been shown to be similar in transgastric and transcolonic NOTES when compared to laparoscopy in por-cine models.83 Concerns about the safety of transluminal access and limitations in equipment remain the greatest barriers to expansion. To date, the most headline-grabbing procedures have been the transvaginal and transgastric removal of the gallbladder84-86 (Fig. 14-25). To ensure safety, all human cases thus far have involved laparoscopic assistance to aid in retrac-tion and ensure adequate closure of the stomach or vagina. To date, thousands of transvaginal and transgastric procedures have been performed internationally, with two large registries dem-onstrating noninferiority to conventional laparoscopy.87 The fact that the vast majority of these procedures are being done trans-vaginally creates an obvious limitation in applicability.The rapid growth of endoscopic technology catalyzed by NOTES has already spun off new technologies capable of performing a wide variety of endoscopic surgical procedures from EMR, to ablation of Barrett’s esophagus, to creation of competent antireflux valves in patients with gastroesophageal reflux disease.Peroral esophageal myotomy (POEM) has shown promise as a NOTES treatment for esophageal achalasia.88 In this proce-dure, a 1.5to 2-cm mucosotomy is created within the anterior esophagus 10 cm proximal to the gastroesophageal junction. A submucosal tunnel is then created using a combination of elec-trocautery, hydrodissection, and carbon dioxide insufflation. The scope is advanced beyond the gastroesophageal junction, and a circular myotomy is performed avoiding disruption of the longitudinal fibers. The mucosotomy is then closed using endo-scopic clips (Fig. 14-26). Over 1000 clinical POEM cases have been performed worldwide. Data from expert NOTES surgeons suggest that this selective myotomy avoids abdominal trauma 4Brunicardi_Ch14_p0453-p0478.indd 47001/03/19 4:59 PM 471MINIMALLY INVASIVE SURGERYCHAPTER 14Figure 14-25. Transgastric cholecystectomy using natural orifice transluminal endoscopic surgery technology and one to three laparoscopic ports has been performed occasionally in several locations around the world. (Reproduced with permission from The Johns Hopkins University School of Medicine, Baltimore, MD; 2007. Illustration by Jennifer Fairman.)and minimally disrupts the normal anatomic characteristics of the gastroesophageal junction while providing significant relief of symptoms.89 Randomized clinical trials and long-term follow-up need to be performed to further evaluate efficacy.Although this application is still considered experimen-tal, there is little doubt that when equivalent operations can be performed with less pain, fewer scars, and less disability, patients will flock to it. NOTES procedures are associated with an increased mental workload and significant learning curve for even experienced surgical endoscopists. Surgeons should engage only when they can perform these procedures with the safety and efficacy demanded by our profession.Single-Incision Laparoscopic SurgeryAs a surgical technique, SILS seems to be a natural progression from conventional laparoscopic surgery. As surgeons sought to reduce the number and size of abdominal wall trocars and NOTES procedures necessitated laparoscopic surveillance, the idea of a hybridization took off. An incision in the umbilicus, a preexisting scar, is thought to be less painful, have fewer wound complications, lead to quicker return to activity, and have a bet-ter cosmetic appearance than conventional laparoscopy. Per-haps one of the earliest examples of SILS is the application of laparoscopic instrumentation to resect lesions in the rectum or sigmoid colon. Using the anus as the portal of entry, transanal endoscopic microsurgery (TEMS) employs a specialized mul-tichannel trocar to reach lesions located 8 to 18 cm away from the anal verge (Fig. 14-27).More deformable versions of these complex trocars have been developed with features to allow insufflation and be ame-nable to maintaining a seal within the natural orifice of the umbili-cus (see Fig. 14-11). Ports typically contain three or four channels. The latter often affords the ability to place a dedicated retractor.There are many challenges faced by the operating surgeon in SILS procedures. These include crowded trocar placement, a lack of triangulation of leftand right-hand instruments, fre-quent crossing or clashing of instruments, limited visualiza-tion, and limited retraction ability. These challenges are mitigated by surgeon’s experience and the development of specialized instruments. Articulating or curved instruments of varying lengths and an extended length can improve working space. Curved instruments are typically reusable and offer less clutter than their more sophisticated counterparts, providing some cost reduction (Fig. 14-28). A low-profile HD scope with or without a deflect-able tip can improve visualization greatly. Even with such instru-mentation, the learning curve is very steep, particularly when the surgeon is forced to work in a cross-handed technique. The accomplished SILS surgeon will possess a tool bag of innovative 5Brunicardi_Ch14_p0453-p0478.indd 47101/03/19 4:59 PM 472BASIC CONSIDERATIONSPART IFigure 14-28. Example of curved instruments used in single-incision laparoscopic surgery. (© 2013 Intuitive Surgical, Inc. Reprinted with permission.)Figure 14-26. A. Peroral endoscopic esophageal myotomy for the treatment of achalasia. (Reproduced with permission from Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myot-omy (POEM) for esophageal achalasia, Endoscopy. 2010 Apr; 42(4):265-271.) B. Serial images showing overtube in submuco-sal tunnel, using needle knife to divide circular muscle fibers of esophagus, and closure of myotomy with clips. (Reproduced with permission from Rieder E, Dunst CM, Kastenmeier AS, et al: Devel-opment and technique of per oral endoscopic myotomy (POEM) for achala, Eur Surg 2011 June;43(3):140–145.) ABFigure 14-27. Transanal endoscopic microsurgery scope. (Repro-duced with permission from The Johns Hopkins University School of Medicine, Baltimore, MD; 2014. Illustration by Corinne Sandone.)strategies to retract structures like the gallbladder away from the operative field. These tricks may range from the use of percutane-ous needlescopic instruments to the application of transfascial sutures. Expert consensus recommendations for efficient SILS are shown in Tables 14-3 and 14-4.8 When performing SILS proce-dures, it is imperative to follow proven tenets of operative con-duct such as visualizing the “critical view” of safety in a laparoscopic cholecystectomy. As safety should always be the paramount concern, the addition of extra trocars or conversion to traditional laparoscopy should not be considered a failure.Contraindications include those true of traditional lapa-roscopy. Relative contraindications include previous surgery and high body mass index (BMI). Patients with a high BMI or central obesity can pose a challenge because the umbilicus may be located far from operative target. Size and morphology of the target organ should always be considered when doing SILS.Many studies have demonstrated equivalency to standard laparoscopic procedures regarding intraoperative and postop-erative complications. However, it is questionable what the full benefit of the dramatic reduction in ergonomics and the increase in complexity provide beyond an improved cosmetic appear-ance. This is in large part due to the already improved benefits of laparoscopic surgery.A meta-analysis performed by Ahmed and colleagues in 2010 found the conversion rate from SILS to conventional lapa-roscopy to be 0% to 24% for cholecystectomies, 0% to 41% Table 14-3Expert panel recommendations for accomplishing single-incision laparoscopic surgery efficientlyMultichannel port preferably to be placed intraumbilically, but an extraumbilical approach can be used in certain casesExtra ports should be used where there is a clinical needWhen applicable, sutures can be useful for added retractionClosure should be accomplished using sutures of absorbable material placed either continuously or interruptedSkin should be closed with absorbable sutures or glueReproduced with permission from Ahmed I, Cianco F, Ferrar V, et al. Current status of single-incision laparoscopic surgery: European experts’ views, Surg Laparosc Endosc Percutan Tech. 2012 Jun;22(3):194-199.Brunicardi_Ch14_p0453-p0478.indd 47201/03/19 4:59 PM 473MINIMALLY INVASIVE SURGERYCHAPTER 14Figure 14-29. A and B. Robotic single-incision surgery platform. (©2013 Intuitive Surgical, Inc. Reprinted with permission.)ABTable 14-4Expert panel recommendations for single-incision laparoscopic surgery equipment and instrumentationRECOMMENDED EQUIPMENT/INSTRUMENTATIONBENEFIT TO SURGEONSlimline instruments with low-profile designReduces internal and external clashingVaried-length instrumentsReduces extracorporeal clashingLonger instrumentsAdvantageous for reaching the surgical fieldArticulating (or prebent) instrumentsRestore triangulationSmall-diameter, low-profile angle scopeReduces clashing by providing additional spaceHigh-definition cameraAchieves high-quality images for intraoperative visualizationReproduced with permission from Ahmed I, Cianco F, Ferrar V, et al. Current status of single-incision laparoscopic surgery: European experts’ views, Surg Laparosc Endosc Percutan Tech. 2012 Jun;22(3):194-199.for appendectomies, and 0% to 33% for nephrectomies.90 The most common complications were intra-abdominal abscesses and wound infections. Existing and emerging robotics platforms may provide the bridge necessary to bypass the significant tech-nical skills learning curve required to operate through a single site (Fig. 14-29).SPECIAL CONSIDERATIONSPediatric LaparoscopyThe advantages of MIS in children may be more significant than in the adult population. MIS in the adolescent is little dif-ferent from that in the adult, and standard instrumentation and trocar positions usually can be used. However, laparoscopy in the infant and young child requires specialized instrumentation. The instruments are shorter (15–20 cm), and many are 3 mm in diameter rather than 5 mm. Because the abdomen of the child is much smaller than that of the adult, a 5-mm telescope pro-vides sufficient illumination for most operations. The develop-ment of 5-mm clippers and bipolar devices has obviated the need for 10-mm trocars in pediatric laparoscopy.91 Because the abdominal wall is much thinner in infants, a pneumoperitoneum pressure of 8 mmHg can provide adequate exposure. DVT is rare in children, so prophylaxis against thrombosis probably is unnecessary. A wide variety of pediatric surgical procedures are frequently performed with MIS access, from pull-through procedures for colonic aganglionosis (Hirschsprung’s disease) to repair of congenital diaphragmatic hernias.92Laparoscopy During PregnancyConcerns about the safety of laparoscopic cholecystectomy or appendectomy in the pregnant patient have been thoroughly investigated and are readily managed. Access to the abdomen in the pregnant patient should take into consideration the height of the uterine fundus, which reaches the umbilicus at 20 weeks. In order not to damage the uterus or its blood supply, most surgeons feel that the open (Hasson) approach should be 6used in favor of direct puncture laparoscopy. The patient should be positioned slightly on the left side to avoid compression of the vena cava by the uterus. Because pregnancy poses a risk for thromboembolism, sequential compression devices are essential for all procedures. Fetal acidosis induced by maternal hypercar-bia also has been raised as a concern. The arterial pH of the fetus follows the pH of the mother linearly; and therefore, fetal acido-sis may be prevented by avoiding a respiratory acidosis in the mother.93 The pneumoperitoneum pressure induced by laparos-copy is not a safety issue either as it has been proved that mid-pregnancy uterine contractions provide a much greater pressure in utero than a pneumoperitoneum of 15 mmHg. More than 100 cases of laparoscopic cholecystectomy in pregnancy have been reported with uniformly good results.94 The operation should be performed during the second trimester of pregnancy if possible. Protection of the fetus against intraoperative X-rays Brunicardi_Ch14_p0453-p0478.indd 47301/03/19 4:59 PM 474BASIC CONSIDERATIONSPART Iis imperative. Some believe it advisable to track fetal pulse rates with a transvaginal ultrasound probe; however, the significance of fetal tachycardia or bradycardia is a bit unclear in the second trimester of pregnancy. To be prudent, however, heart rate decelerations reversibly associated with pneumoperitoneum cre-ation might signal the need to convert to open cholecystectomy or appendectomy.Minimally Invasive Surgery and Cancer TreatmentMIS techniques have been used for many decades to provide palliation for the patient with an obstructive cancer. Laser treat-ment, intracavitary radiation, stenting, and dilation are outpa-tient techniques that can be used to reestablish the continuity of an obstructed esophagus, bile duct, ureter, or airway. MIS techniques also have been used in the staging of cancer. Medias-tinoscopy is still used occasionally before thoracotomy to assess the status of the mediastinal lymph nodes. Laparoscopy also is used to assess the liver in patients being evaluated for pancre-atic, gastric, or hepatic resection. New technology and greater surgical skills allow for accurate minimally invasive staging of cancer.95 Occasionally, it is appropriate to perform pallia-tive measures (e.g., laparoscopic gastrojejunostomy to bypass a pancreatic cancer) at the time of diagnostic laparoscopy if diag-nostic findings preclude attempts at curative resection.Initially controversial, the role of MIS to provide a safe curative treatment of cancer has proven to be no different from the principles of open surgery. All gross and microscopic tumor should be removed (an R0 resection), and an ade-quate lymphadenectomy should be performed to allow accurate staging. Generally, this number has been 10 to 15 lymph nodes, although there is still debate as to the value of more extensive lymphadenectomy. All of the major abdominal cancer opera-tions have been performed with laparoscopy. Of the three major cancer resections of GI cancer (liver lobe, pancreatic head, and esophagus), only esophagectomy is routinely performed by a fair number of centers.96,97 Laparoscopic hepatectomy has attracted a loyal following, and distal pancreatectomy frequently is performed with laparoscopic access. In Japan, laparoscopic-assisted gastrectomy has become quite popular for early gastric cancer, an epidemic in Japan far exceeding that of colon cancer in North America and Northern Europe. The most common can-cer operation performed laparoscopically is segmental colec-tomy, which has proven itself safe and efficacious in a multicenter, controlled, randomized trial.98Considerations in the Elderly and InfirmLaparoscopic cholecystectomy has made possible the removal of a symptomatic gallbladder in many patients previously thought to be too elderly or too ill to undergo a laparotomy. Older patients are more likely to require conversion to lapa-rotomy because of disease chronicity.98Operations on these patients require close monitoring of anesthesia. The intraoperative management of these patients may be more difficult with laparoscopic access than with open access. The advantage of MIS lies in what happens after the operation. Much of the morbidity of surgery in the elderly is a result of impaired mobility. In addition, pulmonary compli-cations, urinary tract sepsis, DVT, pulmonary embolism, con-gestive heart failure, and myocardial infarction often are the result of improper fluid management and decreased mobility. By allowing rapid and early mobilization, laparoscopic surgery 7has made possible the safe performance of procedures in the elderly and infirm.Cirrhosis and Portal HypertensionPatients with hepatic insufficiency pose a significant challenge for any type of surgical intervention.99 The ultimate surgical out-come in this population relates directly to the degree of under-lying hepatic dysfunction.100 Often, this group of patients has minimal reserve, and the stress of an operation will trigger com-plete hepatic failure or hepatorenal syndrome. These patients are at risk for major hemorrhage at all levels, including trocar insertion, operative dissection in a field of dilated veins, and secondary to an underlying coagulopathy. Additionally, ascitic leak from a port site may occur, leading to bacterial peritonitis. Therefore, a watertight port site closure should be carried out in all patients.It is essential that the surgeon be aware of the severity of hepatic cirrhosis as judged by a Model of End-Stage Liver Dis-ease (MELD) score or Child’s classification. Additionally, the presence of portal hypertension is a relative contraindication to laparoscopic surgery until the portal pressures are reduced with portal decompression. For example, if a patient has an incarcer-ated umbilical hernia and ascites, a preoperative paracentesis or transjugular intrahepatic portosystemic shunt procedure in con-junction with aggressive diuresis may be considered. Because these patients commonly are intravascularly depleted, insuffla-tion pressures should be reduced to prevent a decrease in cardiac output, and minimal amounts of Na+-sparing IV fluids should be given.Economics of Minimally Invasive SurgeryMinimally invasive surgical procedures reduce the costs of sur-gery most when length of hospital stay can be shortened and return to work is quickened. For example, shorter hospital stays can be demonstrated in laparoscopic cholecystectomy, Nissen fundoplication, splenectomy, and adrenalectomy. Procedures such as inguinal herniorrhaphy that are already performed as outpatient procedures are less likely to provide cost savings. Procedures that still require a 4to 7-day hospitalization, such as laparoscopy-assisted colectomy, are less likely to deliver a lower bottom line than their open surgery counterparts. None-theless, with responsible use of disposable instrumentation and a commitment to the most effective use of the inpatient setting, most laparoscopic procedures can be made less expensive than their conventional equivalents.Education and Skill AcquisitionHistorically, surgeons in training (residents, registrars, and fel-lows) acquired their skills in minimally invasive techniques through a series of operative experiences of graded complexity. This training occurred on patients. Although such a paradigm did not compromise patient safety, learning in the OR is costly. In addition, the recent worldwide constraint placed on resident work hours makes it attractive to teach laparoscopic skills out-side of the OR.Skills labs started at nearly every surgical training center in the 1990s with low fidelity box-type trainers. These were rudimentary simulated abdominal cavities with a video camera, monitor, trocars, laparoscopic instruments, and target models. These targets were often as simple as a pegboard and rubber rings, or a latex drain to practice suturing and knot tying. Virtual reality training devices present a unique opportunity to improve and enhance experiential learning in endoscopy and laparoscopy Brunicardi_Ch14_p0453-p0478.indd 47401/03/19 4:59 PM 475MINIMALLY INVASIVE SURGERYCHAPTER 14Figure 14-30. The progress of general sur-gery can be reflected by a series of performance curves. General anesthesia and sterile technique allowed the development of maximally inva-sive open surgery over the last 125 years. Video optics allowed the development of minimally invasive surgery over the last 25 years. Nonin-vasive (seamless) surgery will result when a yet undiscovered transformational event allows sur-gery to occur without an incision, and perhaps without anesthesia.PerformanceGeneral anesthesiasterile techniqueVideo optics?1880190019201940196019801985199019952000??Open surgeryLaparoscopic surgerySeamless surgeryProgress in surgeryfor all surgeons. This technology has the advantage of enabling objective measurement of psychomotor skills, which can be used to determine progress in skill acquisition and, ultimately, techni-cal competency.101 Several of these devices have been validated as a means of measuring proficiency in skill performance. More importantly, training on virtual reality platforms has proven to translate to improved operative performance in randomized tri-als.102,103 Currently, surgical skills labs are mandatory for Resi-dency Review Committee credentialing. Successful completion of the Fundamentals of Laparoscopic Surgery (FLS) technical and cognitive examination became a mandatory prerequisite for the American Board of Surgery (ABS) qualification examination in general surgery in 2010. The Fundamentals of Endoscopic Surgery (FES) became a prerequisite to ABS qualification in 2015. In the future, institutions may require simulator training to document specific entrustable professional activities (EPA) related to laparoscopic procedures before privileging in the OR. A Fundamentals of Robotic Surgery (FRS) high stakes exam is on the horizon for future surgical trainees. The American Col-lege of Surgeons has taken a leadership position in accrediting skills labs across the world as American College of Surgeons–accredited educational institutes.TelementoringIn response to the Institute of Medicine’s call for the develop-ment of unique technologic solutions to deliver health care to rural and underserved areas, surgeons are beginning to explore the feasibility of telementoring. Teleconsultation or telemen-toring is two-way audio and visual communication between two geographically separated providers. This communication can take place in the office setting or directly in the OR when complex scenarios are encountered. Although local commu-nication channels may limit its performance in rural areas, the technology is available and currently is being used, espe-cially in states and provinces with large geographically remote populations.103Innovation and Introduction of New ProceduresThe revolution in minimally invasive general surgery, which occurred in 1990, created ethical challenges for the profession. The problem was this: If competence is gained from experience, how was the surgeon to climb the competence curve (otherwise known as the learning curve) without injuring patients? If it was indeed impossible to achieve competence without making mis-takes along the way, how should one effectively communicate this to patients such that they understand the weight of their decisions? Even more fundamentally important is determining the path that should be followed before one recruits the first patient for a new procedure.Although procedure development is fundamentally dif-ferent than drug development (i.e., there is great individual variation in the performance of procedures, but no difference between one tablet and the next), adherence to a process simi-lar to that used to develop a new drug is a reasonable path for a surgical innovator. At the outset, the surgeon must iden-tify the problem that is not solved with current surgical pro-cedures. For example, although the removal of a gallbladder through a Kocher incision is certainly effective, it creates a great deal of disability, pain, and scarification. As a result of those issues, many patients with very symptomatic biliary colic delayed operation until life-threatening complications occurred. Clearly, there was a need for developing a less inva-sive approach (Fig. 14-30).Once the opportunity has been established, the next step involves a search through other disciplines for technologies and techniques that might be applied. Again, this is analogous to the drug industry, where secondary drug indications have often turned out to be more therapeutically important than the primary indication for drug development. The third step is in vivo stud-ies in the most appropriate animal model. These types of studies are controversial because of the resistance to animal experimen-tation, and yet without such studies, many humans would be injured or killed during the developmental phase of medical drugs, devices, and techniques. These steps often are called the preclinical phase of procedure development.The decision as to when such procedures are ready to come out of the lab is a difficult one. Put simply, the proce-dure should be reproducible, provide the desired effect, and not have serious side effects. Once these three criteria are reached, the time for human application has arrived. Before the surgeon discusses the new procedure with patients, it is important to achieve full institutional support. Involvement of the medi-cal board, the chief of the medical staff, and the institutional review board is essential before commencing on a new proce-dure. These bodies are responsible for the use of safe, high-quality medical practices within their institution, and they will demand that great caution and all possible safeguards are in place before proceeding.The dialogue with the patient who is to be first must be thorough, brutally honest, and well documented. The psychology Brunicardi_Ch14_p0453-p0478.indd 47501/03/19 4:59 PM 476BASIC CONSIDERATIONSPART Ithat allows a patient to decide to be first is quite interesting, and may, under certain circumstances, require psychiatric evalua-tion. Certainly, if a dying cancer patient has a chance with a new drug, this makes sense. Similarly, if the standard surgical procedure has a high attendant morbidity and the new procedure offers a substantially better outcome, the decision to be first is understandable. On the other hand, when the benefits of the new approach are small and the risks are largely unknown, a more complete psychological profile may be necessary before proceeding.For new surgical procedures, it generally is wise to assemble the best possible operative team, including a surgeon experienced with the old technique, and assistants who have participated in the earlier animal work. This initial team of experienced physicians and nurses should remain together until full competence with the procedure is attained. This may take 10 procedures, or it may take 50 procedures. The team will know that it has achieved competence when the majority of procedures take the same length of time and the team is relaxed and sure of the flow of the operation. This will complete phase I of the procedure development.In phase II, the efficacy of the procedure is tested in a nonrandomized fashion. Ideally, the outcome of new techniques must be as good as or better than the procedure that is being replaced. This phase should occur at several medical centers to prove that good outcomes are achievable outside of the pioneer-ing institution. These same requirements may be applied to the introduction of new technology into the OR. The value equation requires that the additional measurable procedure quality exceeds the additional measurable cost to the patient or healthcare system. In phase III, a randomized trial pits the new procedure against the old.Once the competence curve has been climbed, it is appro-priate for the team to engage in the education of others. Dur-ing the ascension of the competence curve, other learners in the institution (i.e., surgical residents) may not have the opportunity to participate in the first case series. Although this may be dif-ficult for them, the best interest of the patient must be put before the education of the resident.The second stage of learning occurs when the new pro-cedure has proven its value and a handful of experts exist, but the majority of surgeons have not been trained to perform the new procedure. In this setting, it is relatively unethical for sur-geons to forge ahead with a new procedure in humans as if they had spent the same amount of time in intensive study that the first team did. The fact that one or several surgical teams were able to perform an operation does not ensure that all others with the same medical degrees can perform the operation with equal skill. It behooves the learners to contact the experts and request their assistance to ensure an optimal outcome at the new center. Although it is important that the learners contact the experts, it is equally important that the experts be willing to share their experience with their fellow professionals. As well, the experts should provide feedback to the learners as to whether they feel the learners are equipped to forge ahead on their own. If not, further observation and assistance from the experts are required. Although this approach may sound obvious, it is fraught with difficulties. In many situations, ego, competitiveness, and mon-etary concerns have short-circuited this process and led to poor patient outcomes. To a large extent, MIS has recovered from the black eye it received early in development, when inadequately trained surgeons caused an excessive number of significant complications.If innovative procedures and technologies are to be devel-oped and applied without the mistakes of the past, surgeons must be honest when they answer these questions: Is this procedure safe? Would I consider undergoing this procedure if I developed a surgical indication? Is the procedure as good as or better than the procedure it is replacing? Do I have the skills to apply this procedure safely and with equivalent results to the more expe-rienced surgeon? Answering these questions in the affirmative should be a professional obligation. A negative response should motivate the surgeon to seek an alternative procedure or outside assistance before subjecting a patient to the new procedure.REFERENCESEntries highlighted in bright blue are key references. 1. Hopkins HH. Optical principles of the endoscope. 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J Am Coll Surg. 1997;185(1):33-39. 96. Luketich JD, Alvelo-Rivera M, Buenaventura PO, et al. Mini-mally invasive esophagectomy: outcomes in 222 patients. Ann Surg. 2003;238(4):486-494; discussion 494. 97. Fleshman J, Sargent DJ, Green E, for the Clinical Out-comes of Surgical Therapy Study Group. Laparoscopic col-ectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg. 2007;246(4):655-662; discussion 662. 98. Fried GM, Clas D, Meakins JL. Minimally invasive surgery in the elderly patient. Surg Clin North Am. 1994;74(2):375-387. 99. Borman PC, Terblanche J. Subtotal cholecystectomy: for the difficult gallbladder in portal hypertension and cholecystitis. Surgery. 1985;98(1):1-6. 100. Litwin DWM, Pham Q. Laparoscopic surgery in the compli-cated patient. In: Eubanks WS, Swanstrom LJ, Soper NJ, eds. Mastery of Endoscopic and Laparoscopic Surgery. Philadelphia: Lippincott, Williams & Wilkins; 2000:57. 101. Gallagher AG, Smith CD, Bowers SP, et al. Psychomotor skills assessment in practicing surgeons experienced in per-forming advanced laparoscopic procedures. J Am Coll Surg. 2003;197(3):479-488. 102. Seymour NE, Gallagher AG, Roman SA, et al. Virtual real-ity training improves operating room performance: results of a randomized, double-blinded study. Ann Surg. 2002;236(4): 458-463; discussion 463. 103. Anvari M. Telesurgery: remote knowledge translation in clinical surgery. World J Surg. 2007;31(8):1545-1550.Brunicardi_Ch14_p0453-p0478.indd 47801/03/19 4:59 PM

Molecular Biology, The Atomic Theory of Disease, and Precision SurgeryXin-Hua Feng, Xia Lin, Xinran Li, Juehua Yu, John Nemunaitis, and F. Charles Brunicardi 15chapterOVERVIEW OF MOLECULAR CELL BIOLOGYThe beginning of modern medicine can be traced back to centu-ries ago when physicians and scientists began studying human anatomy from cadavers in morgues and animal physiology fol-lowing hunting expeditions. Gradually, from the study of ani-mals and plants in greater detail and the discovery of microbes, scientific principles governing life led to the emergence of the biologic sciences. As biologic science developed and expanded, scientists and physicians began to utilize its principles to solve challenges of human diseases while continuing to explore the fundamentals of life in greater detail. With ever-evolving state-of-the-art scientific tools, our understanding of how cells, tis-sues, organs, and entire organisms function, down to the level of molecular and subatomic structure, has resulted in modern biology with an enormous impact on modern healthcare and the discovery of amazing treatments for disease at an exponential pace. Significant progress has been made in molecular studies of organ development, cell signaling, and gene regulation. The advent of recombinant DNA technology, polymerase chain reac-tion (PCR) techniques, and next-generation genomic sequenc-ing, which resulted in the sequencing of the human genome, holds the potential to have a transformational influence on healthcare and society this century by not only broadening our understanding of the pathophysiology of disease, but also by bringing about necessary changes in personalized medicine.Today’s practicing surgeons are becoming increasingly aware that many modern surgical procedures rely on the infor-mation gained through molecular research (i.e., precision surgery). Genomic information, such as deleterious BRCA and RET proto-oncogene mutations, is being used to help direct prophylactic procedures to remove potentially harmful tissues before they do damage to patients. Molecular engineering has led to cancer-specific gene therapy that could serve in the near future as a more effective adjunct to surgical debulking of tumors than radiation or chemotherapy, so surgeons will benefit from a clear introduction to how basic biochemical and biologic principles relate to the developing area of molecular biology. This chapter reviews the current information on modern molecular biology for the surgical community.Basic Concepts of Molecular ResearchThe modern era of molecular biology, which has been mainly concerned with how genes govern cell activity, began in 1953 when James D. Watson and Francis H. C. Crick made one of the greatest scientific discoveries by deducing the double-helical structure of deoxyribonucleic acid (DNA).1,2 The year 2003 marked the 50th anniversary of this great discovery. In the same year, the Human Genome Project completed with sequencing approximately 20,000 to 25,000 genes and 3 billion base pairs in human DNA.3 Before 1953, one of the most mysterious aspects of biology was how genetic material was precisely duplicated from one generation to the next. Although DNA had been implicated as genetic material, it was the base-paired structure of DNA that provided a logical inter-pretation of how a double helix could “unzip” to make copies of itself. This DNA synthesis, termed replication, immediately gave rise to the notion that a template was involved in the trans-fer of information between generations, and thus confirmed the suspicion that DNA carried an organism’s hereditary information.Within cells, DNA is packed tightly into chromosomes. One important feature of DNA as genetic material is its abil-ity to encode important information for all of a cell’s functions (Fig. 15-1). Based on the principles of base complementarity, scientists also discovered how information in DNA is accurately transferred into the protein structure. DNA serves as a template for RNA synthesis, termed transcription, including messenger RNA (mRNA, or the protein-encoding RNA), ribosomal RNA (rRNA), and transfer RNA (tRNA). mRNA carries the informa-tion from DNA to make proteins, termed translation, with the assistance of rRNA and tRNA. Each of these steps is precisely 12Overview of Molecular Cell  Biology 479Basic Concepts of Molecular Research /479Molecular Approaches to Surgical Research /480Fundamentals of Molecular  and Cell Biology 480DNA and Heredity /480Gene Regulation /481Human Genome /485Cell Cycle and Apoptosis /486Signal Transduction Pathways /487Gene Therapy and Molecular Drugs in Cancer /490Stem Cell Research /492The Atomic Theory of Disease /493Technologies of Molecular  and Cell Biology 493DNA Cloning /493Detection of Nucleic Acids and Proteins /494Cell Manipulations /499Genetic Manipulations /500Precision Medicine and Surgery /505Targeted Genome Editing Using the CRISPR-Cas9 System /506Brunicardi_Ch15_p0479-p0510.indd 47918/02/19 11:12 AM 480Figure 15-1. The flow of genetic information from DNA to pro-tein to cell functions. The process of transmission of genetic infor-mation from DNA to RNA is called transcription, and the process of transmission from RNA to protein is called translation. Proteins are the essential controlling components for cell structure, cell sig-naling, and metabolism. Genomics and proteomics are the study of the genetic composition of a living organism at the DNA and pro-tein level, respectively. The study of the relationship between genes and their cellular functions is called functional genomics.Key Points1 The biologic sciences have developed drastically in the last 66 years after the uncovering of DNA structure by Watson and Crick.2 The completion of the human genome sequence in 2003 rep-resents a great milestone in modern science.3 The technology emerging from molecular and cellular biol-ogy has revolutionized the understanding of disease and will radically transform the practice of surgery.4 The use of genetically modified mouse models and cell lines using gene therapy and RNA interference therapy has greatly contributed to the understanding of the molecular basis for human diseases and targeted therapies.5 The sequencing of each individual’s genome has the poten-tial to improve the predication, prevention, and targeted treatment of disease, resulting in precision medicine and surgery.6 Fast-developing targeted genome editing tools like the CRISPR-Cas9 system greatly facilitate biomedical research in native conditions and have shown their potential in the treatment of genetic diseases, including cancers, with a high degree of personalization and precision.7 The use of functional genomics and modern molecular anal-yses will facilitate the discovery of actionable genes to guide choice of care, including precision surgery.GenomicsProteomicsFunctionalgenomicsDNA RNAProteinsTranscriptionTranslationStructureMetabolismSignalingCell functionscontrolled in such a way that genes are properly expressed in each cell at a specific time and location. In recent years, new classes of noncoding RNAs (ncRNA), for example, microRNA (or miRNA), piwi-interacting RNA (or piRNA), and long inter-genic noncoding RNA (or lincRNA), have been identified. Although the number of ncRNAs encoded in the human genome is unknown and a lot of ncRNAs have not been validated for their functions, ncRNAs have been associated to regulate gene expression through posttranscriptional gene regulation such as mRNA degradation or epigenetic regulation such as chromatin structure modification and DNA methylation induction.4 Con-sequently, the differential gene activity in a cell determines its actions, properties, and functions.Molecular Approaches to Surgical ResearchRapid advances in molecular and cellular biology over the past half century have revolutionized the understanding of disease and will radically transform the practice of surgery. In the future, molecular techniques will be increasingly applied to surgical disease and will lead to new strategies for the selection and implementation of operative therapy. Surgeons should be familiar with the fundamental principles of molecular and cel-lular biology so that emerging scientific breakthroughs can be translated into improved care of the surgical patient.The greatest advances in the field of molecular biology have been in the areas of analysis and manipulation of DNA.1 Since Watson and Crick’s discovery of DNA structure, an inten-sive effort has been made to unlock the deepest biologic secrets of DNA. Among the avalanche of technical advances, one dis-covery in particular has drastically changed the world of molec-ular biology: the uncovering of the enzymatic and microbiologic techniques that produce recombinant DNA. Recombinant DNA technology involves the enzymatic manipulation of DNA and, subsequently, the cloning of DNA. DNA molecules are cloned for a variety of purposes including safeguarding DNA samples, facilitating sequencing, generating probes, and expressing recombinant proteins in one or more host organisms. DNA can be produced by a number of means, including restricted diges-tion of an existing vector, PCR, and cDNA synthesis. As DNA cloning techniques have developed over the last quarter cen-tury, researchers have moved from studying DNA to studying the functions of proteins, and from cell and animal models to molecular therapies in humans. Expression of recombinant pro-teins provides a method for analyzing gene regulation, structure, and function. In recent years, the uses for recombinant proteins have expanded to include a variety of new applications, includ-ing gene therapy and biopharmaceuticals. The basic molecular approaches for modern surgical research include DNA cloning, cell manipulation, disease modeling in animals, and clinical tri-als in human patients.FUNDAMENTALS OF MOLECULAR AND CELL BIOLOGYDNA and HeredityDNA forms a right-handed, double-helical structure that is composed of two antiparallel strands of unbranched polymeric deoxyribonucleotides linked by phosphodiester bonds between the 5′ carbon of one deoxyribose moiety to the 3′ carbon of the next (Fig. 15-2). DNA is composed of four types of deoxyribo-nucleotides: adenine (A), cytosine (C), guanine (G), and thy-mine (T). The nucleotides are joined together by phosphodiester bonds. In the double-helical structure deduced by Watson and Crick, the two strands of DNA are complementary to each other. Brunicardi_Ch15_p0479-p0510.indd 48018/02/19 11:12 AM 481MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15Building blocks of DNAGTGGCCTAAA5'3'3'5'ATCGATGGCCTAGGCTTA3'5'5'3'5'3'GGGCTADNA strandCAGGCCTTTASugarphosphatePhosphateSugarBaseDouble-stranded DNADNA double helixSugar-phosphatebackboneHydrogen-bondedpairs+NucleotideFigure 15-2. Schematic representation of a DNA molecule form-ing a double helix. DNA is made of four types of nucleotides, which are linked covalently into a DNA strand. A DNA molecule is composed of two DNA strands held together by hydrogen bonds between the pair bases. The arrowheads at the ends of the DNA strands indicate the polarities of the two strands, which run anti-parallel to each other in the DNA molecule. The diagram at the bottom left of the figure shows the DNA molecule straightened out. In reality, the DNA molecule is twisted into a double helix, of which each turn of DNA is made up of 10.4 nucleotide pairs, as shown on the right.Because of size, shape, and chemical composition, A always pairs with T, and C with G, through the formation of hydrogen bonds between complementary bases that stabilize the double helix.Recognition of the hereditary transmission of genetic information is attributed to the Austrian monk, Gregor Mendel. His seminal work, ignored upon publication until its rediscovery in 1900, established the laws of segregation and of independent assortment. These two principles established the existence of paired elementary units of heredity and defined the statistical laws that govern them.5 DNA was isolated in 1869, and a number of important observations of the inherited basis of certain dis-eases were made in the early part of the 20th century. Although today it appears easy to understand how DNA replicates, before the 1950s the idea of DNA as the primary genetic material was not appreciated. The modern era of molecular biology began in 1944 with the demonstration that DNA was the substance that carried genetic information. The first experimental evidence that DNA was genetic material came from simple transforma-tion experiments conducted in the 1940s using Streptococcus pneumoniae. One strain of the bacteria could be converted into another by incubating it with DNA from the other, just as the treatment of the DNA with deoxyribonuclease would inactivate the transforming activity of the DNA. Similarly, in the early 1950s, before the discovery of the double-helical structure of DNA, the entry of viral DNA and not the protein into the host bacterium was believed to be necessary to initiate infection by the bacterial virus or bacteriophage. Key historical events con-cerning genetics are outlined in Table 15-1.For cells to pass on the genetic material (DNA) to each progeny, the amount of DNA must be doubled. Watson and Crick recognized that the complementary base-pair structure of DNA implied the existence of a template-like mechanism for the copying of genetic material.1 The transfer of DNA material from the mother cell to daughter cells takes place during somatic cell division (also called mitosis). Before a cell divides, DNA must be precisely duplicated. During replication, the two strands of DNA separate, and each strand creates a new complementary strand by precise base-pair matching (Fig. 15-3). The two, new, double-stranded DNAs carry the same genetic information, which can then be passed on to two daughter cells. Proofread-ing mechanisms ensure that the replication process occurs in a highly accurate manner. The fidelity of DNA replication is absolutely crucial to maintaining the integrity of the genome from generation to generation. However, mistakes can still occur during this process, resulting in mutations, which may lead to a change of the DNA’s encoded protein and, consequently, a change of the cell’s behavior. The reliable dependence of many features of modern organisms on subtle changes in genome is linked to Mendelian inheritance and also contributes to the pro-cesses of Darwinian evolution. In addition, massive changes, so-called genetic instability, can occur in the genome of somatic cells such as cancer cells.Gene RegulationLiving cells have the necessary machinery to enzymatically transcribe DNA into RNA and translate the mRNA into pro-tein. This machinery accomplishes the two major steps required for gene expression in all organisms: transcription and trans-lation (Fig. 15-4). However, gene regulation is far more com-plex, particularly in eukaryotic organisms. For example, many gene transcripts must be spliced to remove the intervening sequences. The sequences that are spliced off are called introns, which appear to be useless, but in fact may carry some regula-tory information. The sequences that are joined together, and are eventually translated into protein, are called exons. Additional regulation of gene expression includes modification of mRNA, control of mRNA stability, and its nuclear export into cytoplasm (where it is assembled into ribosomes for translation). After mRNA is translated into protein, the levels and functions of the proteins can be further regulated posttranslationally. However, the following sections will mainly focus on gene regulation at transcriptional and translational levels.Transcription. Transcription is the enzymatic process of RNA synthesis from DNA.6 In bacteria, a single RNA polymerase carries out all RNA synthesis, including that of mRNA, rRNA, Brunicardi_Ch15_p0479-p0510.indd 48118/02/19 11:12 AM 482BASIC CONSIDERATIONSPART IFigure 15-3. DNA replication. As the nucleotide A only pairs with T, and G with C, each strand of DNA can determine the nucleotide sequence in its complementary strand. In this way, double-helical DNA can be copied precisely.Table 15-1Historical events in genetics and molecular biologyYEARINVESTIGATOREVENT1865MendelLaws of genetics established1869MiescherDNA isolated1905GarrodHuman inborn errors of metabolism1913SturtevantLinear map of genes1927MullerX-rays cause inheritable genetic damage1928GriffithTransformation discovered1941Beadle and Tatum“One gene, one enzyme” concept1944Avery, MacLeod, McCartyDNA as material of heredity1950McKlintockExistence of transposons confirmed1953Watson and CrickDouble-helical structure of DNA1957Benzer and KornbergRecombination and DNA polymerase1966Nirenberg, Khorana, HolleyGenetic code determined1970Temin and BaltimoreReverse transcriptase1972Cohen, Boyer, BergRecombinant DNA technology1975SouthernTransfer of DNA fragments from sizing gel to nitrocellulose (Southern blot)1977Sanger, Maxim, GilbertDNA sequencing methods1982—GenBank database established1985MullisPolymerase chain reaction1986—Automated DNA sequencing1989CollinsCystic fibrosis gene identified by positional cloning and linkage analysis1990—Human Genome Project initiated1997Roslin InstituteMammalian cloning (Dolly)2001IHGSC and Celera GenomicsDraft versions of human genome sequence published2003—Human Genome Project completedIHGSC = International Human Genome Sequencing Consortium.GTGGCCTAAACAGGCCTTTACAGGCCTTTAGTGGCCTAAACAGGCCTTTAGTGGCCTAAAS strandS strandNew S strandNew S strandTemplate S strandTemplate S strand5'3'3'5'5'5'5'5'3'3'3'Parent DNA double helix (shown flat):3'DNA is a template for its own duplicationBrunicardi_Ch15_p0479-p0510.indd 48218/02/19 11:12 AM 483MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15NucleusCytoplasmDNARNAtranscriptmRNAmRNAProteinActiveproteinmRNAturnoverProteinturnoverTranscriptionRNAtransportTranscriptionalcontrolPosttranscriptionalcontrolTranslationalcontrolPosttranslationalcontrolNuclear envelopeRNAdegradationProteindegradationPosttranslationalmodificationTranslationRNAprocessingFigure 15-4. Four major steps in the control of eukaryotic gene expression. Transcriptional and posttranscriptional control determine the level of messenger RNA (mRNA) that is available to make a protein, while translational and posttranslational control determine the final outcome of functional proteins. Note that posttranscriptional and posttranslational controls consist of several steps.and tRNA. Transcription often is coupled with translation in such a way that an mRNA molecule is completely accessible to ribosomes, and bacterial protein synthesis begins on an mRNA molecule even while it is still being synthesized. Therefore, a discussion of gene regulation with a look at the simpler prokary-otic system precedes that of the more complex transcription and posttranscriptional regulation of eukaryotic genes.Transcription in Bacteria Initiation of transcription in pro-karyotes begins with the recognition of DNA sequences by RNA polymerase. First, the bacterial RNA polymerase cata-lyzes RNA synthesis through loose binding to any region in the double-stranded DNA and then through specific binding to the promoter region with the assistance of accessory pro-teins called σ factors (sigma factors). A promoter region is the DNA region upstream of the transcription initiation site. RNA polymerase binds tightly at the promoter sites and causes the double-stranded DNA structure to unwind. Consequently, few nucleotides can be base-paired with the DNA template to begin transcription. Once transcription begins, the σ factor is released. The growing RNA chain may begin to peel off as the chain elongates. This occurs in such a way that there are always about 10 to 12 nucleotides of the growing RNA chains that are base-paired with the DNA template.The bacterial promoter contains a region of about 40 bases that include two conserved elements called –35 region and –10 region. The numbering system begins at the initiation site, which is designated +1 position, and counts backward (in nega-tive numbers) on the promoter and forward on the transcribed region. Although both regions on different promoters are not the same sequences, they are fairly conserved and very similar. This conservation provides the accurate and rapid initiation of transcription for most bacterial genes. It is also common in bac-teria that one promoter serves to transcribe a series of clustered genes, called an operon. A single transcribed mRNA contains a series of coding regions, each of which is later independently translated. In this way, the protein products are synthesized in a coordinated manner. Most of the time, these proteins are involved in the same metabolic pathway, thus demonstrating that the control by one operon is an efficient system. After ini-tiation of transcription, the polymerase moves along the DNA to elongate the chain of RNA, although at a certain point, it will stop. Each step of RNA synthesis, including initiation, elongation, and termination, will require the integral functions of RNA polymerase as well as the interactions of the poly-merase with regulatory proteins.Transcription in Eukaryotes Transcription mechanisms in eukaryotes differ from those in prokaryotes. The unique features of eukaryotic transcription are as follows: (a) Three separate RNA polymerases are involved in eukaryotes: RNA polymerase I transcribes the precursor of 5.8S, 18S, and 28S rRNAs; RNA polymerase II synthesizes the precursors of mRNA as well as microRNA; and RNA polymerase III makes tRNAs and 5S rRNAs. (b) In eukaryotes, the initial transcript is often the pre-cursor to final mRNAs, tRNAs, and rRNAs. The precursor is then modified and/or processed into its final functional form. RNA splicing is one type of processing to remove the noncoding introns (the region between coding exons) on an mRNA. (c) In contrast to bacterial DNA, eukaryotic DNA often is packaged with histone and nonhistone proteins into chromatins. Transcrip-tion will only occur when the chromatin structure changes in such a way that DNA is accessible to the polymerase. (d) RNA is made in the nucleus and transported into cytoplasm, where translation occurs. Therefore, unlike bacteria, eukaryotes undergo uncoupled transcription and translation.Eukaryotic gene transcription also involves the recogni-tion and binding of RNA polymerase to the promoter DNA. However, the interaction between the polymerase and DNA is far more complex in eukaryotes than in prokaryotes. Because the majority of studies have been focused on the regulation and functions of proteins, this chapter primarily focuses on how protein-encoding mRNA is made by RNA polymerase II.Translation. DNA directs the synthesis of RNA; RNA in turn directs the synthesis of proteins. Proteins are variable-length polypeptide polymers composed of various combinations of 20 different amino acids and are the working molecules of the cell. The process of decoding information on mRNA to synthesize proteins is called translation (see Fig. 15-1). Translation takes place in ribosomes composed of rRNA and ribosomal proteins. The numerous discoveries made during the 1950s made it easy to understand how DNA replication and transcription involve base-pairing between DNA and DNA or DNA and RNA. How-ever, at that time, it was still impossible to comprehend how mRNA transfers the information to the protein-synthesizing machinery. The genetic information on mRNA is composed of Brunicardi_Ch15_p0479-p0510.indd 48318/02/19 11:12 AM 484BASIC CONSIDERATIONSPART ITable 15-2The genetic codeSECOND BASE IN CODON  U  C  A  G    First Base in CodonUUUUPhe[F]UCUSer[S]UAUTyr[Y]UGUCys[C]UThird Base in Codon  UUCPhe[F]UCCSer[S]UACTyr[Y]UGCCys[C]C   UUALeu[L]UCASer[S]UAASTOP—UGASTOP—A   UUGLeu[L]UCGSer[S]UAGSTOP—UGGTrp[W]G  CCUULeu[L]CCUPro[P]CAUHis[H]CGUArg[R]U   CUCLeu[L]CCCPro[P]CACHis[H]CGCArg[R]C   CUALeu[L]CCAPro[P]CAAGln[Q]CGAArg[R]A   CUGLeu[L]CCGPro[P]CAGGln[Q]CGGArg[R]G  AAUUIle[I]ACUThr[T]AAUAsn[N]AGUSer[S]U   AUCIle[I]ACCThr[T]AACAsn[N]AGCSer[S]C   AUAIle[I]ACAThr[T]AAALys[K]AGAArg[R]A   AUGMet[M]ACGThr[T]AAGLys[K]AGGArg[R]G  GGUUVal[V]GCUAla[A]GAUAsp[D]GGUGly[G]U   GUCVal[V]GCCAla[A]GACAsp[D]GGCGly[G]C   GUAVal[V]GCAAla[A]GAAGlu[E]GGAGly[G]A   GUGVal[V]GCGAla[A]GAGGlu[E]GGGGly[G]G A = adenine; C = cytosine; G = guanine; U = uracil; Ala = alanine; Arg = arginine; Asn = asparagine; Asp = aspartic acid; Cys = cysteine; Glu = glutamic acid; Gln = glutamine; Gly = glycine; His = histidine; Ile = isoleucine; Leu = leucine; Lys = lysine; Met = methionine; Phe = phenylalanine; Pro = proline; Ser = serine; Thr = threonine; Trp = tryptophan; Tyr = tyrosine; Val = valine. Letter in [ ] indicates single letter code for amino acid.arranged sequences of four bases that are transferred to the lin-ear arrangement of 20 amino acids on a protein. Amino acids are characterized by a central carbon unit linked to four side chains: an amino group (–NH2), a carboxy group (–COOH), a hydrogen, and a variable (–R) group. The amino acid chain is assembled via peptide bonds between the amino group of one amino acid and the carboxy group of the next. Because of this decoding, the information carried on mRNA relies on tRNA. Translation involves all three RNAs. The precise transfer of information from mRNA to protein is governed by genetic code, the set of rules by which codons are translated into an amino acid (Table 15-2). A codon, a triplet of three bases, codes for one amino acid. In this case, random combinations of the four bases form 4 × 4 × 4, or 64 codes. Because 64 codes are more than enough for 20 amino acids, most amino acids are coded by more than one codon. The start codon is AUG, which also corresponds to methionine; therefore, almost all proteins begin with this amino acid. The sequence of nucleotide triplets that follows the start codon signal is termed the reading frame. The codons on mRNA are sequentially recognized by tRNA adaptor proteins. Specific enzymes termed aminoacyl-tRNA synthetases link a specific amino acid to a specific tRNA. The translation of mRNA to protein requires the ribosomal complex to move step-wise along the mRNA until the initiator methionine sequence is identified. In concert with various protein initiator factors, the methionyl-tRNA is positioned on the mRNA and protein synthesis begins. Each new amino acid is added sequentially by the appropriate tRNA in conjunction with proteins called elongation factors. Protein synthesis proceeds in the amino-to-carboxy-terminus direction.The biologic versatility of proteins is astounding. Among many other functions, proteins serve as enzymes that catalyze critical biochemical reactions, carry signals to and from the extracellular environment, and mediate diverse signaling and regulatory functions in the intracellular environment. They also transport ions and various small molecules across plasma mem-branes. Proteins make up the key structural components of cells and the extracellular matrix and are responsible for cell motility. The unique functional properties of proteins are largely deter-mined by their structure (Fig. 15-5).Regulation of Gene Expression. The human organism is made up of a myriad of different cell types that, despite their vastly different characteristics, contain the same genetic mate-rial. This cellular diversity is controlled by the genome and is accomplished by tight regulation of gene expression. This leads to the synthesis and accumulation of different complements of RNA and, ultimately, to the proteins found in different cell types. For example, muscle and bone express different genes or the same genes at different times. Moreover, the choice of which genes are expressed in a given cell at a given time depends on signals received from its environment. There are multiple levels at which gene expression can be controlled along the pathway from DNA to RNA to protein (see Fig. 15-4). Transcriptional control refers to the mechanism for regulating when and how often a gene is transcribed. Splicing of the primary RNA tran-script (RNA processing control) and selection of completed Brunicardi_Ch15_p0479-p0510.indd 48418/02/19 11:12 AM 485MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15Figure 15-5. Maturation of a functional protein. Although the lin-ear amino acid sequence of a protein often is shown, the function of a protein also is controlled by its correctly folded three-dimensional structure. In addition, many proteins also have covalent posttransla-tional modifications such as phosphorylation or noncovalent bind-ing to a small molecule or a protein.Unfolded inactive proteinFolded inactive protein Mature inactive proteinBinding proteinPosttranslationalmodification(e.g., phosphorylation)PCofactor bindingmRNAs for nuclear export (RNA transport control) represent additional potential regulatory steps. The mRNAs in the cyto-plasm can be selectively translated by ribosomes (translational control) or selectively stabilized or degraded (mRNA degrada-tion control). Finally, the resulting proteins can undergo selec-tive activation, inactivation, or compartmentalization (protein activity control).Because a large number of genes are regulated at the tran-scriptional level, regulation of gene transcripts (i.e., mRNA) often is referred to as gene regulation in a narrow definition. Each of the steps during transcription is properly regulated in eukaryotic cells. Because genes are differentially regulated from one another, one gene can be differentially regulated in differ-ent cell types or at different developmental stages. Therefore, gene regulation at the level of transcription is largely context dependent. However, there is a common scheme that applies to transcription at the molecular level (Fig. 15-6). Each gene promoter possesses unique sequences called TATA boxes that can be recognized and bound by a large complex containing RNA polymerase II, forming the basal transcription machinery. Usually located upstream of the TATA box (but sometimes lon-ger distances) are a number of regulatory sequences referred to as enhancers that are recognized by regulatory proteins called transcription factors. These transcription factors specifically bind to the enhancers, often in response to environmental or developmental cues, and cooperate with each other and with basal transcription factors to initiate transcription. Regulatory sequences that negatively regulate the initiation of transcription also are present on the promoter DNA. The transcription factors that bind to these sites are called repressors, in contrast to the activators that activate transcription. The molecular interactions Figure 15-6. Transcriptional control by RNA polymerase. DNA is packaged into a chromatin structure. TATA = the common sequence on the promoter recognized by TBP and polymerase II holoenzyme; TBP = TATA-binding protein and associated factors; TF = hypothetical transcription factor; TFBS = transcription factor binding site; ball-shaped structures = nucleosomes. Coactivator or corepressor is a factor linking the TF with the Pol II complex.TFCoactivator orCorepressorPol IIHoloenzymeTBPTBPTATATFBSbetween transcription factors and promoter DNA, as well as between the cooperative transcription factors, are highly regu-lated and context-dependent. Specifically, the recruitment of transcription factors to the promoter DNA occurs in response to physiologic signals. A number of structural motifs in these DNA-binding transcription factors facilitate this recognition and interaction. These include the helix-turn-helix, the homeodo-main motif, the zinc finger, the leucine zipper, and the helix-loop-helix motifs.Human GenomeGenome is a collective term for all genes present in one organ-ism. The human genome contains DNA sequences of 3 billion base pairs, carried by 23 pairs of chromosomes. The human genome has an estimated 25,000 to 30,000 genes, and overall it is 99.9% identical in all people.7,8 Approximately 3 million locations where single-base DNA differences exist have been identified and termed single nucleotide polymorphisms. Single nucleotide polymorphisms may be critical determinants of human variation in disease susceptibility and responses to envi-ronmental factors.The completion of the human genome sequence in 2003 represented another great milestone in modern science. The Human Genome Project created the field of genomics, which is the study of genetic material in detail (see Fig. 15-1). The medical field is building on the knowledge, resources, and technologies emanating from the human genome to further the understanding of the relationship of the genes and their muta-tions to human health and disease. This expansion of genomics into human health applications resulted in the field of genomic medicine.The emergence of genomics as a science will transform the practice of medicine and surgery in this century. This break-through has allowed scientists the opportunity to gain remarkable insights into the lives of humans. Ultimately, the goal is to use this information to develop new ways to treat, cure, or even prevent the thousands of diseases that afflict humankind. In the 21st century, work will begin to incorporate the information embedded in the human genome sequence into surgical practices. By doing so, the genomic information can be used for diagnosing and predicting disease and disease suscep-tibility. Diagnostic tests can be designed to detect errant genes in patients suspected of having particular diseases or of being at risk for developing them. Furthermore, exploration into the function of each human gene is now possible, which will shed 3Brunicardi_Ch15_p0479-p0510.indd 48518/02/19 11:12 AM 486BASIC CONSIDERATIONSPART Ilight on how faulty genes play a role in disease causation. This knowledge also makes possible the development of a new gen-eration of therapeutics based on genes. Drug design is being revolutionized as researchers create new classes of medicines based on a reasoned approach to the use of information on gene sequence and protein structure function rather than the tradi-tional trial-and-error method. Drugs targeted to specific sites in the body promise to have fewer side effects than many of today’s medicines. Finally, other applications of genomics will involve the transfer of genes to replace defective versions or the use of gene therapy to enhance normal functions such as immunity.Proteomics refers to the study of the structure and expression of proteins as well as the interactions among pro-teins encoded by a human genome (see Fig. 15-1).9 A num-ber of Internet-based repositories for protein sequences exist, including Swiss-Prot (www.expasy.ch). These databases allow comparisons of newly identified proteins with previously char-acterized sequences to allow prediction of similarities, identifi-cation of splice variants, and prediction of membrane topology and posttranslational modifications. Tools for proteomic profil-ing include two-dimensional gel electrophoresis, time-of-flight mass spectrometry, matrix-assisted laser desorption/ionization, and protein microarrays. Structural proteomics aims to describe the three-dimensional structure of proteins that is critical to understanding function. Functional genomics seeks to assign a biochemical, physiologic, cell biologic, and/or developmental function to each predicted gene. An ever-increasing arsenal of approaches, including transgenic animals, RNA interference (RNAi), and various systematic mutational strategies, will allow dissection of functions associated with newly discovered genes. Although the potential of this field of study is vast, it is in its early stages.It is anticipated that a genomic and proteomic approach to human disease will lead to a new understanding of pathogenesis that will aid in the development of effective strategies for early diagnosis and treatment.10 For example, identification of altered protein expression in organs, cells, subcellular structures, or protein complexes may lead to development of new biomark-ers for disease detection. Moreover, improved understanding of how protein structure determines function will allow rational identification of therapeutic targets, and thereby not only accel-erate drug development, but also lead to new strategies to evalu-ate therapeutic efficacy and potential toxicity.9Cell Cycle and ApoptosisEvery organism is composed of many different cell types at dif-ferent developmental stages. Some cell types continue to grow, while some cells stop growing after a developmental stage or resume growth after a break. For example, embryonic stem cells grow continuously, while nerve cells and striated muscle cells stop dividing after maturation. Cell cycle is the process for every cell including DNA replication and protein synthe-sis, DNA segregation in half, and package DNA and protein in two newly formed cells to enable passage of identical genetic information from one parental cell to two daughter cells. Thus, the cell cycle is the fundamental mechanism to maintain tissue homeostasis. A cell cycle comprises four periods: G1 (first gap phase before DNA synthesis), S (synthesis phase when DNA replication occurs), G2 (the gap phase before mitosis), and M (mitosis, the phase when two daughter cells with identical DNA are generated) (Fig. 15-7). After a full cycle, the daughter Figure 15-7. The cell cycle and its control system. M is the mito-sis phase, when the nucleus and the cytoplasm divide; S is the phase when DNA is duplicated; G1 is the gap between M and S; G2 is the gap between S and M. A complex of cyclin and cyclin-dependent kinase (CDK) controls specific events of each phase. Without cyclin, CDK is inactive. Different cyclin/CDK complexes are shown around the cell cycle. A, B, D, and E stand for cyclin A, cyclin B, cyclin D, and cyclin E, respectively.B/CDK1A/CDK1A/CDK2E/CDK2D/CDK4D/CDK6G1G2SMMitosisDNA replicationcells enter G1 again, and when they receive appropriate signals, undergo another cycle, and so on. The machinery that drives cell cycle progression is made up of a group of enzymes called cyclin-dependent kinases (CDKs). Cyclin expression fluctuates during the cell cycle, and cyclins are essential for CDK activi-ties and form complexes with CDK. The cyclin A/CDK1 and cyclin B/CDK1 drive the progression for the M phase, while cyclin A/CDK2 is the primary S phase complex. Early G1 cyclin D/CDK4/6 or late G1 cyclin E/CDK2 controls the G1-S transi-tion. There also are negative regulators for CDK termed CDK inhibitors, which inhibit the assembly or activity of the cyclin-CDK complex. Expression of cyclins and CDK inhibitors often is regulated by developmental and environmental factors.The cell cycle is connected with signal transduction path-ways as well as gene expression. Although the S and M phases rarely are subjected to changes imposed by extracellular sig-nals, the G1 and G2 phases are the primary periods when cells decide whether or not to move on to the next phase. During the G1 phase, cells receive greenor red-light signals, S phase entry or G1 arrest, respectively. Growing cells proliferate only when supplied with appropriate mitogenic growth factors. Cells become committed to entry of the cell cycle only toward the end of G1. Mitogenic signals stimulate the activity of early G1 CDKs (e.g., cyclin D/CDK4) that inhibit the activity of pRb protein and activate the transcription factor called E2F to induce the expression of batteries of genes essential for G1-S progression. Meanwhile, cells also receive antiproliferative signals such as those from tumor suppressors. These antiproliferative signals also act in the G1 phase to stop cells’ progress into the S phase by inducing CKI production. For example, when DNA is dam-aged, cells will repair the damage before entering the S phase. Therefore, G1 contains one of the most important checkpoints for cell cycle progression. If the analogy is made that CDK is to a cell as an engine is to a car, then cyclins and CKI are the gas pedal and brake, respectively. Accelerated proliferation or Brunicardi_Ch15_p0479-p0510.indd 48618/02/19 11:12 AM 487MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15improper cell cycle progression with damaged DNA would be disastrous. Genetic gain-of-function mutations in oncogenes (that often promote expression or activity of the cyclin/CDK complex) or loss-of-function mutations in tumor suppressor (that stimulate production of CKI) are causal factors for malig-nant transformation.In addition to cell cycle control, cells use genetically pro-grammed mechanisms to kill cells. This cellular process, called apoptosis or programmed cell death, is essential for the mainte-nance of tissue homeostasis (Fig. 15-8).Normal tissues undergo proper apoptosis to remove unwanted cells, those that have completed their jobs or have been damaged or improperly proliferated. Apoptosis can be activated by many physiologic stimuli such as death receptor signals (e.g., Fas or cytokine tumor necrosis factor), growth fac-tor deprivation, DNA damage, and stress signals. Two major pathways control the biochemical mechanisms governing apop-tosis: the death receptor and mitochondrial. However, recent advances in apoptosis research suggest an interconnection of the two pathways. What is central to the apoptotic machinery is the activation of a cascade of proteinases called caspases. Similar to CDK in the cell cycle, activities and expression of caspases are well controlled by positive and negative regulators. The complex machinery of apoptosis must be tightly controlled. Perturbations of this process can cause neoplastic transforma-tion or other diseases.Signal Transduction PathwaysGene expression in a genome is controlled in a temporal and spatial manner, at least in part by signaling pathways.11 A sig-naling pathway generally begins at the cell surface and, after a signaling relay by a cascade of intracellular effectors, ends up in the nucleus (Fig. 15-9). All cells have the ability to sense changes in their external environment. The bioactive substances to which cells can respond are many and include proteins, short peptides, amino acids, nucleotides/nucleosides, steroids, reti-noids, fatty acids, and dissolved gases. Some of these substances are lipophilic and thereby can cross the plasma membrane by NucleusDeath signal(e.g., TNF or Fas)DeathreceptorPlasmamembraneActivation ofcaspase cascadeCytochrome creleaseDeathreceptorsignalingpathwayMitochondrionNormal target cellApoptotic target cellFigure 15-8. A simplified view of the apop-tosis pathways. Extracellular death receptor pathways include the activation of Fas and tumor necrosis factor (TNF) receptors and consequent activation of the caspase path-way. Intracellular death pathway indicates the release of cytochrome c from mitochon-dria, which also triggers the activation of the caspase cascade. During apoptosis, cells undergo DNA fragmentation and nuclear and cell membrane breakdown and are eventually digested by other cells.Ligand(e.g., growth factor)Cell-surfacereceptorPlasmamembraneNucleusGeneexpressionLigand(e.g., hormone)Signaling cascadeIntracellularreceptorFigure 15-9. Cell-surface and intracellular receptor pathways. Extracellular signaling pathway: Most growth factors and other hydrophilic signaling molecules are unable to move across the plasma membrane and directly activate cell-surface receptors such as G-protein–coupled receptors and enzyme-linked receptors. The receptor serves as the receiver and in turn activates the downstream signals in the cell. Intracellular signaling pathway: Hormones or other diffusible molecules enter the cell and bind to the intracel-lular receptor in the cytoplasm or in the nucleus. Either extracel-lular or intracellular signals often reach the nucleus to control gene expression.Brunicardi_Ch15_p0479-p0510.indd 48718/02/19 11:12 AM 488BASIC CONSIDERATIONSPART Idiffusion to bind to a specific target protein within the cyto-plasm (intracellular receptor). Other substances bind directly with a transmembrane protein (cell-surface receptor). Binding of ligand to receptor initiates a series of biochemical reactions (signal transduction) typically involving protein-protein inter-actions and the transfer of high-energy phosphate groups, lead-ing to various cellular end responses.Control and specificity through simple protein-protein interactions—referred to as adhesive interactions—is a com-mon feature of signal transduction pathways in cells.12 Signaling also involves catalytic activities of signaling molecules, such as protein kinases/phosphatases, that modify the structures of key signaling proteins. Upon binding and/or modification by upstream signaling molecules, downstream effectors undergo a conformational (allosteric) change and, consequently, a change in function. The signal that originates at the cell surface and is relayed by the cytoplasmic proteins often ultimately reaches the transcriptional apparatus in the nucleus. It alters the DNA binding and activities of transcription factors that directly turn genes on or off in response to the stimuli. Abnormal alterations in signaling activities and capacities in otherwise normal cells can lead to diseases such as cancer.Advances in biology in the last two decades have dramati-cally expanded the view on how cells are wired with signal-ing pathways. In a given cell, many signaling pathways operate simultaneously and crosstalk with one another. A cell gener-ally may react to a hormonal signal in a variety of ways: (a) by changing its metabolite or protein, (b) by generating an electric current, or (c) by contracting. Cells continually are subject to multiple input signals that simultaneously and sequentially acti-vate multiple receptorand non–receptor-mediated signal trans-duction pathways, which form a signaling network. Although the regulators responsible for cell behavior are rapidly identified as a result of genomic and proteomic techniques, the specific functions of the individual proteins, how they assemble, and the networks that control cellular behavior remain to be defined. An increased understanding of cell regulatory pathways—and how they are disrupted in disease—will likely reveal common themes based on protein interaction domains that direct associa-tions of proteins with other polypeptides, phospholipids, nucleic acids, and other regulatory molecules. Advances in the under-standing of signaling networks will require methods of inves-tigation that move beyond traditional “linear” approaches into medical informatics and computational biology. The bewilder-ing biocomplexity of such networks mandates multidisciplinary and transdisciplinary research collaboration. The vast amount of information that is rapidly emerging from genomic and pro-teomic data mining will require the development of new model-ing methodologies within the emerging disciplines of medical mathematics and physics.Signaling pathways often are grouped according to the properties of signaling receptors. Many hydrophobic signaling molecules are able to diffuse across plasma membranes and directly reach specific cytoplasmic targets. Steroid hormones, thyroid hormones, retinoids, and vitamin D are examples that exert their activity upon binding to structurally related recep-tor proteins that are members of the nuclear hormone receptor superfamily. Ligand binding induces a conformational change that enhances transcriptional activity of these receptors. Most extracellular signaling molecules interact with transmembrane protein receptors that couple ligand binding to intracellular sig-nals, leading to biologic actions.There are three major classes of cell-surface receptors: transmitter-gated ion channels, seven-transmembrane G-protein–coupled receptors (GPCRs), and enzyme-linked receptors. The superfamily of GPCRs is one of the largest families of proteins, representing over 800 genes of the human genome. Members of this superfamily share a characteristic seven-transmembrane configuration. The ligands for these receptors are diverse and include hormones, chemokines, neurotransmitters, protein-ases, inflammatory mediators, and even sensory signals such as odorants and photons. Most GPCRs signal through het-erotrimeric G proteins, which are guanine-nucleotide regula-tory complexes. Thus, the receptor serves as the receiver, the G protein serves as the transducer, and the enzyme serves as the effector arm. Enzyme-linked receptors possess an extracellular ligand-recognition domain and a cytosolic domain that either has intrinsic enzymatic activity or directly links with an enzyme. Structurally, these receptors usually have only one transmembrane-spanning domain. Of at least five forms of enzyme-linked recep-tors classified by the nature of the enzyme activity to which they are coupled, the growth factor receptors such as tyrosine kinase receptor or serine/threonine kinase receptors mediate diverse cellular events including cell growth, differentiation, metabolism, and survival/apoptosis. Dysregulation (particularly mutations) of these receptors is thought to underlie conditions of abnormal cellular proliferation in the context of cancer. The following sections will further review two examples of growth factor signaling pathways and their connection with human diseases.Insulin Pathway and Diabetes.13 The discovery of insulin in the early 1920s is one of the most dramatic events in the treatment of human disease. Insulin is a peptide hormone that is secreted by the β-cell of the pancreas. Insulin is required for the growth and metabolism of most mammalian cells, which contain cell-surface insulin receptors (InsR). Insulin binding to InsR activates the kinase activity of InsR. InsR then adds phosphoryl groups, a process referred to as phosphorylation, and subsequently activates its immediate intracellular effector, called insulin receptor substrate (IRS). IRS plays a central role in coordinating the signaling of insulin by activating distinct sig-naling pathways, the PI3K-Akt pathway and MAPK pathway, both of which possess multiple protein kinases that can control transcription, protein synthesis, and glycolysis (Fig. 15-10).The primary physiologic role of insulin is in glucose homeostasis, which is accomplished through the stimulation of glucose uptake into insulin-sensitive tissues such as fat and skeletal muscle. Defects in insulin synthesis/secretion and/or responsiveness are major causal factors in diabetes, one of the leading causes of death and disability in the United States, affecting an estimated 16 million Americans. Type 2 diabetes accounts for about 90% of all cases of diabetes. Clustering of type 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. More than 90% of affected individuals have insulin resistance, which develops when the body is no longer able to respond correctly to insu-lin circulating in the blood. Although relatively little is known about the biochemical basis of this metabolic disorder, it is clear that the insulin-signaling pathways malfunction in this disease. It is also known that genetic mutations in the InsR or IRS cause type 2 diabetes, although which one is not certain. The majority of type 2 diabetes cases may result from defects in downstream-signaling components in the insulin-signaling pathway. Brunicardi_Ch15_p0479-p0510.indd 48818/02/19 11:12 AM 489MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15PlasmamembraneNucleusInsulinreceptor(InsR)GeneexpressionMAPKcascadeLipid & glucosemetabolismCellsurvivalIRSInsulinAdaptorPI3KFigure 15-10. Insulin-signaling pathway. Insulin is a peptide growth factor that binds to and activates the heterotetrameric recep-tor complex (InsR). InsR possesses protein tyrosine kinase activity and is able to phosphorylate the downstream insulin receptor sub-strate (IRS). Phosphorylated IRS serves as a scaffold and controls the activation of multiple downstream pathways for gene expres-sion, cell survival, and glucose metabolism. Inactivation of the insulin pathway can lead to type 2 diabetes.Type 2 diabetes also is associated with declining β-cell func-tion, resulting in reduced insulin secretion; these pathways are under intense study. A full understanding of the basis of insulin resistance is crucial for the development of new therapies for type 2 diabetes. Furthermore, apart from type 2 diabetes, insulin resistance is a central feature of several other common human disorders, including atherosclerosis and coronary artery disease, hypertension, and obesity.Transforming Growth Factor-a (TGF-a) Pathway and Cancers.14 Growth factor signaling controls cell growth, differ-entiation, and apoptosis. Although insulin and many mitogenic growth factors promote cell proliferation, some growth factors and hormones inhibit cell proliferation. TGF-β is one of them. The balance between mitogens and TGF-β plays an important role in controlling the proper pace of cell cycle progression. The growth inhibition function of TGF-β signaling in epithelial cells plays a major role in maintaining tissue homeostasis.The TGF-β superfamily comprises a large number of struc-turally related growth and differentiation factors that act through a receptor complex at the cell surface (Fig. 15-11). The com-plex consists of transmembrane serine/threonine kinases. The receptor signals through activation of heterotrimeric complexes of intracellular effectors called SMADs (which are contracted from homologous Caenorhabditis elegans Sma and Drosophila Mad, two evolutionarily conserved genes for TGF-β signaling). Upon phosphorylation by the receptors, SMAD complexes translocate into the nucleus, where they bind to gene promoters and cooperate with specific transcription factors to regulate the expression of genes that control cell proliferation and differen-tiation. For example, TGF-β strongly induces the transcription PlasmamembraneTGF b receptorGeneexpressionNucleusSMADTGF bAnti-proliferationFigure 15-11. TGF-β signaling pathway. The TGF-β family has at least 29 members encoded in the human genome. They are also peptide growth factors. Each member binds to a heterotetrameric complex consisting of a distinct set of type I and type II recep-tors. TGF-β receptors are protein serine/threonine kinases and can phosphorylate the downstream substrates called SMAD proteins. Phosphorylated SMADs are directly transported into the nucleus, where they bind to the DNA and regulate gene expression that is responsible for inhibition of cell proliferation. Inactivation of the TGF-β pathway through genetic mutations in the TGF-β receptors or SMADs is frequent in human cancer, leading to the uncontrolled proliferation of cancer cells.of a gene called p15INK4B (a type of CKI) and, at the same time, reduces the expression of many oncogenes such as c-Myc. The outcome of the altered gene expression leads to the inhibition of cell cycle progression. Meanwhile, the strength and dura-tion of TGF-β signaling is fine-tuned by a variety of positive or negative modulators, including protein phosphatases. Therefore, controlled activation of TGF-β signaling is an intrinsic mecha-nism for cells to ensure controlled proliferation.Resistance to TGF-β’s anticancer action is one hall-mark of human cancer cells. TGF-β receptors and SMADs are identified as tumor suppressors. The TGF-β signaling circuit can be disrupted in a variety of ways and in different types of human tumors. Some lose TGF-β responsiveness through downregulation or mutations of their TGF-β receptors. The cytoplasmic SMAD4 protein, which transduces signals from ligand-activated TGF-β receptors to downstream targets, may be eliminated through mutation of its encoding gene. The locus encoding cell cycle inhibitor p15INK4B may be deleted. Alterna-tively, the immediate downstream target of its actions, cyclin-dependent kinase 4 (CDK4), may become unresponsive to the inhibitory actions of p15INK4B because of mutations that block p15INK4B binding. The resulting cyclin D/CDK4 complexes con-stitutively inactivate tumor suppressor pRb by hyperphosphory-lation. Finally, functional pRb, the end target of this pathway, may be lost through mutation of its gene. For example, in pan-creatic and colorectal cancers, 100% of cells derived from these cancers carry genetic defects in the TGF-β signaling pathway. Therefore, the antiproliferative pathway converging onto pRb Brunicardi_Ch15_p0479-p0510.indd 48918/02/19 11:12 AM 490BASIC CONSIDERATIONSPART Iand the cell division cycle is, in one way or another, disrupted in a majority of human cancer cells. Besides cancer, dysregu-lation of TGF-β signaling also has been associated with other human diseases such as Marfan’s syndrome and thoracic aortic aneurysm.Gene Therapy and Molecular Drugs in CancerModern advances in the use of molecular biology to manipulate genomes have greatly contributed to the understanding of the molecular basis for how cells live, die, or differentiate. Given the fact that human diseases arise from improper changes in the genome, the continuous understanding of how the genome func-tions will make it possible to tailor medicine on an individual basis. Although significant hurdles remain, the course toward therapeutic application of molecular biology already has been mapped out by many proof-of-principle studies in the literature. In this section, cancer is used as an example to elaborate some therapeutic applications of molecular biology. Modern molecu-lar medicine includes gene therapy and molecular drugs that target genes or gene products within human cells.Cancer is a complex disease, involving uncontrolled growth and spread of tumor cells (Fig. 15-12). Cancer development depends on the acquisition and selection of specific character-istics that set the tumor cell apart from normal somatic cells. Cancer cells have defects in regulatory circuits that govern nor-mal cell proliferation and homeostasis. Many lines of evidence indicate that tumorigenesis in humans is a multistep process and that these steps reflect genetic alterations that drive the progres-sive transformation of normal human cells into highly malignant derivatives. The genomes of tumor cells are invariably altered at multiple sites, having suffered disruption through lesions as sub-tle as point mutations and as obvious as changes in chromosome complement. A succession of genetic changes, each conferring one or another type of growth advantage, leads to the progressive conversion of normal human cells into cancer cells.Cancer research in the past 20 years has generated a rich and complex body of knowledge, revealing cancer to be a dis-ease involving dynamic changes in the genome. The causes of cancer include genetic predisposition, environmental influences, infectious agents, and aging. These transform normal cells into cancerous ones by derailing a wide spectrum of regulatory pathways including signal transduction pathways, cell cycle machinery, or apoptotic pathways.15,16 The early notion that cancer was caused by mutations in genes critical for the control of cell growth implied that genome stability is important for preventing oncogenesis. There are two classes of cancer genes in which alteration has been identified in human and animal cancer cells: oncogenes, with dominant gain-of-function muta-tions, and tumor suppressor genes, with recessive loss-of-function mutations. In normal cells, oncogenes promote cell growth by activating cell cycle progression, whereas tumor suppres-sors counteract oncogenes’ functions. Therefore, the balance between oncogenes and tumor suppressors maintains a well-controlled state of cell growth.During the development of most types of human cancer, cancer cells can break away from primary tumor masses, invade adjacent tissues, and hence travel to distant sites where they form new colonies. This spreading process of tumor cells, called metastasis, is the cause of 90% of human cancer deaths. Meta-static cancer cells that enter the bloodstream can reach virtu-ally all tissues of the body. Bones are one of the most common places for these cells to settle and start growing again. Bone Figure 15-12. Tumor clonal evolution and metastasis. A tumor develops from mutant cells with multiple genetic mutations. Through repeated alterations in the genome, mutant epithelial cells are able to develop into a cluster of cells (called a tumor clone) that proliferates in an uncontrollable fashion. Further changes in the tumor cells can transform the tumor cells into a population of cells that can enter the blood vessels and repopulate in a new location.Tumor cells escape fromblood vessel and proliferateto form metastatic tumorsBlood vesselTumor cells break looseand enter bloodstreamUncontrolled cellproliferationCell proliferationCell proliferationCell with multiplemutationsCell with two mutationsMutant epithelial cellNormal epithelial cellmetastasis is one of the most frequent causes of pain in people with cancer. It also can cause bones to break and create other symptoms and problems for patients.The progression in the knowledge of cancer biology has been accelerating in recent years. All of the scientific knowledge Brunicardi_Ch15_p0479-p0510.indd 49018/02/19 11:12 AM 491MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15acquired through hard work and discovery has made it possible for cancer treatment and prevention. As a result of explosive new discoveries, some modern treatments were developed. The success of these therapies, together with traditional treatments such as surgical procedures, is further underscored by the fact that in 2002 the cancer rate was reduced in the United States. Current approaches to the treatment of cancer involve killing cancer cells with toxic chemicals, radiation, or surgery. Alterna-tively, several new biologicand gene-based therapies are aimed at enhancing the body’s natural defenses against invading can-cers. Understanding the biology of cancer cells has led to the development of designer therapies for cancer prevention and treatment. Gene therapy, immune system modulation, geneti-cally engineered antibodies, and molecularly designed chemical drugs are all promising fronts in the war against cancer.Immunotherapy. The growth of the body is controlled by many natural signals through complex signaling pathways. Some of these natural agents have been used in cancer treatment and have been proven effective for fighting several cancers through the clinical trial process. These naturally occurring biologic agents, such as interferons, interleukins, and other cytokines, can now be produced in the laboratory. These agents, as well as the synthetic agents that mimic the natural signals, are given to patients to influence the natural immune response agents either by directly altering the cancer cell growth or by acting indirectly to help healthy cells control the cancer. One of the most exciting applications of immunotherapy has come from the identification of certain tumor targets called antigens and the aiming of an antibody at these targets. This was first used as a means of local-izing tumors in the body for diagnosis and was more recently used to attack cancer cells. Trastuzumab (Herceptin) is an exam-ple of such a drug.17 Trastuzumab is a monoclonal antibody that neutralizes the mitogenic activity of cell-surface growth fac-tor receptor HER-2, which is overexpressed in approximately 25% of breast cancers. HER-2–overexpressing tumors tend to grow faster and generally are more likely to recur than tumors that do not overproduce HER-2. Trastuzumab is designed to attack cancer cells that overexpress HER-2 by slowing or pre-venting the growth of these cells, resulting in increased survival of HER-2–positive breast cancer patients. Another significant example is the administration of interleukin-2 (IL-2) to patients with metastatic melanoma or kidney cancer, which has been shown to mediate the durable regression of metastatic cancer. IL-2, a cytokine produced by human helper T lymphocytes, has a wide range of immune regulatory effects, including the expansion of lymphocytes following activation by a specific antigen. Although IL-2 has no direct impact on cancer cells, the impact of IL-2 on cancers in vivo derives from its ability to expand lymphocytes with antitumor activity. The expanded lymphocyte pool enables recognition of the antigen on cancer cells. Thus, the molecular identification of cancer antigens has opened new possibilities for the development of effective immunotherapies for patients with cancer. Clinical studies using immunization with peptides derived from cancer antigens have shown that high levels of lymphocytes with antitumor activity can be produced in cancer-bearing patients. Highly avid antitu-mor lymphocytes can be isolated from immunized patients and grown in vitro for use in cell-transfer therapies.Chemotherapy. The primary function of anticancer chemicals is to block different steps involved in cell growth and replica-tion. These chemicals often block a critical chemical reaction in a signal transduction pathway or during DNA replication or gene expression. For example, STI571, also known as Gleevec, is one of the first molecularly targeted drugs based on the changes that cancer causes in cells.18 STI571 offers promise for the treatment of chronic myeloid leukemia (CML) and may soon surpass interferon-γ as the standard treatment for the disease. In CML, STI571 is targeted at the Bcr-Abl kinase, an activated oncogene product in CML (Fig. 15-13). Bcr-Abl is an overly activated protein kinase resulting from a specific genetic abnor-mality generated by chromosomal translocation that is found in the cells of patients with CML. STI571-mediated inhibi-tion of Bcr-Abl kinase activity not only prevents cell growth of Bcr-Abl–transformed leukemic cells, but also induces apoptosis. Clinically, the drug quickly corrects the blood cell abnormali-ties caused by the leukemia in a majority of patients, achiev-ing a complete disappearance of the leukemic blood cells and the return of normal blood cells. Additionally, the drug appears to have some effect on other cancers including certain brain tumors and gastrointestinal (GI) stromal tumors, a very rare type of stomach cancer.Gene Therapy. Gene therapy is an experimental treatment that involves genetically altering a patient’s own tumor cells or lym-phocytes (cells of the immune system, some of which can attack cancer cells). For years, the concept of gene therapy has held promise as a new, potentially potent weapon to attack cancer. Although a rapid progression in the understanding of the molec-ular and clinical aspects of gene therapy has been witnessed in the past decade, gene therapy treatment has not yet been shown to be superior to standard treatments in humans.Inactive(In the absence of ATP)Overly activeUncontrolledcell proliferationBlockedcell proliferationBlocked activityATPSubstrateBcr-AblkinasePO4TyrSTI571SubstrateBcr-AblkinaseTyrSubstrateBcr-AblkinaseTyrFigure 15-13. Mechanism of STI571 as a molecular drug. Bcr-Abl is an overly activated oncogene product resulting from a specific genetic abnormality generated by chromo-somal translocation that is found in cells of patients with chronic myeloid leukemia. Bcr-Abl is an activated protein kinase and thus requires adenosine triphosphate (ATP) to phosphorylate substrates, which in turn promote cell proliferation. STI571 is a small molecule that competes with the ATP-bind-ing site and thus blocks the transfer of phos-phoryl group to substrate. PO4 = phosphate; Tyr = tyrosine.Brunicardi_Ch15_p0479-p0510.indd 49118/02/19 11:12 AM 492BASIC CONSIDERATIONSPART ISeveral problems must be resolved to transform it into a clinically relevant form of therapy. The major issues that limit its translation to the clinic are improving the selectivity of tumor targeting, improving the delivery to the tumor, and the enhance-ment of the transduction rate of the cells of interest. In most gene therapy trials for malignant diseases, tumors can be accessed and directly injected (in situ gene therapy). In situ gene therapy also offers a better distribution of the vector virus throughout the tumor. Finally, a combination of gene therapy strategies will be more effective than the use of a single gene therapy system. An important aspect of effective gene therapy involves the choice of appropriate genes for manipulation. Genes that promote the production of messenger chemicals or other immune-active sub-stances can be transferred into the patient’s cells. These include genes that inhibit cell cycle progression, induce apoptosis, enhance host immunity against cancer cells, block the ability of cancer cells to metastasize, and cause tumor cells to undergo suicide. Recent development of RNAi technology, which uses a loss-of-function approach to block gene functions, ensures a new wave of hopes for gene therapy. Nonetheless, gene therapy is still experimental and is being studied in clinical trials for many different types of cancer. The mapping of genes respon-sible for human cancer is likely to provide new targets for gene therapy in the future. The preliminary results of gene therapy for cancer are encouraging, and as advancements are made in the understanding of the molecular biology of human cancer, the future of this rapidly developing field holds great potential for treating cancer.It is noteworthy that the use of multiple therapeutic meth-ods has proven more powerful than a single method. The use of chemotherapy after surgery to destroy the few remaining cancerous cells in the body is called adjuvant therapy. Adju-vant therapy was first tested and found to be effective in breast cancer. It was later adopted for use in other cancers. A major discovery in chemotherapy is the advantage of multiple che-motherapeutic agents (known as combination or cocktail chemotherapy) over single agents. Some types of fast-growing leukemias and lymphomas (tumors involving the cells of the bone marrow and lymph nodes) responded extremely well to combination chemotherapy, and clinical trials led to gradual improvement of the drug combinations used. Many of these tumors can be cured today by combination chemotherapy. As cancer cells carry multiple genetic defects, the use of combina-tion chemotherapy, immunotherapy, and gene therapies may be more effective in treating cancers.Stem Cell ResearchStem cell biology represents a cutting-edge scientific research field with potential clinical applications.19 It may have an enor-mous impact on human health by offering hope for curing human diseases such as diabetes mellitus, Parkinson’s disease, neuro-logic degeneration, and congenital heart disease. Stem cells are endowed with two remarkable properties (Fig. 15-14). First, stem cells can proliferate in an undifferentiated but pluripotent state and, as a result, can self-renew. Second, they have the abil-ity to differentiate into many specialized cell types. There are two groups of stem cells: embryonic stem (ES) cells and adult stem cells.Human ES cells (hESCs) are derived from early preim-plantation embryos called blastocysts (5 days postfertilization) and are capable of generating all differentiated germ layers in the body by chimera assays or 2-D/3-D differentiation in a Self-renewalStem cellDifferentiationTerminallydifferentiatedcellFigure 15-14. Stem cells. A stem cell is capable of self-renewal (unlimited cell cycle) and differentiation (becoming nondividing cells with specialized functions). Differentiating stem cells often undergo additional cell divisions before they become fully mature cells that carry out specific tissue functions.dish—ectoderm, mesoderm, and endoderm—and therefore are considered pluripotent. There are two pluripotent states associ-ated with hESCs, one of which is the classic culture with bFGF (basic fibroblast growth factor) and knock out replacer (KSR), termed as “primed” pluripotent state. More recently, “naive” hESC culture methods have been introduced based on mouse studies, by supplementing 2i inhibitors (MEK1 and GSK3β inhibitors) into the medium in addition to bFGF.Adult stem cells are present in and can be isolated from adult tissues. They often are tissue specific and only can gen-erate the cell types comprising a particular tissue in the body; therefore, they are considered multipotent. However, in some cases, they can transdifferentiate into cell types found in other tissues, called transdifferentiation. For example, hematopoietic stem cells are adult stem cells. They reside in bone marrow and are capable of generating all cell types of the blood and immune system. Another example is mesenchymal stem cells (MSCs), which is initially identified in the bone marrow (BM) to sup-port hematopoietic stem cell homeostasis. In addition to BM, MSCs are also present in adipose tissue, umbilical cord, pla-centa, amniotic fluid, dental pulp, skeletal muscle, tendons, and synovial, etc., and are reported to obtain the ability to differen-tiate into osteogenic, chondrogenic, and adipogenic lineages in vitro. Due to their characteristics of easy acquisition (from adi-pose tissue, for example), strong ex vivo proliferation, immune-modulatory function, and ability to migrate to damaged tissue, MSCs have been utilized in regenerative medicine.Stem cells can be grown in culture and be induced to dif-ferentiate into a particular cell type, either in vitro or in vivo. With the recent and continually increasing improvement in culturing stem cells, scientists are beginning to understand the molecular mechanisms of stem cell self-renewal and differentia-tion in response to environmental cues. It is believed that dis-covery of the signals that control self-renewal vs differentiation will be extremely important for the therapeutic use of stem cells in treating disease. It is possible that success in the study of the changes in signal transduction pathways in stem cells will lead to the development of therapies to replace diseased or damaged cells in the body using stem cell derivatives. Recently, stem cell research has been transformed by the discovery from the Shinya Yamanaka group and the James Thomsen group, who have found that a simple genetic manipulation can reprogram adult differentiated cells back into pluripotent stem cells.20,21 This exciting discovery not only bypasses the ethical issues of using early embryos to generate ES cells, but also ensures a Brunicardi_Ch15_p0479-p0510.indd 49218/02/19 11:12 AM 493MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15potentially limitless source of patient-specific stem cells for tis-sue engineering and regenerative medicine.The Atomic Theory of Disease22As early as the 5th century b.c., the ancient Greek Democritus first proposed that matter is composed of indivisible particles called “atoms.” In the 17th and 18th centuries, Isaac Newton described the expansion of gases as rushed atoms into empty space. The existence of atoms was doubted until the discovery of subatomic particles in the 20th century, which demonstrated that the atom was actually divisible into protons, neutrons, and electrons.Over 100 years after this discovery, direct impacts from utilizing subatomic particles were revealed. This began with the discovery of the X-ray. The most advanced and well-applied atomic technologies include accurate imaging such as X-ray computed tomography (CT) scan, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). Additional applica-tions include radiation oncology, which utilizes ionizing parti-cles to treat malignant diseases by inducing double-strand DNA breaks resulting in programed cell death.The staggering advances in anatomy, physiology, and molecular biology over the past centuries have led us to our current state in which the atom is now the anatomy of the 21st century. As 99% of the body is composed of six elements (oxygen, carbon, hydrogen, nitrogen, calcium, and phosphorus), the next great advance in medicine will be bridging the sub-atomic, molecular, and genomic levels by forming an atomic theory of disease, which states that alterations in the composi-tion of subatomic particles are the root cause of disease. The atomic theory of disease would include genetic alterations at the atomic/subatomic level that are akin to single nucleotide polymorphisms (SNPs), in which alleles for a gene differ on the exact nucleotide in a single location, which can change the ulti-mate protein structure. This can lead to subtle changes in func-tion or dramatic results that cause pathology. We hypothesize that on a subatomic level, there could potentially be polymor-phisms as well, in which there are subtle changes in the sea of subatomic particles. Isotopes, discovered 100 years ago, would fall into this category of subatomic polymorphism, as they dif-fer in the number of neutrons present in the atom. Differences in other particles may not change the mass of the atom, but may alter some of the characteristics of the atom. This is where the basic human variations originate because an atomic polymerism would result in particular genetic change. Remarkably, somatic point mutations of KRAS and P53 are caused by a single proton shift in cytosine, which is known as tautomerization of cyto-sine. In turn, the tautomerized cytosine binds with adenine, and not guanine, thus leading to point mutations in KRAS and P53, which are well known driver mutations for many cancers. This is another example of alterations in subatomic particles that directly cause disease.A known example of a change in the subatomic milieu of an element leading to a disease process is that of methemo-globinemia, a disorder characterized by an overabundance of methemoglobin. Methemoglobin contains an oxidized form of iron (carrying an extra electron), as opposed to the reduced form in normal hemoglobin. This results in a shift in the oxygen-hemoglobin dissociation curve to the left, causing hypoxia. Met-hemoglobinemia can be congenital, due to a defect in an enzyme that normally reduces methemoglobin back to hemoglobin, or acquired, caused by breakdown products of drugs that can oxi-dize hemoglobin. Although there is less than 1% of methemo-globin normally present in human tissues, affecting local blood flow and inflammation through its effects on nitric oxide and heme, large quantities can lead to respiratory failure and death.Another example would be exposure to external energy such as radiation that leads to instability of nuclear genome. In Chernobyl and Fukushima, radiolabeled food was metabolized and incorporated into body cells and decay to emit gamma radi-ation, causing DNA damage. This radiation damage occurs pri-marily at a subatomic level from a radiobiologic point of view with a direct or indirect ionization of atoms. The clinical results depend on the tissue characteristics and the equilibrium between the damage applied to normal and diseased tissues.TECHNOLOGIES OF MOLECULAR AND CELL BIOLOGYDNA CloningSince the advent of recombinant DNA technology three decades ago, hundreds of thousands of genes have been identi-fied. Recombinant DNA technology is the technology that uses advanced enzymatic and microbiologic techniques to manipu-late DNA.23 Pure pieces of any DNA can be inserted into bac-teriophage DNA or other carrier DNA such as plasmids to produce recombinant DNA in bacteria. In this way, DNA can be reconstructed, amplified, and used to manipulate the functions of individual cells or even organisms. This technology, often referred to as DNA cloning, is the basis of all other DNA analy-sis methods. It is only with the awesome power of recombinant DNA technology that the completion of the Human Genome Project was possible. It also has led to the identification of the entire gene complements of organisms such as viruses, bacteria, worms, flies, and plants.Molecular cloning refers to the process of cloning a DNA fragment of interest into a DNA vector that ultimately is deliv-ered into bacterial or mammalian cells or tissues24,25 (Fig. 15-15). This represents a very basic technique that is widely used in almost all areas of biomedical research. DNA vectors often are called plasmids, which are extrachromosomal molecules of DNA that vary in size and can replicate and be transmitted from bacterial cell to cell. Plasmids can be propagated either in the cytoplasm or after insertion, as part of the bacterial chromosome in Escherichia coli. The process of molecular cloning involves several steps of manipulation of DNA. First, the vector plasmid DNA is cleaved with a restriction enzyme to create compatible ends with the foreign DNA fragment to be cloned. The vec-tor and the DNA fragment are then joined in vitro by a DNA ligase. Alternatively, DNA cloning can be simply done through the so-called Gateway Technology that allows for the rapid and efficient transfer of DNA fragments between different cloning vectors while maintaining reading frame and orientation, with-out the use of restriction endonucleases and DNA ligase. The technology, which is based on the site-specific recombination system of bacteriophage l, is simple, fast, robust, and automat-able and thus compatible for high-throughput DNA cloning.Finally, the ligation product or the Gateway reaction prod-uct is introduced into competent host bacteria; this procedure is called transformation, which can be done by either calcium/heat shock or electroporation. Precautions must be taken in every step of cloning to generate the desired DNA construct. Brunicardi_Ch15_p0479-p0510.indd 49318/02/19 11:12 AM 494BASIC CONSIDERATIONSPART IFigure 15-15. Generation of recombinant DNA. The vector is a circular DNA molecule that is capable of replicating in Escherichia coli cells. Insert DNA (often your favorite gene) is ligated to the vector after ends of both DNA are properly treated with restriction enzymes. Ligated DNA (i.e., the recombinant plasmid DNA) is then transformed into E. coli cells, where it replicates to produce recombinant progenies. E. coli cells carrying the recombinant plasmid can be propagated to yield large quantities of plasmid DNA.InsertDNA of interestDigest withrestriction enzymeVectorLigationRecombinantplasmidIntroduceinto E. coliE. coli containingrecombinant plasmidPropagationE. coli containingrecombinant plasmidThe vector must be correctly prepared to maximize the creation of recombinants; for example, it must be enzymatically treated to prevent self-ligation. Host bacteria must be made sufficiently competent to permit the entry of recombinant plasmids into cells. The selection of desired recombinant plasmid-bearing E. coli normally is achieved by the property of drug resistance conferred by the plasmid vectors. The plasmids encoding mark-ers provide specific resistance to (i.e., the ability to grow in the presence of) antibiotics such as ampicillin, kanamycin, and tetracycline. The foreign component in the plasmid vector can be a mammalian expression cassette, which can direct expres-sion of foreign genes in mammalian cells. The resulting plasmid vector can be amplified in E. coli to prepare large quantities of DNA for its subsequent applications such as transfection, gene therapy, transgenics, and knockout mice.Detection of Nucleic Acids and ProteinsSouthern Blot Hybridization. Southern blotting refers to the technique of transferring DNA fragments from an electropho-resis gel to a membrane support and the subsequent analysis of the fragments by hybridization with a radioactively or chemi-luminescently labeled probe (Fig. 15-16).26 Southern blotting is named after E. M. Southern, who in 1975 first described the technique of DNA analysis. It enables reliable and efficient analysis of size-fractionated DNA fragments in an immobilized membrane support. Southern blotting is composed of several steps. It normally begins with the digestion of the DNA samples with appropriate restriction enzymes, which will discriminate wild-type and mutant DNA by size and the separation of DNA samples in an agarose gel by electrophoresis with appropriate DNA size markers, called the DNA ladder. The DNA gel is stained with a dye, usually ethidium bromide, and photographed with a ruler laid alongside the gel so that band positions can later be identified on the membrane. The DNA gel then is treated so the DNA fragments are denatured (i.e., strand separation). The DNA then is transferred onto a nitrocellulose membrane by capillary diffusion or under electricity. After immobilization, the DNA can be subjected to hybridization analysis, enabling bands with sequence similarity to a radioactively or chemilumi-nescently labeled probe to be identified.The development of Southern transfer and the associated hybridization techniques made it possible for the first time to obtain information about the physical organization of single and multicopy sequences in complex genomes. The later applica-tion of Southern blotting hybridization to the study of restriction fragment length polymorphisms opened up new possibilities DNA is digested withrestriction enzymes.DNA fragments are denaturedand separated by gelelectrophoresis.DNA fragments are transferredto a membrane filter.The filter is hybridized with a radioactive DNA probe.DNA fragment that is hybridized to the radioactive DNA is detected by autoradiography.Radioactive probeFigure 15-16. Southern blotting. Restriction enzymatic fragments of DNA are separated by agarose gel electrophoresis, transferred to a membrane filter, and then hybridized to a radioactive probe.such as genetic fingerprinting and prenatal diagnosis of genetic diseases.Northern Blot Hybridization. Northern blotting refers to the technique of size fractionation of RNA in a gel and the transfer-ring of an RNA sample to a solid support (membrane) in such a manner that the relative positions of the RNA molecules are maintained. The resulting membrane then is hybridized with a labeled probe complementary to the mRNA of interest. Signals generated from detection of the membrane can be used to deter-mine the size and abundance of the target RNA. In principle, Brunicardi_Ch15_p0479-p0510.indd 49418/02/19 11:12 AM 495MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15Northern blot hybridization is similar to Southern blot hybrid-ization (and hence its name), with the exception that RNA, not DNA, is on the membrane. Although reverse-transcriptase PCR has been used in many applications (described in the next sec-tion, “Polymerase Chain Reaction”), Northern analysis is the only method that provides information regarding mRNA size and has remained a standard method for detection and quantita-tion of mRNA. The process of Northern hybridization involves several steps, as does Southern hybridization, including elec-trophoresis of RNA samples in an agarose-formaldehyde gel, transfer to a membrane support, and hybridization to a radio-actively labeled DNA probe. Data from hybridization allow Etc.Double-strandedDNAHeat toseparatestrandsHybridization of primers+DNA polymerase+dATP+dGTP+dCTP+dTTP5'5'DNAfromsynthesisprimersStep 1Step 2Step 3First cycleSeparate DNA strandsand add primerDNAsynthesisRegion ofdouble-stranded DNA to beamplifiedDNA oligonucleotideprimersSeparate DNA strandsand annual primerDNAsynthesisSeparate DNA strandsand annual primerDNAsynthesisFirst cycleProducing two double-strandedDNA moleculesSecond cycleProducing four double-strandedDNA moleculesThird cycleProducing eight double-strandedDNA moleculesABFigure 15-17. Amplification of DNA using the polymerase chain reaction (PCR) technique. Knowledge of the DNA sequence to be ampli-fied is used to design two synthetic DNA oligonucleotides, each complementary to the sequence on one strand of the DNA double helix at opposite ends of the region to be amplified. These oligonucleotides serve as primers for in vitro DNA synthesis, which is performed by a DNA polymerase, and they determine the segment of the DNA that is amplified. A. PCR starts with a double-stranded DNA, and each cycle of the reaction begins with a brief heat treatment to separate the two strands (Step 1). After strand separation, cooling of the DNA in the presence of a large excess of the two primer DNA oligonucleotides allows these primers to hybridize to complementary sequences in the two DNA strands (Step 2). This mixture is then incubated with DNA polymerase and the four deoxyribonucleoside triphosphates so that DNA is synthesized, starting from the two primers (Step 3). The entire cycle is then begun again by a heat treatment to separate the newly synthesized DNA strands. B. As the procedure is performed over and over again, the newly synthesized fragments serve as templates in their turn, and, within a few cycles, the predominant DNA is identical to the sequence bracketed by and including the two primers in the original template. Of the DNA put into the original reaction, only the sequence bracketed by the two primers is amplified because there are no primers attached anywhere else. In the example illustrated in B, three cycles of reaction produce 16 DNA chains, eight of which (boxed in brown) are the same length as and correspond exactly to one or the other strand of the original bracketed sequence shown at the far left; the other strands contain extra DNA downstream of the original sequence, which is replicated in the first few cycles. After three more cycles, 240 of the 256 DNA chains cor-respond exactly to the original bracketed sequence, and after several more cycles, essentially all of the DNA strands have this unique length. quantification of steady-state mRNA levels and, at the same time, provide information related to the presence, size, and integrity of discrete mRNA species. Thus, Northern blot analy-sis, also termed RNA gel blot analysis, commonly is used in molecular biology studies relating to gene expression.Polymerase Chain Reaction. PCR is an in vitro method for the polymerase-directed amplification of specific DNA sequences using two oligonucleotide primers that hybridize to opposite strands and flank the region of interest in the tar-get DNA (Fig. 15-17).27 One cycle of PCR reaction involves template denaturation, primer annealing, and the extension of Brunicardi_Ch15_p0479-p0510.indd 49518/02/19 11:12 AM 496BASIC CONSIDERATIONSPART Ithe annealed primers by DNA polymerase. Because the primer extension products synthesized in one cycle can serve as a template in the next, the number of target DNA copies nearly doubles at each cycle. Thus, a repeated series of cycles result in the exponential accumulation of a specific fragment in which the termini are sharply defined by the 5′ ends of the primers. The introduction of the thermostable DNA polymerase (e.g., Taq polymerase) transforms the PCR into a simple and robust reaction. The reaction components (e.g., template, primers, Taq polymerase, 2′-deoxynucleoside 5′-triphosphates, and buffer) could all be assembled and the amplification reaction carried out by simply cycling the temperatures within the reaction tube. The specificity and yield in amplifying a particular DNA frag-ment by PCR reaction are affected by the proper setting of the reaction parameters (e.g., enzyme, primer, and Mg2+ concen-tration, as well as the temperature cycling profile). Modifying various PCR parameters to optimize the specificity of amplifi-cation yields more homogenous products, even in rare template reactions.The emergence of the PCR technique has dramatically altered the approach to both fundamental and applied bio-logic problems. The capability of amplifying a specific DNA fragment from a gene or the whole genome greatly advances the study of the gene and its function. It is simple, yet robust, speedy, and most of all, flexible. As a recombinant DNA tool, it underlies almost all of molecular biology. This revolution-ary technique enabled the modern methods for the isolation of genes, construction of a DNA vector, introduction of alterations into DNA, and quantitation of gene expression, making it a fun-damental cornerstone of genetic and molecular analysis.Immunoblotting and Immunoprecipitation. Analyses of proteins are primarily carried out by antibody-directed immu-nologic techniques. For example, Western blotting, also called immunoblotting, is performed to detect protein levels in a popu-lation of cells or tissues, whereas immunoprecipitation is used to concentrate proteins from a larger pool. Using specific antibod-ies, microscopic analysis called immunofluorescence and immu-nohistochemistry is possible for the subcellular localization and expression of proteins in cells or tissues, respectively.Immunoblotting refers to the process of identifying a pro-tein from a mixture of proteins (Fig. 15-18). It consists of five steps: (a) sample preparation; (b) electrophoresis (separation of a protein mixture by sodium dodecyl sulfate-polyacrylamide gel electrophoresis); (c) transfer (the electrophoretic transfer of proteins from gel onto membrane support [e.g., nitrocel-lulose, nylon, or polyvinylidene difluoride]); (d) staining (the subsequent immunodetection of target proteins with specific antibody); and (e) development (colorimetric, chemilumines-cent, and recently fluorescent visualization of the antibody-recognized protein). Thus, immunoblotting combines the resolution of gel electrophoresis with the specificity of immu-nochemical detection. Immunoblotting is a powerful tool used to determine a number of important characteristics of proteins. For example, immunoblotting analysis will determine the pres-ence and the quantity of a protein in a given cellular condition and its relative molecular weight. Immunoblotting also can be used to determine whether posttranslational modification such as phosphorylation has occurred on a protein. Importantly, through immunoblotting analysis, a comparison of the protein levels and modification states in normal vs diseased tissues is possible.Cell tissue lysates• Sample preparation• Gel electrophoresis Separation of proteins• Western transfer Transfer of proteins to membrane• Immunostaining Block membrane 1°/2° antibody staining• Development Colorimetric/chemiluminescence detection123456123456Figure 15-18. Immunoblotting. Proteins are prepared from cells or tissues, separated according to size by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transferred to a membrane filter. Detection of a protein of interest can be done by sequential incubation with a primary antibody directed against the protein, and then with an enzyme-conjugated secondary antibody that rec-ognizes the primary antibody. Visualization of the protein is carried out by using colorimetric or luminescent substrates for the conju-gated enzyme.Immunoprecipitation, another widely used immunochemi-cal technique, is a method that uses antibody to enrich a pro-tein of interest and any other proteins that are associated with it (Fig. 15-19). The principle of the technique lies in the property of a strong and specific affinity between antibodies and their anti-gens to locate and pull down target proteins in solution. Once the antibody-antigen (target protein) complexes are formed in the solution, they are collected and purified using small agarose beads with covalently attached protein A or protein G. Both protein A and protein G specifically interact with the antibodies, Brunicardi_Ch15_p0479-p0510.indd 49618/02/19 11:12 AM 497MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15Enriched YFP & YBPsWashSDS-PAGEAnti-YFP beadsAnti-YFP conjugated to beadsYour favorite protein (YFP)YFP-binding proteins (YBPs)Junk proteinsFigure 15-19. Immunoprecipitation. Proteins prepared from cells or tissues can be enriched using an antibody directed against them. The anti-body is first conjugated to agarose beads and then incubated with protein mixture. Due to the spe-cific high-affinity interaction between antibody and its antigen (the protein), the antigen-antibody complex can be collected on beads by centrifuga-tion. The immunoprecipitated protein can then be analyzed by immunoblotting. Alternatively, if pro-teins are radiolabeled in cells or tissues, detection of immunoprecipitated proteins can be achieved by simple sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography.thus forming a large immobilized complex of antibody-antigen bound to beads. The purified protein can then be analyzed by a number of biochemical methods. When immunoprecipitation is combined with immunoblotting, it can be used for the sensitive detection of proteins in low concentrations, which would other-wise be difficult to detect. Moreover, combined immunoprecipi-tation and immunoblotting analysis is very efficient in analyzing the protein-protein interactions or determining the posttransla-tional modifications of proteins. In addition, immunoprecipi-tated proteins can be used as preparative steps for assays such as intrinsic or associated enzymatic activities. The success of immunoprecipitation is influenced by two major factors: (a) the abundance of the protein in the original preparation and (b) the specificity and affinity of the antibody for this protein.Recently, immunoprecipitation is even used to enrich modi-fied DNA (for example, 5-methylcytosine) for bisulfite sequenc-ing. Besides proteins of interest, specific antibodies can also be raised against specially modified DNA. Like the protein immuno-precipitation, modified DNA can be pulled down, taking advan-tage of the specificity and affinity of antibody to antigen.DNA Microarray. Now that the human genome sequence is completed, the primary focus of biologists is rapidly shifting toward gaining an understanding of how genes function. One of the interesting findings about the human genome is that there are only approximately 25,000 to 30,000 protein-encoding genes. However, it is known that genes and their products function in a complicated and yet orchestrated fashion and that the surprisingly small number of genes from the genome sequence is sufficient to make a human being. Nonetheless, with the tens of thousands of genes present in the genome, traditional methods in molecular biology, which generally work on a one-gene-in-one-experiment basis, cannot generate the whole picture of genome function. In the past several years, a new technology called DNA microarray has attracted tremendous interest among biologists as well as cli-nicians. This technology promises to monitor the whole genome on a single chip so researchers can have a better picture of the interactions among thousands of genes simultaneously.DNA microarray, also called gene chip, DNA chip, and gene array, refers to large sets of probes of known sequences orderly arranged on a small chip, enabling many hybridization reactions to be carried out in parallel in a small device (Fig. 15-20).28 Like Southern and Northern hybridization, the underlying principle of this technology is the remarkable abil-ity of nucleic acids to form a duplex between two strands with complementary base sequences. DNA microarray provides a medium for matching known and unknown DNA samples based on base-pairing rules and automating the process of identify-ing the unknowns. Microarrays require specialized robotics and imaging equipment that spot the samples on a glass or nylon substrate, carry out the hybridization, and analyze the data gener-ated. DNA microarrays containing different sets of genes from a variety of organisms are now commercially available, allowing biologists to simply purchase the chips and perform hybridiza-tion and data collection. The massive scale of microarray experi-ments requires the aid of computers. They are used during the capturing of the image of the hybridized target, the conversion of the image into usable measures of the extent of hybridization, and the interpretation of the extent of hybridization into a mean-ingful measure of the amount of the complementary sequence in the target. Some data-analysis packages are available commer-cially or can be found in the core facility of certain institutions.DNA microarray technology has produced many signifi-cant results in quite different areas of application. There are two major application forms for the technology: identifica-tion of sequence (gene/gene mutation) in multiple regions of a genome and determination of expression level (abundance) of large numbers of genes simultaneously. For example, analysis of genomic DNA detects amplifications and deletions found in human tumors. Differential gene expression analysis also has uncovered networks of genes differentially present in can-cers that cannot be distinguished by conventional means. Sig-nificantly, recent advancements in next-generation sequencing (e.g., Solexa and 454 technology) have demonstrated the preci-sion and speed to analyze gene expression in any genome.Next-Generation Sequencing.29,30 First-generation sequenc-ing, also termed Sanger’s sequencing, requires a single-stranded DNA template, a specific DNA primer, a DNA polymerase, nor-mal deoxynucleoside triphosphates (dNTPs), and modified di-deoxynucleotidetriphosphates (ddNTPs). In the process of DNA sequencing, DNA polymerase adds random dNTP or ddNTP Brunicardi_Ch15_p0479-p0510.indd 49718/02/19 11:12 AM 498BASIC CONSIDERATIONSPART ICell #1Cell #2mRNAcDNADNA microarrayDNA microarray datacDNAmRNAFigure 15-20. DNA microarrays. DNA microarrays, also referred to as gene chips, have arrayed oligonucleotides or com-plementary DNAs (cDNAs) corresponding to tens or hundreds of distinct genes. DNA microarray is used to comparatively analyze gene expression in different cells or tissues. Messenger RNAs (mRNAs) extracted from different sources are converted into cDNAs, which are then labeled with different fluorescent dyes. The two fluorescent cDNA probes are mixed and hybridized to the same DNA microarrays. The ratio of red to green fluorescence at each spot on the chip represents the relative expression of levels of that gene between two different cells. In the example shown in the figure, cDNA from cell #1 is labeled with red fluorescence and that from cell #2 is labeled with green fluorescence. On the micro-array, red spots demonstrate that the gene in the cell sample #1 is expressed at a higher level than the corresponding gene in cell sample #2. The green spots indicate that the gene in the cell sam-ple #2 is expressed at a higher level than the corresponding gene in the cell sample #1. Yellow spots represent equal expression of the gene in both cell samples.after the primer. If ddNTP is incorporated at the end of the chain, it terminizes the reaction and results in DNA fragments of different sizes. The ddNTPs could be radioactively or fluo-rescently labeled for auto-machine detection. Usually, Sanger’s sequencing is able to read sequence below 1 kb with the quality deteriorating after 700 bp. The accuracy and success rate largely depends on the DNA polymerase used.Recombinant DNA technology greatly impacts the com-pletion of the Human Genome Project due to the invention of shotgun sequencing, which includes breaking the genome DNA into small pieces and randomly cloning those pieces into DNA vectors that are easily sequenced. Based on the overlapping sequence of each clone, computer analysis can be programmed to map and align the DNA sequence that will ultimately cover the whole human genome.Based on shotgun sequencing, as the sequencing technol-ogies advance, next-generation sequencing (NGS), also called second-generation sequencing, has become one of the most powerful tools to analyze DNA mutation, identify epigenetic modification, and profile gene expression or ncRNA expression.31 The next-generation sequencing process usually includes library construction, sequencing, and data analysis. There are three major NGS platforms: Roche 454, Life Technologies Ion Tor-rent, and Illumina Solexa. Take the Illumina next-generation sequencing as an example: DNA are shared or digested into small pieces and then used to generate a DNA library with adapt-ers on both ends of each DNA piece. Then, the DNA library is diluted and loaded on a chamber of a slide, called a lane, for cluster amplification. Cycled fluorescent deoxyribonucleotide triphosphates (dNTPs) are then added to the chamber to enable DNA polymerization, resulting in different fluorescent emis-sion representing different dNTP reading on different clusters, into a microscope. The fluorescent signal is transformed into sequencing data that will be aligned and mapped to a standard genome database. The advantages of next-generation sequenc-ing include the following: no necessity of DNA cloning; fast and cost-effective; and a huge amount of data to give good depth and accuracy of the sequence.Based on the applications, the most common next-generation sequencing technologies for whole-genome sequencing are whole-genome DNA sequencing, whole-genome bisulfite sequencing (BS-seq), RNA sequencing (RNA-seq), and chro-matin immunoprecipitation (ChIP) sequencing (ChIP-seq). Whole-genome DNA sequencing is purely to sequence the DNA sequence of a genome without any preprocessing of the DNA, reflecting any deletions, replications, and mutations within the genomic DNA. Given that the genomic information for human is enormous, to achieve great depth and accuracy the genome needs to be sequenced multiple times to reach statistic significance and pass quality control. Therefore, whole-genome DNA sequencing is still considered to be costly for diagnosis as well as for research purposes. Under clinical settings, one of the most applied DNA sequencing technologies is whole-exome sequencing, i.e., using techniques to capture and analyze exons in all coding genes, given that most known diseases are due to mutations in spliced-in regions of coding genes. Whole-exome sequencing is mostly used for detecting single nucleotide vari-ants and is less reliable in detecting insertion-deletion variants or small copy number variants.BS-seq is commonly used to identify DNA methyla-tion on the genome (5-methylcytosine [5mC]). The process always involves a bisulfite treatment of DNA before library Brunicardi_Ch15_p0479-p0510.indd 49818/02/19 11:12 AM 499MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15construction, during which the unmethylated cytosine will be transformed to a uracil, resulting in reading as a thymine in data output, whereas 5mC is protected and remains as cytosine in data output. Thus, 5mC and cytosine are distinguished this way. To perform whole-genome BS-seq, the library construc-tion starts with a decent amount of DNA followed by a complete conversion of unmethylated cytosine. Because it is also counted as whole-genome sequencing, a certain depth of data needs to be achieved for accurate and convincing results. To develop an affordable genome-wide DNA methylation analysis, the reduced representation bisulfite sequencing (RRBS) approach has been applied to enrich CpG-dense regions of the genome by digesting genomic DNA using a methylation-insensitive restric-tion enzyme, usually MspI. This method covers a majority of promoters as well as some repetitive regions in the genome.RNA-seq is usually performed to analyze transcription for the same purpose as performing a microarray. However, RNA-seq is more accurate and provides more information such as splicing variants than traditional microarray. Usually, cDNA that is reversely transcribed from extracted RNA is used to generate libraries. Depending on the needs, mRNA and ncRNA can be enriched in different protocols for RNA extraction. Currently, techniques have been improved to perform RNA profiling on a single cell level. Single-cell RNA sequencing (scRNA-seq) allows expression analysis of individual cells in a population. One use is to examine heterogeneity in tumor cells. Although low copy number genes are usually poorly detected, scRNA-seq on a large number of cells can reveal rare cell subpopula-tions and uncommon RNA expression patterns among different subpopulations.ChIP-seq is always used to map the location of a DNA-binding protein in the genome. Prior to library construction, ChIP is performed to enrich DNA bound by the protein of interest (POI). First, POI and DNA are cross-linked before sonication. Then, a specific antibody is used to pull down POI and attached DNA fragments. After the protein and DNA are reverse cross-linked, DNA is purified to make the ChIP-seq library. If using an antibody against particular transcription fac-tor (TF), DNA sequences bound by this TF are pulled down CellisolationPrimaryculturePropagationTissuesampleProduction of recombinant proteinsAnalysis of gene functionTransfectionwith DNAABFigure 15-21. Cell culture and transfection. A. Primary cells can be isolated from tissues and cultured in medium for a limited period of time. After genetic manipulations to over-come the cell aging process, primary cells can be immortalized into cell lines for long-term culture. B. DNA can be introduced into cells to produce recombinant gene products or to ana-lyze the biologic functions of the gene.and examined. The TF binding consensus sequences is then pre-dicted, and if the TF binds to a promoter region, it is likely that the gene using this promoter is regulated by this TF. If using an antibody against an epigenetic modification, the modified regions are marked up into the genome to facilitate identifica-tion of potential epigenetic regulating mechanisms.By using next-generation sequencing technology, any potential mutations in a patient can be scrutinized as well as any defects in epigenetic modification. By combining data from different kinds of sequencing (DNA-seq, RNA-seq, ChIP-seq), better understanding of mutation or transcription-caused diseases aligning with epigenetic regulation can be achieved, which will greatly facilitate the diagnosis of patients and per-sonalization of medicine in a fast and economic way by prevent-ing unnecessary medical costs and procedures.Third-generation sequencing has emerged rapidly at the research level to involve single molecule real-time sequencing (SMRT). Although first developed and marketed by Pacific Biosciences (Pac Bio), Roche is now leading this technology. Third-generation sequencing allows amplification-free single-molecule sequencing with read length extension up to mega-bases and reduced sequencing coverage bias. It can be used to build the gap in the human genome (for example, low complex-ity regions), provide access to structural genomic variants, and simultaneously analyze genome-wide single-nucleotide methyl-ation. So far, clinical application and research is heavily depen-dent on NGS, especially standardizing and reducing the cost of post-NGS analysis. Third-generation sequencing is under fast development and has been adapted to aid and append NGS.Cell ManipulationsCell Culture. Cell culture has become one of the most power-ful tools in biomedical laboratories, as cultured cells are being used in a diversity of biologic fields ranging from biochemistry to molecular and cellular biology.32 Through their ability to be maintained in vitro, cells can be manipulated by the introduc-tion of genes of interest (cell transfection) and be transferred into in vivo biologic receivers (cell transplantation) to study the biologic effect of the interested genes (Fig. 15-21). In common Brunicardi_Ch15_p0479-p0510.indd 49918/02/19 11:12 AM 500BASIC CONSIDERATIONSPART Ilaboratory settings, cells are cultured either as a monolayer (in which cells grow as one layer on culture dishes), considered 2-D, or in suspension or biomedical material skeleton such as hydrogel, considered 3-D.It is important to know the wealth of information concern-ing cell culturing before attempting the procedure. For example, conditions of culture will depend on the cell types to be cultured (e.g., origins of the cells such as epithelial or fibroblasts, or pri-mary vs immortalized/transformed cells). It is also necessary to use a cell type-specific culture medium that varies in combi-nation of growth factors and serum concentrations. If primary cells are derived from human patients or animals, some com-mercial resources have a variety of culture media available for testing. Generally, cells are manipulated in a sterile hood, and the working surfaces are wiped with 70% to 80% ethyl alcohol solution. Cultured cells are usually maintained in a humidified 5% carbon dioxide incubator at 37°C (98.6°F) to maintain a Ph value raging from 7.2 ∼ 7.4 and need to be examined daily under an inverted microscope to check for possible contamination and confluency (the area cells occupy on the dish). In some cases, cells need to be maintained in hypoxia, and the oxygen input could be reduced to as low as 1%. As a general rule, cells should be fed with fresh medium every 2 to 3 days and split when they reach confluency. Depending on the growth rate of cells, the actual time and number of plates required to split cells in two varies from cell line to cell line. Splitting a monolayer requires the detachment of cells from plates by using a trypsin or colla-genase treatment, of which concentration and time period vary depending on cell lines. If cultured cells grow continuously in suspension, they are split or subcultured by dilution.Because cell lines may change their properties when cul-tured, it is not possible to maintain cell lines in culture indefi-nitely. Therefore, it is essential to store cells at various time passages for future use. The common procedure to use is cryo-preservation. The solution for cryopreservation is usually fetal calf serum containing 10% dimethyl sulfoxide or glycerol, stored in liquid nitrogen (−196°C [−320.8°F]) for years of pres-ervation. However, the viability and health of cells when thawed will decrease over time even in liquid nitrogen.Cell Transfection. Cells are cultured for two reasons: to main-tain and to manipulate them (see Fig. 15-21). The transfer of foreign macromolecules, such as nucleic acid, into living cells provides an efficient method for studying a variety of cellular processes and functions at the molecular level. DNA transfec-tion has become an important tool for studying the regulation and function of genes. The cDNA to be expressed should be in a plasmid vector, behind an appropriate promoter working in mammalian cells (e.g., the constitutively active cytomegalo-virus promoter or inducible promoter). Depending on the cell type, many ways of introducing DNA into mammalian cells have been developed. Commonly used approaches include cal-cium phosphate, electroporation, liposome-mediated transfec-tion, the nonliposomal formulation, and the use of viral vectors. These methods have shown variable success when attempting to transfect a wide variety of cells. Transfection can be performed in the presence or absence of serum. It is suggested to test the transfection efficiency of cell lines of interest by comparing transfection with several different approaches. For a detailed transfection protocol, it is best to follow the manufacturer’s instructions for the particular reagent. General considerations for a successful transfection depend on several parameters, such as the quality and quantity of DNA and cell culture (type of cell and growth phase). To minimize variations in both of these in transfection experiments, it is best to use cells that are healthy, proliferate well, and are plated at a constant density.Depending on the transfection method, DNA expression can be transient or stable. Using calcium phosphate and lipo-some-mediated transfection, after DNA is introduced into the cells it is normally maintained epitopically in cells and will be diluted while host cells undergo cell division. Therefore, func-tional assays should be performed 24 to 72 hours after transfec-tion, also termed transient transfection. In many applications, it is important to study the long-term effects of DNA in cells by stable transfection. Thus, electroporation and viral vector are often used in these situations to enable integration of ectopic DNA into the host genome. Stable cell clones can be selected when plasmids carry an antibiotic-resistant marker. In the pres-ence of antibiotics, only those cells that continuously carry the antibiotic-resistant marker (after generations of cell division) can survive. One application of stable transfection is the gen-eration of transgenic or knockout mouse models, in which the transgene has to be integrated in the mouse genome in the ES cells, followed by microinjection of those transgenic ES cells into blastocysts to generate chimera mice. Stable cells also can be transplanted into host organs to test the effect of transgenic cells in vivo.Genetic ManipulationsUnderstanding how genes control the growth and differentia-tion of the mammalian organism has been the most challenging topic of modern research. It is essential for us to understand how genetic mutations and chemicals lead to the pathologic condi-tion of human bodies. The knowledge and ability to change the genetic program will inevitably make a great impact on society and have far-reaching effects on how we think of ourselves.The mouse has become firmly established as the primary experimental model for studying how genes control mammalian development. Genetically altered mice are powerful tools to study the function and regulation of genes as well as modeling human diseases.33 The gene function can be studied by cre-ating mutant mice through homologous recombination (gene knockout). A gene of interest (GOI) also can be intro-duced into the mouse (transgenic mouse) to study its effect on development or diseases. Because mouse models do not pre-cisely represent human biology, genetic manipulations of human somatic or ES cells provide a great means for the understanding of the molecular networks in human cells in addition to mouse models. In all cases, the gene to be manipulated must first be cloned. Gene cloning has been made easy by recombinant DNA technology and the availability of human and mouse genomes (see “Human Genome”). The following section briefly describes the technologies and the principles behind combining both mouse genetics and human cell culture to explore gene function and disease mechanisms.Transgenic Mice. During the past 20 years, DNA cloning and other techniques have allowed the introduction of new genetic material into the mouse germline. As early as 1980, the first genetic material was successfully introduced into the mouse germline by using pronuclear microinjection of DNA (Fig. 15-22). These animals, called transgenic, contain for-eign DNA within their genomes. In simple terms, a transgenic mouse is created by the microinjection of ectopic DNA into the one-celled mouse embryo to induce integration, allowing the 4Brunicardi_Ch15_p0479-p0510.indd 50018/02/19 11:12 AM 501MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15DNAPronucleusDNA microinjected intopronucleus of fertilized eggFoster mothercarryingmicroinjected DNATransgenicmouseFigure 15-22. Transgenic mouse tech-nology. DNA is microinjected into a pro-nucleus of a fertilized egg, which is then transplanted into a foster mother. The microinjected egg develops offspring mice. Incorporation of the injected DNA into offspring is indicated by the differ-ent coat color of offspring mice.efficient introduction of cloned genes into the following devel-oping mouse somatic tissues, as well as into the germline.Designs of a Transgene The transgenic technique has proven to be extremely important for basic investigations of gene regu-lation, creation of animal models of human disease, and genetic engineering of livestock. The design of a transgene construct is a simple task. Like constructs used in cell transfection, a simple transgene construct consists of a protein-encoding gene and a promoter that precedes it. The most common applications for the use of transgenic mice are similar to those in the cell culture system: (a) to study the functions of proteins encoded by the transgene, (b) to analyze the tissue-specific and developmental-stage–specific activity of a gene promoter, and (c) to generate reporter lines to facilitate biomedical studies. Examples of the first application include overexpression of oncogenes, growth factors, hormones, and other key regulatory genes, as well as genes of viral origins. Overexpression of the transgene normally represents gain-of-function mutations. The tissue distribution or expression of a transgene is determined primarily by cis-acting promoter enhancer elements within or in the immediate vicin-ity of the genes themselves. Thus, controlled expression of the transgene can be made possible by using an inducible or tissue-specific promoter. Furthermore, transgenic mice carry-ing dominant negative mutations of a regulatory gene also have been generated. For example, a truncated growth factor receptor that can bind to the ligand, but loses its catalytic activity when expressed in mice, can block the growth factor binding to the endogenous protein. In this way, the transgenic mice exhibit a loss of function of phenotype, possibly resembling the knockout of the endogenous gene. The second application of the trans-genic expression is to analyze the gene promoter of interest. The gene promoter of interest normally is fused to a reporter gene that encodes β-galactosidase (also called LacZ), luciferase, or green fluorescence protein. Chemical staining of LacZ activity or detection of chemiluminescence/fluorescence can easily visu-alize the expression of the reporter gene. The third application originates from the second: when the activity of the promoter is known, a fluorescent reporter gene (such as GFP) will be driven by the tissue-specific promoter, therefore labeling a particular type of cells at a particular stage. This application is generally used to isolate a special cell type expressing the GFP reporter by fluorescence-activated cell sorting (FACS), as well as lineage-tracing experiments.Production of Transgenic Mice The success of generating transgenic mice is largely dependent on the proper quality and concentration of the DNA supplied for microinjection. For DNA to be microinjected into mouse embryos, it should be linear-ized by restriction digestion to increase the chance of proper transgene integration. Concentration of DNA should be accu-rately determined. Mice that develop from injected eggs often are termed founder mice.Genotyping of Transgenic Mice The screening of founder mice and the transgenic lines derived from the founders is accomplished by determining the integration of the injected gene into the genome. This normally is achieved by performing PCR or Southern blot analysis with a small amount of DNA extracted from the mouse tail. Once a given founder mouse is identified to be transgenic, it will be mated to begin establish-ing a transgenic line. Usually, for a given gene, more than one transgenic line is generated to assure that the phenotype is due to transgene but not to the interruption of the gene where the transgene integrates into.Analysis of Phenotype of Transgenic Mice Phenotypes of transgenic mice are dictated by both the expression pattern and biologic functions of the transgene. Depending on the promoter and the transgene, phenotypes can be predictable or unpredict-able. Elucidation of the functions of the transgene-encoded pro-tein in vitro often offers some clue to what the protein might function to do in vivo. When a constitutively active promoter is used to drive the expression of transgenes, mice should express the gene in every tissue; however, this mouse model may not allow the identification and study of the earliest events in dis-ease pathogenesis. Ideally, the use of tissue-specific or induc-ible promoter allows one to determine if the pathogenic protein leads to a reversible or irreversible disease process in a cell-autonomous manner. For example, rat insulin promoter can tar-get transgene expression exclusively in the β-cells of pancreatic islets. The phenotype of insulin promoter-mediated transgenic mice is projected to affect the function of human β-cells.Gene Knockout in Mice. The first recorded knockout mouse was created by Mario R. Capecchi, Sir Martin J. Evans, and Oliver Smithies in 1989. They were awarded the 2007 Nobel Prize in Physiology or Medicine. The isolation and genetic manipulation of mouse ES cells represents one of the most important milestones for modern genetic technologies.34 Sev-eral unique properties of ES cells, such as the pluripotency to differentiate into all germ layers in an embryo, including the germline, make them an efficient vehicle to introduce genetic alterations in mice. An important breakthrough from this idea is to generate gene-targeted mutation in mice, first by introduc-ing the targeting vector into the ES cells, allowing selection Brunicardi_Ch15_p0479-p0510.indd 50118/02/19 11:12 AM 502BASIC CONSIDERATIONSPART IES cells growingin tissue cultureAltered versionof target geneconstructed bygenetic engineeringLet each cellgrow to forma colonyTest for the rarecolony in whichthe DNA fragmenthas replaced one copy of the normal geneES cells with one copy of target genereplaced by mutant geneInjectES cellsintoearly embryoFemale mouseMate and wait3 daysIsolatedearlyembryoEarly embryo partlyformed fromES cellsIntroduceearly embryo intopseudopregnantmouseSomatic cellsof offspring tested forpresence ofaltered gene, and selected mice bredto test for genein germline cellsTransgenic mouse with one copy of target genereplaced by altered gene in germlineABBirthIntroduce a DNA fragmentcontaining altered geneinto many cellsFigure 15-23. Knockout mouse technology. Summary of the procedures used for making gene replacements in mice. In the first step (A), an altered version of the gene is introduced into cultured embryonic stem (ES) cells. Only a few rare ES cells will have their corresponding normal genes replaced by the altered gene through a homologous recombination event. Although the procedure is often laborious, these rare cells can be identified and cultured to produce many descendants, each of which carries an altered gene in place of one of its two normal corresponding genes. In the next step of the procedure (B), these altered ES cells are injected into a very early mouse embryo; the cells are incorporated into the growing embryo, and a mouse produced by such an embryo will contain some somatic cells that carry the altered gene. Some of these mice also will contain germline cells that contain the altered gene. When bred with a normal mouse, some of the progeny of these mice will contain the altered gene in all of their cells. If two such mice are in turn bred (not shown), some of the progeny will contain two altered genes (one on each chromosome) in all of their cells. If the original gene alteration completely inactivates the function of the gene, these mice are known as knockout mice. When such mice are missing genes that function during development, they often die with specific defects long before they reach adulthood. These defects are carefully analyzed to help decipher the normal function of the missing gene. (Reproduced with permission from Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 6th ed. New York, NY: WW Norton Company; 2015.)for successful homologous recombination in a dish, then intro-ducing the selected ES clone into the blastocysts, and finally recovering animals bearing the mutant allele from the germline (Fig. 15-23). This not only makes mouse genetics a powerful approach to address important gene functions, but also identifies the mouse as a great system to model human disease.Targeting Vector The basic concept in building a target vec-tor to knock out a gene is to use two segments of homologous sequence to a GOI that flank a part of the gene essential for functions (e.g., the coding region). In the targeting vector, a pos-itive selectable marker (e.g., the neo gene) is placed between the homology arms. Upon the homologous recombination between the arms of the vector and the corresponding genomic regions of the GOI in ES cells, the positive selectable marker will replace the essential segment of the target gene, thus creating a null allele. In addition, a negative selectable marker also can Brunicardi_Ch15_p0479-p0510.indd 50218/02/19 11:12 AM 503MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15be used alone or in combination with the positive selectable marker, but must be placed outside of the homologous arms to enrich for homologous recombination. To create a conditional knockout (i.e., gene knockout in a spatiotemporal fashion), site-specific recombinases such as the popular cre-loxP system are used. If the consensus loxP sequences that are recognized by cre recombinases are properly designed into targeting loci, con-trolled expression of the recombinase as a transgene can result in the site-specific recombination at the right time and in the right place (i.e., cell type or tissue). This method, often referred to as conditional knockout, is markedly useful to prevent devel-opmental compensations and to introduce null mutations in the adult mouse that would otherwise be lethal. To bring in addi-tional control to tissue-specific cre, an inducible cre could be adopted on top of the tissue-specific promoter. The most popu-lar inducible cre includes CreER: CreER encodes a cre fused with estrogen receptor located to cytosol. With the signaling of tamoxifen, CreER is released and then translocates into the nucleus to induce the recombination of loxP. Therefore, the tim-ing of recombination could be precisely determined by control-ling the time of administering tamoxifen. Overall, this cre-loxP system allows for spatial and temporal control over transgene expression and takes advantage of inducers with minimal pleio-tropic effects.Introduction of the Targeting Vector into ES Cells ES cell lines can be obtained from other investigators or commer-cial sources or established from blastocyst-stage embryos. To maintain ES cells at their full developmental potential, opti-mal growth conditions should be provided in culture. If cul-ture conditions are inappropriate or inadequate, ES cells may acquire genetic lesions or alter their gene expression patterns and consequently decrease their pluripotency. Excellent proto-cols are available in public domains or in mouse facilities in most institutions.To alter the genome of ES cells, the targeting vector DNA then is transfected into ES cells. Electroporation is the most widely used and the most efficient transfection method for ES cells. Similar procedures for stable cell transfection are used for selecting ES cells that carry the targeting vector. High-quality, targeting-vector DNA free of contaminating chemicals is first linearized and then electroporated into ES cells. Stable ES cells are selected in the presence of a positive selectable antibiotic drug. After a certain period of time and depending on the type of antibiotics, all sensitive cells die, and the resistant cells grow into individual colonies of the appropriate size for subcloning by picking. It is extremely important to minimize the time dur-ing which ES cells are in culture between selection and injection into blastocysts. Before injecting the ES cells, DNA is prepared from ES colonies to screen for positive ES cells that exhibit the correct integration or homologous recombination of the target-ing vector. Positive ES colonies are then expanded and used for creation of chimeras.Creation of the Chimera A chimeric organism is one in which cells originate from more than one embryo source. Here, chi-meric mice are denoted as those that contain some tissues from the ES cells with an altered genome. When these ES cells give rise to the lineage of the germ layer, the germ cells carrying the altered genome can be passed on to the offspring, thus creating the germline transmission from ES cells. There are two methods for introducing ES cells into preimplantation-stage embryos: injection and aggregation. The injection of embryonic cells directly into the cavity of blastocysts is one of the fundamen-tal methods for generating chimeras, but aggregation chimeras also have become an important alternative for transmitting the ES cell genome into mice. Since every tissue type of a chimera should contain cells from different origins, the mixture of rec-ognizable markers (e.g., coat color) that are specific to the donor mouse and the ES cells can be used to identify chimeric mice. However, most experimenters probably use existing mouse core facilities already established in some institutions or contract a commercial vendor for the creation of a chimera.Genotyping and Phenotyping of Knockout Animals The next step is to analyze whether germline transmission of tar-geted mutation occurs in mice. DNA from a small amount of tissue from offspring of the chimera is extracted and subjected to genomic PCR or Southern blot DNA hybridization. Positive mice (i.e., those with properly integrated targeting vector into the genome) will be used for the propagation of more knockout mice for phenotype analysis. When the knockout genes are cru-cial for early embryogenesis, mice often die in utero, an occur-rence called embryonic lethality. When this happens, only the phenotype of the homozygous (both alleles ablated) knockout mouse embryos and the phenotype of the heterozygous (only one allele ablated) adult mice can be studied. Because most researchers are interested in the phenotype of adult mice, in par-ticular when using mice as disease models, it is recommended to create the conditional knockout using the cre-loxP system so that the GOI can be knocked out at will.To date, more than 5000 genes have been disrupted by homologous recombination and transmitted through the germline. The phenotypic studies of these mice provide ample information about the functions of these genes in growth and differentiation of organisms and during development of human diseases.RNA Interference. Although gene ablation in animal models provides an important means to understand the in vivo functions of GOI, animal models may not adequately represent human biology. Alternatively, gene targeting can be used to knock out genes in human cells, including human ES cells. Gene targeting in human ES cells by homologous recombination has extremely low efficiency, although there are more new techniques emerg-ing aimed at increasing the targeting efficiency. A number of recent advances have made gene targeting in somatic cells as easy as in murine ES cells.33 However, gene targeting (knocking out both alleles) in somatic cells is a time-consuming process.Development of RNAi technology in the past few years has provided a more promising approach to understanding the biologic functions of human genes in human cells.35 RNAi is an ancient natural mechanism by which small, double-stranded RNA (dsRNA) acts as a guide for an enzyme complex that destroys complementary RNA and downregulates gene expres-sion in a sequence-specific manner. Although the mechanism by which dsRNA suppresses gene expression is not entirely understood, experimental data provide important insights. In nonmammalian systems such as Drosophila, it appears that longer dsRNA is processed into 21–23 nt dsRNA (called small interfering RNA or siRNA) by an enzyme called Dicer contain-ing RNase III motifs. The siRNA apparently then acts as a guide sequence within a multicomponent nuclease complex to target complementary mRNA for degradation. Because long dsRNA induces a potent antiviral response pathway in mammalian cells, short siRNAs are used to perform gene silencing experiments in mammalian cells (Fig. 15-24).Brunicardi_Ch15_p0479-p0510.indd 50318/02/19 11:12 AM 504BASIC CONSIDERATIONSPART IPol IIITTTTTshRNAsiRNADicerRISCUUUUUUmRNAm7GAAAAAAmRNA targeted by siRNAUUm7GAAAAAAmRNA cleaved and degradedm7GAAAAAAFigure 15-24. RNA interference in mammalian cells. Small interfering RNA (siRNA) can be produced from a polymerase III–driven expres-sion vector. Such a vector first synthesizes a 19–29 nt double-stranded (ds)RNA stem and a loop (labeled as shRNA in the figure), and then the RNase complex called Dicer processes the hairpin RNA into a small dsRNA (labeled as siRNA in the figure). siRNA can be chemically synthesized and directly introduced into the target cell. In the cell, through RNA-induced silencing complex (RISC), siRNA recognizes and degrades target messenger RNAs (mRNAs).For siRNA studies in mammalian cells, researchers have used two 21-mer RNAs with 19 complementary nucleotides and 3′ terminal noncomplementary dimers of thymidine or uri-dine. The antisense siRNA strand is fully complementary to the mRNA target sequence. Target sequences for an siRNA are identified visually or by software.The target 19 nucleotides should be compared to an appro-priate genome database to eliminate any sequences with sig-nificant homology to other genes. Those sequences that appear to be specific to the GOI are the potential siRNA target sites. A few of these target sites are selected for siRNA design. The antisense siRNA strand is the reverse complement of the target sequence. The sense strand of the siRNA is the same sequence as the target mRNA sequence. A deoxythymidine dimer is rou-tinely incorporated at the 3′ end of the sense strand siRNA, although it is unknown whether this noncomplementary dinu-cleotide is important for the activity of siRNAs.There are two ways to introduce siRNA to knock down gene expression in human cells:1. RNA transfection: siRNA can be made chemically or using an in vitro transcription method. Like DNA oligos, chemically synthesized siRNA oligos can be commercially ordered. However, synthetic siRNA is expensive, and sev-eral siRNAs may have to be tried before a particular gene is successfully silenced. In vitro transcription provides a more economic approach. Both short and long RNA can be synthesized using bacteriophage RNA polymerase T7, T3, or SP6. In the case of long dsRNAs, RNase such as recom-binant Dicers will be used to process the long dsRNA into a mixture of 21–23 nt siRNA. siRNA oligos or mixtures can be transfected into a few characterized cell lines such as HeLa (human cervical carcinoma) and 293T cells (human kidney carcinoma). Transfection of siRNA directly into pri-mary cells may be difficult.2. DNA transfection: Expression vectors for expressing siRNA have been made using RNA polymerase III promoters such as U6 and H1. These promoters precisely transcribe a hairpin structure of dsRNA, which will be processed into siRNA in the cell (see Fig. 15-24). Therefore, properly designed DNA oligos corresponding to the desired siRNA will be inserted downstream of the U6 or H1 promoter. There are two advan-tages of the siRNA expression vectors over siRNA oligos. First, it is easier to transfect DNA into cells. Second, sta-ble populations of cells can be generated that maintain the long-term silencing of target genes. Furthermore, the siRNA expression cassette can be incorporated into a retroviral or adenoviral vector to provide a wide spectrum of applications in gene therapy.There has been a fast and fruitful development of RNAi tools for in vitro and in vivo use in mammals. These novel approaches, together with future developments, will be crucial to put RNAi technology to use for effective disease therapy or to exert the awesome power of mammalian genetics. Therefore, the applications of RNAi to human health are enormous. siRNA can be applied as a new tool for sequence-specific regulation of gene expression in functional genomics and biomedical studies. With the availability of the human genome sequences, RNAi approaches hold tremendous promise for unleashing the dor-mant potential of sequenced genomes.Practical applications of RNAi will possibly result in new therapeutic interventions. In 2002, the concept of using siRNA in battling infectious diseases and carcinogenesis was proven effective. These include notable successes in blocking repli-cation of viruses, such as HIV, hepatitis B virus, and hepati-tis C virus, in cultured cells using siRNA targeted at the viral genome or the human gene encoding viral receptors. RNAi has been shown to antagonize the effects of hepatitis C virus in mouse models. In cancers, silencing of oncogenes such as c-Myc or Ras can slow down the proliferation rate of cancer cells. Finally, siRNA also has potential applications for some dominant genetic disorders.The 21st century, already heralded as the “century of the gene,” carries great promise for alleviating suffering from dis-ease and improving human health. On the whole, completion of Brunicardi_Ch15_p0479-p0510.indd 50418/02/19 11:12 AM 505MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15the human genome blueprint, the promise of gene therapy and molecular therapies, and the existence of stem cells have cap-tured the imagination of the public and the biomedical commu-nity. Aside from their potential in curing human diseases, these emerging technologies also have provoked many political, eco-nomic, religious, and ethical discussions. As more is discerned about the technologic scientific advances, more attention must also be paid to concerns for their inherent risks and social impli-cations. It is important for surgeons to play a leadership role in the emergence of personalized medicine and surgery, as sur-geons have access to the diseased tissues. Surgeons should be establishing collaborations with the genomic and molecular sci-entists to develop genomic biobanks in order to study the genome and molecular signaling of the disease tissues that will help with an understanding of the underlying cause of an indi-vidual’s disease and ultimately lead to effective, targeted thera-pies. Surgeons must take this enormous opportunity to collaborate with basic and clinical scientists to develop the field of precision medicine and surgery this century.Bifunctional RNAi Technology.36 Over the last 20 years, the field has worked to define oncogene and nononcogene addic-tion, discriminate between driver and passenger genes, and appreciate the complexity of complex, robust, network interac-tions. These insights have led to a preliminary understanding of therapeutically relevant sensitivity and resistance pathway signal patterns requiring multiple target modulation. However, this knowledge has not been effectively or reproducibly clini-cally translated. Clinical response is usually far greater when a combination of single-target molecular therapy is administered. However, it must also be realized that targeting two or more pathways may also increase the toxicity profile, particularly if target specificity is limited. When attempted, off-target toxic-ity has been demonstrated with combination small-molecule therapy. In contrast, multitargeting bifunctional short hairpin (bi-shRNA) DNA vectors are designed to limit off-target effect given the high specificity for the genes they are designed to target.Exogenously applied hairpin constructs can be designed to be incorporated into cleavage-dependent RISC or cleav-age-independent RISC complexes, or both. The concept of a bifunctional shRNA37 is to increase knockdown efficiency without loss of sequence specificity by engaging both siRNA and miRNA-like (i.e., common biogenic pathway but comple-mentary to target sequence) RISCs, thereby concurrently acti-vating nucleolytic (Ago2-RISC) and nonnucleolytic (Ago1, 3, 4 ± Ago2-RISC) processes.38 Each bi-shRNA contains both a matched stem sequence to promote Ago2-mediated passenger strand cleavage and a second partial mismatched stem sequence for cleavage-independent passenger strand departure. Thus, functionality of the effectors is set by programmed passenger strand guided RISC loading rather than Ago subset distribution in the cancer cell. Both component Ago2 and Ago (1, 2, 4 ± 3) RNAi moieties are fully complementary to the mRNA target sequence. Preliminary data indicate reduced “off-target effects” by shRNA compared with target-identical siRNAs. More than two mismatches in sequences within the target region drasti-cally reduce knockdown effect to undetectable levels (unpub-lished results). The design process involves in silico scanning of the entire human mRNA RefSeq database to avoid any potential sequence-related “off-target effects.” Published data also indicate persistent susceptibility to shRNA-mediated gene 5knockdown despite recent evidence of reduced Dicer expression in human cancer cells.39The first clinical experience with the bi-shRNA platform involved the ex vivo knockdown of furin, a Ca2+-dependent, nonredundant proprotein convertase that is essential for pro-teolytic maturational processing of immunosuppressive TGF-β isoforms (β1 and β2). An autologous whole-cell cancer vac-cine, FANG™ (furin-knockdown and GMCSF-augmented),40 was produced based on a dual function immunosensitization principle of augmenting tumor antigen expression, presentation, and processing via granulocyte-macrophage colony-stimulating factor (GMCSF) cytokine transgene expression and attenuating secretory immunosuppressive TGF-β. Harvested, autologous cancer cells are transfected with the GMCSF/bi-shRNAfurin (FANG) expression plasmid via electroporation. A phase I clinical trial (BB-IND 14205) involving 52 cancer patients was recently completed. Results demonstrated better than 90% knockdown of the bi-shRNA target, furin, and better than 90% knockdown of furin-regulated proteins TGF-β1 and TGF-β2, thereby confirming the mechanistic expectation of this novel RNAi platform. Moreover, predicted extensive GMCSF expres-sion verified our ability to successfully construct multi-cassette vectors with good manufacturing practice techniques fulfilling Food and Drug Administration requirements for clinical testing.Twenty-seven patients received one or more vaccine dose, and 23 patients achieved stable disease as their best response. No toxic effect was identified. Median survival of the FANG™-treated patients from time of procurement was 554 days and has not been reached from time of treatment. Expected survival of similar patients is historically less than 1 year. Sequential enzyme-linked immunosorbent spot (ELISPOT) analysis revealed a dramatic and significant increase in immune response from baseline to month 4 in half of the FANG™-treated patients. Comparison of survival between ELISPOT-positive and ELISPOT-negative patients demonstrated a statistically significant increase in survival from time of procurement (P = .045) and time of treatment (P = .025).These phase 1 study results demonstrated mechanism, safety, and effectiveness of the bi-shRNA technology and clini-cal functionality of a multitargeting (dual) DNA expression vec-tor. Further utilization of bi-shRNAi technology is under way clinically (targeting STMN1, a microtubule modulation criti-cal to cancer program) and preclinically targeting PDX141 (an oncogene-like transcription factor for pancreatic embryogenesis using nonviral nanoparticle delivery mechanisms).42Precision Medicine and Surgery43Genes determine our susceptibility to diseases and direct our body’s response to medicine. Because an individual’s genes dif-fer from those of another, the determination of each individual’s genome has the potential to improve the predication, prevention, and treatment of disease. Sequencing of individual genomes holds the key to realize this revolution called precision medicine and surgery. Next-generation sequencing, such as Illumina sequencing and 454 pyrosequencing technology, is promising to reduce the time and cost so that genome sequencing can be affordable within healthcare systems. The goal of precision medicine and surgery is to identify the gene variations in each individual and to target the specific gene variations causing the disease by choosing personalized treatments that effectively work in association with the individual’s genomic profile. The importance of surgeons in this transformational field of Brunicardi_Ch15_p0479-p0510.indd 50518/02/19 11:12 AM 506BASIC CONSIDERATIONSPART Ibiomedical science is that surgeons have access to the diseased tissues on a daily basis. Surgeons should partner with the genomic scientists to develop genomic biobanks in order to study the genome of the disease tissues and determine how this information can improve the outcomes of surgery, i.e., precision surgery. These discovery studies are rapidly leading to the uncovering of mutations and SNPs that are the underlying cause of an individual’s disease and ultimately lead to targeted thera-pies. Although precision medicine and surgery holds the poten-tial to revolutionize the practice of modern medicine, there currently exists a gap between our ability to sequence any given individual’s genome and how clinicians can apply this informa-tion to guide care. There is a rapidly growing list of single genes that are currently guiding care, and these genes are listed as type 1 precision genes. Examples of these genes are BRCA1, RET proto-oncogene, and CHD1 mutation, which guide potential use of mastectomy, thyroidectomy, and gastrec-tomy, respectively; however, the great challenge before the sci-entific and medical community this century is to learn to use the entire genome to guide precision care.Targeted Genome Editing Using the CRISPR-Cas9 SystemConventional genetic manipulations have proven their value in biomedical research. Researchers today depend on the manipu-lation of genetic materials in cells or in animal models in almost every project they work on. These genetic manipulation tech-niques (see “Genetic Manipulations”), though sufficient for gen-eral research purposes, suffer from disadvantages. Transfection of target genes into cells is quick and specific, but nonnative. RNA interference (RNAi) is easy to perform and targets native genes, but RNAi never fully eliminates the target gene, and off-target effects are commonly seen using RNAi. Gene knockout mice provide an ideal platform to study native genes with clean background, but conventional knockout methods are time-consuming and costly.An entirely new gene-editing method now known as the CRISPR-Cas9 system has emerged since 201344-46 and has quickly gained popularity among biologists for gene edit-ing. This new method is easy to perform, can work specifi-cally on the desired gene or DNA sequence, and can generate gene knockout, knock-in, point mutation, or the insertion of an epitope tag in almost any cell line or animal models with high efficiencies.CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats.47 It is a region on the genomic DNA first discovered in the microbes as an adapted immune system against exogenous DNA. A typical CRISPR region contains a cluster of short (21–48 bp) DNA repeats (ranging from 2 to hundreds) interspaced by nonrepetitive sequences called spacers.47 Within a CRISPR region, while each spacer has its unique sequence, the sequence of the repeats is highly conserved. Several genes, called the CRISPR-associated (Cas) genes, are almost always found directly flanking the CRISPR region.Extensive studies in the past decade revealed the function of the CRISPR-cas system in DNA-interfering. When bacte-ria or archaea carrying the CRISPR-cas system are invaded by phage or plasmid DNA, a new spacer can be added to the CRISPR region with its sequence identical to the “proto-spacer,” a fragment of the invading DNA.47 It was found that the proto-spacer must be followed by a recognition sequence (NGG in the case of Cas9) called proto-spacer associated motif 67(PAM).46 With constitutive transcription, the CRISPR region is transcribed as mRNA, and cut by Cas proteins to generate RNA fragments minimally containing one spacer and parts of the repetitive sequence.47 This fragment associates with target DNA through Watson-Crick base-pairing and directs the cutting of target DNA by Cas proteins with nuclease activity.Several CRISPR-Cas systems have been characterized, with a variety of Cas proteins found in these systems. Cas9 in the type II system from Streptococcus pyogenes is the most commonly used Cas for gene editing.46,48 Cas9 contains one RuvC-like nuclease domain near its N-terminal and one HNH-like nuclease domain in the middle of the protein. The RuvC-like domain cuts the proto-spacer strand (the strand with PAM), and the HNH-like domain cuts the strand pairing with the spacer,49 resulting in a double-strand break (DSB) on the target DNA. It is known that Cas9 cuts a blunt end 3 bp 5’ to the PAM sequence.46 The specificity provided by the spacer, or so-called “guide RNA,” and the ability of Cas9 to cut double-stranded DNA means that this system can specifically target anywhere in a genome with a known sequence.CRISPR-Cas9–Guided Gene Editing. The CRISPR-Cas9 sys-tem was made suitable for gene editing in mammalian cell lines and in animal models through several years of optimization. The key concept for CRISPR-Cas9–mediated gene editing is to introduce DNA strand break and let the cell repair the break. Through the repair process, sequence deletions, insertions, and mutations can be applied to the target gene.Two DNA repair pathways are utilized in CRISPR-Cas9–mediated gene editing: the nonhomologous end-joining (NHEJ) pathway and the homology-directed repair (HDR).49 When a homologous repair template is unavailable, the NHEJ path-way joins the ends of the DSB together, usually with random insertion/deletion (indel) mutations. Such mutations within an open reading frame can cause frameshift and/or premature stop codons. When a repair template is available, however, the cell may choose HDR and repair the DSB through pairing with the template. The HDR pathway can introduce longer insertion/ deletion mutations than NHEJ and can specify the mutated sequence (by contrast, NHEJ creates random mutations). However, HDR is usually only active in dividing cells and is of a lower efficiency than NHEJ. Its efficiency also depends on gene loca-tion, cell type, and the repair template.50 Therefore, the choice of the pathway depends on the need of the outcome: to simply create a gene knockout, NHEJ is much simpler and highly effi-cient; to achieve precise gene editing (introduce a specific muta-tion, add or delete a specific sequence), HDR must be used. The two pathways have similar protocols, but they differ in certain details in experimental designs.Gene Editing Through NHEJ Tools for NHEJ-mediated gene editing can be incorporated onto one simple plasmid, including a single-guide RNA (sgRNA) sequence containing the guide RNA, a U6 promoter driving the expression of the sgRNA, and an expression cassette including codon-optimized Cas9 fused with nuclear localization sequences (NLS) and an optional selection marker (puromycin resistance or a GFP).46 NHEJ is usually used to knock out a target gene (Fig. 15-24). Generally, a 20 bp sequence preceding a PAM sequence (NGG for Cas9) is selected as the guide RNA sequence. This sequence can be chosen within the first couple of exons through running online search engines against the target genome to minimize off-target probabilities. The guide RNA sequence is then inserted into the Brunicardi_Ch15_p0479-p0510.indd 50618/02/19 11:12 AM 507MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15Figure 15-25. CRISPR-Cas9–mediated gene editing through NHEJ or HDR. The Cas9 protein cleaves target DNA through its RuvC-like and HNH-like domains, guided by the sgRNA. The cell repairs the double-strand break through either NHEJ or HDR. In NHEJ, the broken ends are recognized, bound, and tethered by end-binding protein complexes. The ends are then processed and ligated but may result in ran-dom insertion/deletion (experimentally, deletions are more commonly seen) mutations at the break site. The repair process in HDR, however, generates no random error due to the presence of a homologous repair template. During the repair, the broken strands find the homologous template and proceed with DNA synthesis using the template. This results in a repaired DNA that has the same sequence as the repair template. Therefore, point mutations, insertions, or deletions carried on the template will be inherited by the repaired DNA and thus achieve precise gene editing.designed site within the sgRNA, and the constructed plasmid is transfected into target cells. Expressed Cas9 proteins would associate with expressed sgRNAs to mediate DSB directed by the guide RNA sequence. For cell lines, pure mutant clones can be generated by separating single colonies. Knockout mutations can be confirmed through PCR amplification of the target region and sequencing. If antibodies against the target protein are avail-able, western blotting can be used as a supplemental method to DNA sequencing results to confirm the knockout of the gene.Gene Editing Through HDR HDR requires a homologous tem-plate to repair the DSB. Therefore, apart from the guide RNA, another sequence homologous to the flanking regions of the DSB needs to be present (Fig. 15-25). The homologous sequence can carry insertions, deletions, and mutations to replace the sequence at the DSB, thus achieving precise gene editing on the target. The homologous sequence can be introduced into the cell either as a template on a plasmid or as a single-stranded oligonucleotide.46 After the induction of the DSB, the homologous template pairs with the flanking regions of the DSB and serves as the template for the repair of the break site. HDR happens at lower efficiency than NHEJ and therefore is of lower success rate than NHEJ-mediated gene editing. Therefore, HDR is only recommended when precise mutations are desired. Fast screen of positive mutant clones can be achieved by incorporating restriction enzyme cutting sites within the homologous template.Reducing Off-Target Effects Using Cas9 Nickase The CRISPR-Cas9 system uses a 20 bp guide RNA for sequence recognition. Due to the similar length of recognition sequence to RNAi techniques, CRISPR-Cas9 system also suffers from off-target effects. Because CRISPR-Cas9 requires a PAM site directly following the guide RNA sequence, one way to reduce off-targets is to run through online databases against the genome of the target cell to select a target sequence with the least number of possible off-targets (CRISPR-Cas9 system tolerates no more than three mismatches). On the other hand, a mutant version of the Cas9 called Cas9 nickase can be used to minimize the risk of off-targets.As mentioned, Cas9 contains one RuvC-like and one HNH-like nuclease domain, each responsible for cutting one strand.49 The D10A mutant Cas9 (Cas9 nickase) lacks the activ-ity of the RuvC-like domain, leaving the proto-spacer strand intact and a nick on the antisense strand.46 Using two prop-erly spaced (0–20 bp apart), oppositely oriented guide RNA, the Cas9 nickase will leave two single-strand nicks on both strands in close proximity, creating a double-strand break with 5’ overhangs on both strands. This leads to NHEJ or HDR at this breaking site, while other off-target single-strand nicks will be repaired without impact. This strategy doubles the number of base pairs required for site recognition, reducing off-target possibilities almost to zero (from about 1 off-target in 30 million bp to 1 in 1000 trillion bp).Application of the CRISPR-Cas9 System in Biomedical Sciences The biggest advantage of the CRISPR-Cas9 system is its ability to edit genes in almost any cell type and any ani-mal model with high efficiency and accuracy. Plus, it is easy to design and easy to use. Within a couple of years, success-ful gene editing in C. elegans,51 zebrafish,52 fruit fly,53 mouse,54 dogs,55 and even nonhuman primates56 was achieved. CRISPR-Cas9 was also reported to be successful in a variety of cell types including stem cells.Currently, CRISPR-Cas9 is most used for editing single genes, through gene knockout, gene mutation, or the addition of an epitope tag to a native gene, for functional characterization of the gene of interest. For example, oncogenes or tumor suppres-sor genes can be knocked out to identify the causative gene for a particular cancer type; point mutations in functional domains homologous templateprecise editingNHEJ5’3’5’3’5’3’5’3’5’3’3’5’3’5’3’5’3’5’3’5’3’Cas9 RuvC domainHNHdomainPAMsgRNA5’5’3’HDRRandom insertion/deletionBrunicardi_Ch15_p0479-p0510.indd 50718/02/19 11:12 AM 508BASIC CONSIDERATIONSPART Imay illustrate the mechanism of action of a protein; for proteins without available antibodies, epitope tags can be inserted onto the native gene for the detection of the native protein.Apart from single gene editing, CRISPR-Cas9 can be used for large scale loss-of-function gene screen. Multiple lentiviral guide RNA libraries have been established covering the whole human/mouse genome or particular subsets.Owing to its ability to bind to specific nucleotide sequences, CRISPR-Cas9 has also been used for non–gene-editing purposes. To achieve this, both the RuvC-like and the HNH-like domains are mutated to give a catalytically inactive Cas9 (dCas9). Directed by guide RNA, this dCas9 can bind to particu-lar genes to reversibly suppress or activate gene transcription by the fusion of transcription activators or suppressors with dCas9. Epigenetic modulators (e.g., DNA methylase) can also be fused with dCas9 to achieve controlled epigenetic modulations. More-over, dCas9 can also be fused with fluorescent markers such as GFP to track a particular DNA region in live cells.The most exciting potential application of the CRISPR-Cas9 system is perhaps the correction or modification of dis-ease-causing genes in human embryos or in human patients to eradicate disease-causing genes. However, extension of this application may lead to the creation of the so called “perfect human,” hence raising huge ethical concerns and controversies.57 Because of such ethical considerations, gene editing in human embryos should be cautiously conducted. Nonetheless, reports have shown the great potential of this powerful gene-editing technique in correcting gene mutations.58-60In conclusion, the CRISPR-Cas9 system is the most pow-erful gene-editing system characterized so far, showing its strong ability to edit genes efficiently and precisely. Its applica-tions greatly benefit biomedical researches and, with a solution to ethical issues, can greatly benefit clinical medicine as well.REFERENCESEntries highlighted in bright blue are key references. 1. Watson JD, Crick FH. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature. 1953;171(4356):737-738. 2. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed. 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Ausubel FM, Brent R, Kingston RE, et al. Current Protocols in Molecular Biology. 3rd ed. New York: John Wiley & Sons; 1995. 26. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975;98(3):503. 27. Mullis K, Faloona F, Scharf S, Saiki R, Horn G, Erlich H. Specific enzymatic amplification of DNA in vitro: the poly-merase chain reaction. Cold Spring Harb Symp Quant Biol. 1986;51(pt 1):263-273. 28. Bowtell D, Sambrook J. DNA Microarrays: A Molecular Clon-ing Manual. 1st ed. New York: Cold Spring Harbor Laboratory Press; 2002. 29. Caruccio N. Preparation of next-generation sequencing libraries using Nextera™ technology: simultaneous DNA fragmentation and adaptor tagging by in vitro transposition. Methods Mol Biol. 2011;733:241-255. 30. Pettersson E, Lundeberg J, Ahmadian A. Generations of sequencing technologies. Genomics. 2009;93(2):105-111. 31. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399-405. 32. Bonifacino JS, Dasso M, Harford JB, et al. Current Protocols in Cell Biology. New York: John Wiley & Sons; 2003. 33. Nagy A. Manipulating the Mouse Embryo: A Laboratory Manual. 3rd ed. New York: Cold Spring Harbor Laboratory Press; 2002. 34. Evans M. Discovering pluripotency: 30 years of mouse embry-onic stem cells. Nat Rev Mol Cell Biol. 2011;12(10):680-686. 35. Steitz JA. In: Hannon GH, ed. RNAi: A Guide to Gene Silenc-ing. New York: Cold Spring Harbor Laboratory Press; 2003.Brunicardi_Ch15_p0479-p0510.indd 50818/02/19 11:12 AM 509MOLECULAR BIOLOGY, THE ATOMIC THEORY OF DISEASE, AND PRECISION SURGERYCHAPTER 15 36. Rao DD, Senzer N, Wang Z, Kumar P, Jay CM, Nemunaitis J. Bifunctional short hairpin RNA (bi-shRNA): design and pathway to clinical application. Methods Mol Biol. 2013; 942:259-278. 37. Rao DD, Maples PB, Senzer N, et al. 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Brunicardi_Ch15_p0479-p0510.indd 51018/02/19 11:12 AMThis page intentionally left blankIIPart Specific ConsiderationsBrunicardi_Ch16_p0511-p0540.indd 51119/02/19 3:08 PMBrunicardi_Ch16_p0511-p0540.indd 51219/02/19 3:08 PMThis page intentionally left blankThe Skin and Subcutaneous TissuePatrick Harbour and David H. Song 16chapterINTRODUCTIONThe skin is a complex organ encompassing the body’s surface and is continuous with the mucous membranes. Accounting for approximately 15% of total body weight, it is the largest organ in the human body. Enabled by an array of tissue and cell types, intact skin protects the body from external insults. However, the skin is also the source of a myriad of pathologies that include inflammatory disorders, mechanical and thermal injuries, infec-tious diseases, and benign and malignant tumors. The intrica-cies and complexities of this organ and associated pathologies are reasons the skin and subcutaneous tissue remain of great interest and require the attention of various surgical disciplines that include plastic surgery, dermatology, general surgery, and surgical oncology.ANATOMY AND HISTOLOGYBackgroundIt is important that surgeons understand completely the cutane-ous anatomy and its variability as they play an enormous role in patient health and satisfaction. The skin is made up of tissues derived from both the ectodermal and mesodermal germ cell layers.1 Three distinct tissue layers comprise the organ, and differ in composition based on location, age, sex, and ethnicity, among other variables. The outermost layer is the epidermis, which is predominantly characterized by a protective, highly keratinized layer of cells. The next layer is the dermis, which is made up of an organized collagen network to support the numerous epider-mal appendages, neurovascular structures, and supportive cells within the skin. The fatty layer below the dermis is collectively known as the hypodermis and functions in body processes of thermoregulation and energy storage, among others. These three distinct layers function together harmoniously and participate in numerous activities essential to life.2EpidermisThe epidermis is the outermost layer of the cutaneous tissue, and consists primarily of continually regenerating keratinocytes. The tissue is also stratified, forming four to five histologically distinct layers, depending on the location in the body. These layers are, from deep to superficial, the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum (Fig. 16-1). The different layers of the epidermis represent layers of keratinocytes at differing stages of their approximately thirty-day life cycle. A minority of other cell types are found in different layers of the epidermis as well. Some of these cells are permanent residents, while others are visitors from other parts of the body. All the epidermal appendages, such as sweat glands and pilosebaceous follicles, are derived from this tissue. The thickness of the epidermis is quite variable with regard to location and age, ranging from 75 to 150 µm in thin skin (eyelids) to 0.4 to 1.5 mm in thick skin (palms and soles).2 The epidermis lacks any vascular Introduction513Anatomy and Histology513Background / 513Epidermis / 513Epidermal Components / 514Epidermal Appendages / 515Dermal Components / 516Cells / 516Cutaneous Vasculature / 516Cutaneous Innervation / 517Hypodermis / 517Inflammatory Conditions517Hidradenitis Suppurativa / 517Pyoderma Gangrenosum / 517Epidermal Necrolysis / 517Injuries518Radiation-Induced Injuries / 518Trauma-Induced Injuries / 519Caustic Injury / 520Thermal Injury / 521Pressure Injury / 523Bioengineered Skin Substitutes524Bacterial Infections of the Skin and Subcutaneous Tissue524Introduction / 524Uncomplicated Skin Infections / 524Complicated Skin Infections / 524Actinomycosis / 526Viral Infections with Surgical Implications526Human Papillomavirus Infections / 526Cutaneous Manifestations of Human Immunodeficiency Virus / 527Benign Tumors527Hemangioma / 527Nevi / 527Cystic Lesions / 527Keratosis / 528Soft Tissue Tumors / 528Neural Tumors / 528Malignant Tumors528Basal Cell Carcinoma / 528Squamous Cell Carcinoma / 529Melanoma / 530Merkel Cell Carcinoma / 534Kaposi’s Sarcoma / 535Dermatofibrosarcoma Protuberans / 535Malignant Fibrous Histiocytoma (Undifferentiated Pleomorphic Sarcoma and Myxofibrosarcoma) / 535Angiosarcoma / 535Extramammary Paget’s Disease / 536Conclusion536Brunicardi_Ch16_p0511-p0540.indd 51319/02/19 3:08 PM 514Hair shaftStratum corneumPigment ligamentStratum germinativumStratum spinosumStratum basaleArrector pili muscleSebaceous glandHair folliclePapilla of hairBlood andlymph vesselsNerve ÿberSweatporeDermalpapillaSensory nerve ending for touchEpidermisDermisSubcutis(hypodermis)VeinArteryPaciniancorpuscleSweatglandFigure 16-1. Schematic representation of the skin and its appendages. Note that the root of the hair follicle may extend beneath the dermis into the subcutis.structures and obtains all nutrients from the dermal vasculature by diffusion.3Epidermal ComponentsKeratinocytes. Keratinocytes typically make up about 90% of the cells of the epidermis. These cells have four to five distinct stages in their life cycle, each visibly different under light microscopy. The stratum basale, or germinative layer, is a deep, single layer of asynchronous, continuously rep-licating cuboidal to columnar epithelial cells and is the 1beginning of the life cycle of the keratinocytes of the epidermis. This layer is bound to its basement membrane by complexes made of keratin filaments and anchoring structures called hemidesmosomes. They are bound to other keratinocytes by structures called desmosomes. High mitotic activity and thus large nuclei and basophilic staining characterize the stratum basale on light microscopy. This layer also lines the epidermal appendages that reside largely within the substance of the der-mis and later serves as a regenerative source of epithelium in the event of partial thickness wounds.Key Points1 The epidermis consists of continually regenerating strati-fied epithelium, and 90% of cells are ectodermally derived keratinocytes.2 Pilosebaceous units are lined by the germinal epithelium of the epidermis and thus serve as an important source of epidermal regeneration after partial-thickness injury or split-thickness skin graft.3 Dermal fibers are predominantly made of type I and III collagen in a 4:1 ratio. They are responsible for the mechanical resistance of skin.4 The drugs most commonly associated with epidermal necrolysis include aromatic anticonvulsants, sulfonamides, allopurinol, oxicams (nonsteroidal anti-inflammatory drugs), and nevirapine.5 In wounds being allowed to heal secondarily, negative pressure wound therapy can increase the rate of granula-tion tissue formation.6 Staphylococcus aureus is the most common isolate of all skin infections. Impetigo, cellulitis, erysipelas, folliculitis, furuncles, and simple abscesses are examples of uncompli-cated infections, whereas deep-tissue infections, extensive cellulitis, necrotizing fasciitis, and myonecrosis are exam-ples of complicated infections.7 Hemangiomas arise from benign proliferation of endothe-lial cells surrounding blood-filled cavities. They most commonly present after birth, rapidly grow during the first year of life, and gradually involute in most cases.8 Basal cell carcinoma represents the most common tumor diagnosed in the United States, and the nodular variant is the most common subtype. The natural progression of basal cell carcinoma is one of local invasion rather than distant metastasis.9 Squamous cell carcinoma is the second most common skin cancer, and typically arises from an actinic keratosis precur-sor. Primary treatment modalities are surgical excision and Mohs microsurgery. Cautery and ablation, cryotherapy, drug therapy, and radiation therapy are alternative treatments.10 Tumor thickness, ulceration, and mitotic rate are the most important prognostic indicators of survival in melanoma. Sentinel lymph node biopsy is often used to stage indi-viduals with biopsy-proven high risk melanoma and clini-cally node-negative disease.Brunicardi_Ch16_p0511-p0540.indd 51419/02/19 3:08 PM 515THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16The next layer is the stratum spinosum, or “spiny” layer. This layer is from five to fifteen cells in thickness and is so named due to the spinous appearance of the intercellular des-mosomal attachments under light microscopy. The production of keratin in this cell layer is responsible for their eosinophilic appearance on hematoxylin and eosin (H&E) staining.As the keratinocytes continue to migrate superficially, they begin to flatten and develop basophilic keratohyalin gran-ules. There are also structures called lamellar granules within these cells that contain the lipids and glycolipids that will ulti-mately undergo exocytosis to produce the lipid layer around the cells. It is in this layer that the keratinocytes manufacture many of the structures that will eventually serve to protect the skin and underlying tissues from environmental insult.4 At the super-ficial aspect of this layer, the keratinocytes begin to undergo programmed cell death, losing all cellular structures except for the keratin filaments and their associated proteins. In thick skin, such as that found on the palms and soles, there is a layer of flat, translucent keratinocytes called the stratum lucidum.The final stage of the keratinocyte life cycle results in the layer of the epidermis known as the stratum corneum, or cor-nified layer. The protein-rich, flattened keratinocytes are now anucleate and surrounded by a lipid-rich matrix. Together the cells and surrounding matrix of this layer serve to protect the tissue from mechanical, chemical, and bacterial disruption while preventing insensible water losses through the skin.4,5Langerhans Cells. Of the cells in the epidermis, 3% to 6% are immune cells known as Langerhans cells.6 Typically found within the stratum spinosum, these mobile, dendritic cells inter-digitate between keratinocytes of the epidermis to create a dense network, sampling any antigens that attempt to pass through the cutaneous tissue. Through use of their characteristic rodor racket-shaped Birbeck granules, they take up antigens for pre-sentation to T-cells.7 These monocyte-derived cells represent a large part of the skin’s adaptive immunity. Because of the effec-tiveness of their antigen presentation, Langerhans cells could be utilized as vaccine vehicles in the future.8 The Langerhans cells are functionally impaired by UV radiation, specifically UVB radiation, and may play a role in the development of cutaneous malignancies after UV radiation exposure.9Melanocytes. Within the stratum basale are melanocytes, the cells responsible for production of the pigment melanin in the skin. These neural crest-derived cells are present in a density of four to ten keratinocytes per melanocytes, and about 500 to 2000 melanocytes per mm2 of cutaneous tissue. This density varies based on location in the body, but differences in skin pig-mentation are based on the activity of individual melanocytes and not the number of melanocytes. In darker-skinned ethnici-ties, melanocytes create and store melanosomes in keratinocytes at a higher rate, but still have a pale-staining cytoplasm on light microscopy. Hemidesmosomes also attach these cells to the basement membrane, but the intercellular desmosomal connec-tions are not present. The melanocytes interact with keratino-cytes of the stratum basale and spinosum via long cytoplasmic extensions leading to invaginations in several keratinocytes. Tyrosinase is created and distributed into melanosomes, and these organelles travel along the dendritic processes to eventu-ally become phagocytized by keratinocytes and distributed in a supranuclear orientation. This umbrella-like cap then serves to protect the nuclear material from damage by radiation; this could explain why light-skinned ethnicities are more prone to the development of cutaneous malignancies.10,11 Melanocytes express the bcl-2 protein, S100 protein, and vimentin, which are important in the pathology and histologic diagnosis of disorders of melanocytes.Merkel Cells. Merkel cells are slow-adapting mechanorecep-tors of unclear origin essential for light touch sensation. Thus, they typically aggregate among basal keratinocytes of the skin in areas where light tactile sensation is warranted, such as the digits, lips, and bases of some hair follicles.12-14 They are joined to keratinocytes in the basal layer by desmosomes and have dense neurosecretory granules containing peptides. These neu-rosecretory granules allow communication with the CNS via afferent, unmyelinated nerve fibers that contact the basolateral portion of the cell via expanded terminal discs.3 The clinical significance of Merkel cells arises in the setting of Merkel cell carcinoma, a rare, but difficult-to-treat malignancy.Lymphocytes. Less than 1% of the cells in the epidermis are lymphocytes, and these are found primarily within the basal layer of keratinocytes. They typically express an effector memory T-cell phenotype.15,16Toker Cells. Toker cells are found in the epidermis of the nip-ple in 10% of both males and females and were first described in 1970. While distinct from Paget’s cells, immunohistochemical studies have implicated them as a possible source of Paget’s disease of the nipple.17-20Epidermal AppendagesSweat Glands. Sweat glands, like other epidermal appendages, are derived from the embryologic ectoderm, but the bulk of their substance resides within the dermis. Their structure consists of a tubular-shaped exocrine gland and excretory duct. Eccrine sweat glands make up a majority of the sweat glands in the body and are extremely important to the process of thermoregu-lation. Solutes are released into the gland via exocytosis. They are present in greatest numbers on the palms, soles, axillae, and forehead. Collectively they produce approximately 10 L/d in an adult. These glands are the most effective means of temperature regulation in humans via evaporative heat loss.A second type of sweat gland, known as the apocrine sweat gland, is found around the axilla, anus, areola, eyelid, and external auditory canal. The cells in this gland undergo an excretion process that involves decapitation of part of the cell. These apocrine glands are typically activated by sex hormones and thus activate around the time of puberty. The secretion from apocrine glands is initially odorless, but bacteria in the region may cause an odor to develop. Pheromone production may have been a function of the apocrine glands, but this may now be vestigial. While eccrine sweat glands are activated by the cho-linergic system, apocrine glands are activated by the adrenergic system.There is also a third type of sweat gland called apoeccrine. This is similar to an apocrine gland but opens directly to the skin surface and does not present until puberty. 21 Both types of glands are surrounded by a layer of myoepithelial cells that can contract and assist in the excretion of glandular contents to the skin surface.Pilosebaceous Units. A pilosebaceous unit is a multicompo-nent unit made up of a hair follicle, sebaceous gland, an erector pili muscle, and a sensory organ. These units are responsible for the production of hair and sebum and are present almost entirely Brunicardi_Ch16_p0511-p0540.indd 51519/02/19 3:08 PM 516SPECIFIC CONSIDERATIONSPART IIthroughout the body, sparing the palms, soles, and mucosa. They are lined by the germinal epithelium of the epidermis and thus serve as an important source of epidermal regenera-tion after partial-thickness injury or split-thickness skin graft. The sebaceous glands secrete sebum into the follicle and skin via a duct. The lipid-secreting glands are largely influenced by androgens and become functionally active during puberty. They are present in greatest numbers on the face and scalp.Nails. The nails are keratinaceous structures overlying the dis-tal phalanges of the fingers and toes. The nail is made of three main parts. The proximal portion of the nail, continuous with the germinal nail matrix, is the nail root. The root is an adher-ence point for the nail. The nail plate is the portion of the nail that lies on top of the nail bed, the shape of which is determined by the underlying phalanx. The third part of the nail is the free edge, which overlies a thickened portion of epidermis known as the hyponychium. The nail functions to protect the distal digits and augment the function of the pulp of the digits as a source of counter-pressure.Dermal ComponentsArchitecture. The dermis is a mesoderm-derived tissue that protects and supports the epidermis while anchoring it to the underlying subcutaneous tissue. It consists primarily of three unique components: a fibrous structure, the ground substance that surrounds those fibers, and the cell population that is sup-ported by the dermis. In addition, the dermis houses the neuro-vasculature that supports the epidermis and facilitates interaction with the outward environment, as well as the epidermal append-ages previously described. The dermis varies in thickness based upon body region, thinnest in the eyelids and reaching a thick-ness of up to 4 mm on the back, and is composed of two distinct layers, the papillary layer and the reticular layer. The papillary layer is made up of papillae that interdigitate with the rete ridges of the deep portion of the epidermis. This structure increases the surface area between the dermis and epidermis, increasing the resistance to shear forces as well as facilitating greater diffusion of nutrients across the dermal-epidermal junction. The papil-lary layer is characterized by a greater density of cells, and the reticular layer is almost entirely made up of a coarse network of fibers and the ground substance that surrounds it.Fibers and Ground Substance. Ninety-eight percent of the dry weight of the dermis is made up of collagen, typically 80% to 90% type I collagen and 8% to 12% type III collagen. Collagen types IV and VII are also found in much smaller quantities in the dermo-epidermal junction. The structure of the fibers varies along the depth of the dermis. At the superficial part of the dermis, in the papillary layer, the collagen bundles are arranged more loosely and are primarily made up of type III collagen.22 Deeper in the reticular layer of the dermis, the col-lagen fibrils are larger in diameter and organized into interwo-ven bundles surrounded by elastic fibers all within the hydrated ground substance. In a healthy adult, these dermal fibers are in a constant state of breakdown and production, dictated by the activity of matrix metalloproteases and fibroblasts, respectively. The activity of the MMPs is induced by UV radiation, thus lead-ing to increased degradation and disorganization of the collagen fibers, resulting in wrinkling and weakening of the dermis in sun-exposed areas.The retractile properties of skin are due in part to elas-tic fibers found throughout the dermis. These fibers, like the collagen fibers, are thinner and more perpendicularly oriented in the papillary dermis and become thicker and parallel in the reticular dermis. These elastic fibers are also produced by fibro-blasts, but they are unique in that they can stretch to twice their original length, and return to their original configuration. The elastic fibers are also in a constant state of turnover that can be negatively impacted by the effects of UV radiation.The fibrous network of the dermis lies within a hydrated amorphous ground substance made of a variety of proteoglycans and glycosaminoglycans, molecules that can contain up to 1000 times their weight in water. This ground substance facilitates the development of the structure of the dermis and cell migration within the dermis. It also assists in redistributing forces placed on the cutaneous tissues.CellsFibroblasts. Fibroblasts, like most cells in the dermis, are found in the loose, papillary layer, and are the fundamental cells of the dermis. They are responsible for producing all der-mal fibers and the ground substance within which those fibers reside. They are typically spindleor stellate-shaped and have a well-developed rough endoplasmic reticulum, typical of cells engaging in active protein production. The fibroblasts can also differentiate into myofibroblasts, cell types that harbor myofila-ments of smooth muscle actin and, more rarely, desmin, which help to decrease the surface area of the wound by contraction.23 Because of these fundamental functions of fibroblasts, they are the workhorses of wound healing, while macrophages are the orchestrators.Dermal Dendrocytes. Dermal dendrocytes are comprised of a variety of mesenchymal dendritic cells recognizable mainly by immunohistochemistry. They are responsible for antigen uptake and processing for presentation to the immune system, as well as the orchestration of processes involved in wound healing and tissue remodeling. They are typically found in the papillary dermis around vascular structures as well as sweat glands and pilosebaceous units.Mast Cells. Mast cells are effector secretory cells of the immune system that are responsible for immediate type 1 hyper-sensitivity reactions. When primed with IgE antibodies, encoun-ter with a provoking antigen causes the release of histamine and cytokines, leading to vasodilation and dermatitis commonly seen in allergic reactions.Cutaneous VasculatureWhile the epidermis is void of any vasculature structures, the dermis has a rich supply of blood and nutrients supported by paired plexuses connected by a system of arteriovenous shunts. The superficial, subpapillary plexus is located between the papillary and reticular dermis and provides a vascular loop to every papilla of the papillary dermis.24 The deep dermal plexus is located at the junction of the reticular dermis and hypodermis, and it derives its blood supply from perforating arteries of larger vessels below the cutaneous tissues. The arteriovenous shunts connecting the two horizontal plexuses can divert blood flow to or away from the skin when necessary to conserve or release body heat, or to divert blood flow to vital organs when needed. Associated with the vascular loops of the dermal papillae are the blind-ended beginnings of lymphatic vessels, which serve to transport extravasated fluid and proteins from the soft tissues back into the venous circulatory system.23Brunicardi_Ch16_p0511-p0540.indd 51619/02/19 3:08 PM 517THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16Cutaneous InnervationThe skin is a highly specialized tool for interacting with our environment and, as such, carries a rich network of nervous tis-sue to facilitate this purpose. An afferent component made up of free nerve endings and specialized corpuscular receptors is responsible for conveying to our brain information about the environment, while numerous functions of the cutaneous tis-sues, such as AV-shunting, piloerection, and sweat secretion are controlled by the myelinated and unmyelinated fibers of an efferent component of the CNS.25HypodermisThe hypodermis, or subcutaneous tissue, is a richly vascularized loose connective tissue that separates and attaches the dermis to the underlying muscle and fascia. It is made up primarily of pockets of lipid-laden adipocytes separated by septae that contain cellular components similar to the dermis, neurovas-cular structures supplying the cutaneous tissue, and the deepest parts of sweat glands.26 The hypodermis serves multiple func-tions—namely insulation, storage of energy, and protection from mechanical forces, allowing the skin to glide over the underlying tissues.INFLAMMATORY CONDITIONSHidradenitis SuppurativaHidradenitis suppurativa, also known as acne inversa, is a pain-ful skin condition typically affecting areas of the body bear-ing apocrine glands—typically the axillae, perineum, and the inframammary and inguinal folds. It is characterized by tender, deep nodules that can expand, coalesce, spontaneously drain, and form persistent sinus tracts in some cases leading to sig-nificant scarring and hyperkeratosis. There can be superimposed bacterial infection during episodic flares of the disease as well. In women, flares often occur premenstrually.Hidradenitis suppurativa typically affects females (female to male ratio of 3:1), most commonly during the third decade of life and has demonstrated associations with smoking and obesity.27 While the etiology of hidradenitis is incompletely understood, it is thought to be the consequence of a genetic pre-disposition exacerbated by environmental factors. About one-third of affected patients endorse a family history of the disease. A specific gene locus has not been identified, but mutations in the γ-secretase gene have been linked to the disease in some familial cases.28 The histologic progression of the disease is characterized by atrophy of the sebaceous gland, followed by inflammation of the pilosebaceous unit from both the innate and adaptive immune systems, causing hyperkeratosis and eventual granuloma forma-tion.29 Some studies have shown involvement of the IL12-IL23 pathway and TNF-α, supporting the theory that the disease is at least in part caused by an inflammatory disorder.30,31The diagnosis of hidradenitis is clinical, and the presenta-tion is most commonly categorized by the Hurley classification system, divided into three stages. Single or multiple nodules or abscesses without any sinus tracts or scarring would be classi-fied as stage 1 disease. As abscesses recur and sinus tracts and scarring form, the disease is classified as Hurley stage 2. Stage 3 is the most advanced stage, with diffuse disease and intercon-nected sinus tracts and abscesses.Treatment is typically based on Hurley staging, with topi-cal and systemic antibiotics (typically clindamycin) being used for stage I and II disease,32 while radical excision, laser treat-ment, and biologic agents are reserved for more advanced stage II and III disease.33-36 Even with complete surgical resection, recurrence rates are still high, reaching up to 50% in the infra-mammary and inguino-perineal regions. Because of increased risks of recurrence with primary closure, it is preferable to pur-sue other methods of wound closure, like split-thickness skin grafting, local or regional flaps, and healing by secondary inten-tion. Topical antimicrobial creams should be used during the healing process.Pyoderma GangrenosumPyoderma gangrenosum is an uncommon inflammatory con-dition of the skin characterized by the development of sterile pustules which progress to painful, ulcerating lesions with purple borders. This disease is typically diagnosed between the ages of 40 and 60 years and has a slightly higher prevalence in females. Although the exact etiology is currently unknown, it typically arises in individuals with a hematologic malignancy or inflammatory disorder, such as inflammatory bowel disease or rheumatoid arthritis. The most commonly affected sites are the legs, but lesions can occur anywhere. Extracutaneous mani-festations are also possible, and it can affect mucosal tissue and solid organs. While the initial pathology is sterile, it can easily become secondarily infected. The diagnosis of this condition is based upon history and clinical presentation after the exclu-sion of infectious etiologies. There are five distinct types of pyoderma gangrenosum described: vegetative, pustular, peris-tomal, ulcerative, and bullous. The pathogenesis of this disease is incompletely understood, but it is thought to be a genetic predisposition that is triggered by an environmental influence. An inciting cutaneous injury can often be identified preceding the ulceration. Histopathologic studies have demonstrated sig-nificantly elevated levels of inflammatory cytokines, as well as neutrophils exhibiting aberrant chemotactic signaling.37-39 Treat-ment of pyoderma gangrenosum generally involves treatment of the underlying disorder (i.e., management of Crohn’s disease) as well as systemic anti-inflammatory medications such as steroids or immunosuppressants like calcineurin inhibitors. Patients with Crohn’s disease and PG treated with infliximab (tumor necrosis factor [TNF]-α inhibitor) and etanercept (TNF-α antagonist) had a marked improvement in their PG.40,41 In cases of peri-stomal pyoderma gangrenosum, topical calcineurin inhibitors have been shown to be useful.42 Concurrent treatment with sys-temic and topical antimicrobials, as well as local wound care, including the debridement of purulent exudate and devitalized tissue, is also beneficial. Surgical therapy without proper sys-temic treatment will generally result in recurrent disease. Final wound closure can be achieved with primary closure or grafts.Epidermal NecrolysisEpidermal necrolysis (EN) is a rare mucocutaneous disorder characterized by cutaneous destruction at the dermoepidermal junction. EN is commonly referred to as either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) depending on the extent of skin involvement present. SJS refers to cases in which <10% of total body surface area is involved, while cases with >30% involvement are considered TEN, with an SJS-TEN overlap syndrome referring to all cases in between. These two disorders are now considered to be the same clinical entity that vary simply on the extent of cutaneous involvement. Erythema multiforme was once considered as part of the clinical subgroup Brunicardi_Ch16_p0511-p0540.indd 51719/02/19 3:08 PM 518SPECIFIC CONSIDERATIONSPART IIFigure 16-2. Blisters on the forearm of a patient several days after exposure to vancomycin. Note the clear antishear dressing and the dark silver-impregnated antimicrobial dressing (Acticoat).encompassing SJS and TEN, but it is now thought to be a sepa-rate entity related to herpetic or Mycoplasma infections.The clinical presentation usually occurs within 8 weeks of initiation of a new drug treatment and is characterized by a macular rash beginning in the face and trunk and progressing to the extremities within hours to days. A positive Nikolsky sign is often present, in which lateral pressure on the skin causes separation of the epidermis from the dermis. (Fig. 16-2). The macular rashes then begin to blister and coalesce, forming bul-lae that eventually burst, leaving partial thickness wounds with exposed dermis. Mucous membrane involvement is seen in 90% of cases and can involve the oral, genital, and ocular mucosa, as well as the respiratory and gastrointestinal tracts. The cutaneous manifestations can also be associated with high fever and pain. It is important to distinguish EN from infectious etiologies like staphylococcal scalded skin syndrome due to their similar clini-cal presentation.While the etiology is not entirely clear, it is well docu-mented to be a reaction to various drugs. While over 100 drugs have been implicated as the inciting agent of EN,43,44 there are a handful of high-risk drugs that account for a majority of the cases.45 The drugs most commonly associated with EN include aromatic anticonvulsants, sulfonamides, allopurinol, oxi-cams (nonsteroidal anti-inflammatory drugs), and nevirap-ine. The pathophysiology is also incompletely understood, but it has generally been accepted that it involves cell-mediated cytotoxicity targeted at keratinocytes and the cytokine-induced expression of “death-receptors” like Fas-L. Recently, studies have demonstrated greatly increased concentrations of granuly-sin, an apoptotic protein secreted by cytotoxic T cells, within EN lesions, and thus this protein may be implicated in the patho-genesis of EN.46 A genetic component may also exist, and genetic testing before carbamazepine treatment is recommended in people of Han Chinese ancestry to exclude carriers of HLA-B1502.47The prognosis of EN is generally related to the surface area affected and secondary complications of extensive cutane-ous damage, like secondary infections and loss of hemodynamic stability due to increased insensible losses and third spacing of fluid. Modern burnand ICU-care has decreased mortality 4significantly.48 The first principle of management of EN is dis-continuation of the offending agent, and in drugs with short half-lives, this can significantly increase chances of survival.49 Other management principles include maintenance of euvolemia, early enteral feeding, and measures to reduce risk of infection. This includes surgical debridement of devitalized tissue, the use of topical antibiotics or antimicrobial dressings, nonadherent dress-ings, or temporary biologic or synthetic grafts until the underly-ing dermis can reepithelialize. The cornea should regularly be inspected with a Wood’s lamp to evaluate for corneal sloughing. The use of systemic corticosteroids in the acute setting is con-troversial as there have been mixed results. Some studies have shown a slowed disease progression when corticosteroid therapy was administered early,50 while others showed increased rates of sepsis and overall mortality with no effect on disease progression. IVIG has also been used in an effort to inhibit the Fas-L cytotoxic pathway, with some mixed results. A 2007 meta-analysis of nine IVIG trials concluded that high-dose IVIG improves survival,51 while a large retrospective analysis in 2013 concluded that there was no mortality benefit.52 Other agents, like cyclosporine A, plasmapheresis and anti-TNF-α have been studied with mixed results.48 Recent guidelines out of the United Kingdom confirm that there is still no treatment with clearly demonstrated benefit in the management of EN.53 The cutaneous manifestations of EN generally progress for 7 to 10 days, while reepithelialization gen-erally occurs over 3 weeks.INJURIESRadiation-Induced InjuriesRadiation injuries can result from exposure to electromag-netic radiation from industrial/occupation applications or, more commonly, from environmental exposure and medical treatments. This is especially true in the continually evolv-ing role of radiation therapy in the multidisciplinary approach to oncologic disease and other skin conditions. In addition to treatment for lymphomas, head and neck squamous cell car-cinomas, and prostate adenocarcinoma, it is often an adjuvant or neoadjuvant component of the surgical treatment of rectal, breast, esophageal, and cervical cancers. Although the new modalities and principles of radiation therapy have allowed for more precise administration of this therapy, there is still collateral damage in the cutaneous and visceral tissues sur-rounding the treatment site.Environmental sources of radiation damage are typi-cally from UV radiation. UVC rays are filtered by the ozone layer, so the only UV rays that humans typically encounter are UVA (320–400 nm) and UVB (290–320 nm).54 The amount of exposure to UV radiation is dependent on seasonal, temporal, geographic and environmental variables. Ninety-five percent of the UV rays that reach the earth’s surface are UVA rays. This radiation is less energetic (longer wavelength) than UVB rays and affects the cutaneous tissues differently. UVA waves pen-etrate deeper into the tissues, with 20% to 30% reaching the deep dermis. UVB rays are mostly absorbed in the epidermis, with 70% reaching the stratum corneum, 20% reaching the deep epidermis, and only 10% reaching the papillary dermis. Major chromophores in the cutaneous tissue include nucleic acids, aro-matic amino acids, and melanin.The short-term effects of solar radiation include erythema and pigmentation. The resultant erythema peaks at 6 to 24 hours Brunicardi_Ch16_p0511-p0540.indd 51819/02/19 3:08 PM 519THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16after exposure. The pigmentation occurs differently for UVA and UVB rays. Pigmentation occurs because of photooxidation of melanin by UVA radiation. Partial fading of this pigment change occurs within an hour after exposure, but with higher and repeated doses of UVA, stable residual pigmentation is observed. UVB waves induce neomelanization, increasing the total amount of melanin in the epidermal tissues and resulting in an effect that is observable 72 hours after exposure. The increase in melanin as a result of UVB exposure serves as a protective mechanism to defend the nuclei of the basal keratinocytes from further radiation-induced damage by absorbing the high-energy radiation in future exposures. Long-term effects of exposure to UV radiation can lead to chronic skin changes, such as irregular pigmentation, melasma, postinflammatory pigmentation, and actinic lentigines (sun spots). Lysozyme, an enzyme secreted by cells of the immune system, typically inhibits the activity of collagenase and elastase, playing a role in turnover of the elas-tin and collagen network of the dermis. Long-term exposure to UV radiation increases the activity of lysozyme, thus impairing the natural turnover of these fibers, resulting in a disorganized accumulation of elastin, and an increase in the ratio of type III to type I collagen. This results in loss of firmness and resilience of the skin, leading to wrinkles and an aged appearance.The other major source of radiation injury that a surgeon will likely encounter is from therapeutic radiation. The vari-ous forms of radiation work to destroy the replicative potential of the target cells via damage to the nucleic acid structures in the cell. This is typically used to treat oncologic disease, but it can also be used to treat benign disease like eczema, psoria-sis, and keloid scarring at relatively low exposures. While this goal is accomplished, surrounding tissues are also affected and damaged. The most radiosensitive components of the cutane-ous tissue are the basal keratinocytes, hair follicle stem cells, and melanocytes. Exposure to this intense radiation results in disorganized, uncontrolled cell death, leading to the release of reactive oxygen species and further damage and inflammation to the surrounding cellular network. Damage to the basal kera-tinocytes and fibroblasts hinders the replicative capacity of the epidermis and dermis, respectively.Acute skin changes to these structures manifest within weeks as erythema, edema, and alopecia. Permanent hyper-pigmentation, tightening, thickening, and fibrosis of the skin become apparent as the tissue attempts to heal. In severe radia-tion injury, there can be complete loss of the epidermis, resulting in partial-thickness wounds and fibrinous exudate. Reepitheli-alization typically occurs 14 days following initial injury, pro-vided other variables affecting wound healing are optimized (bacterial colonization, nutrition.) Long-term effects include compromise of the functional integrity of the skin secondary to thrombosis and necrosis of capillaries, hypovascularity, telangi-ectasia, ulceration, fibrosis, poor wound healing, and infection. These can present weeks to years after exposure.Treatment of minor radiation injury includes skin mois-turizers and local wound care when appropriate. Severe radia-tion injury may warrant surgical excision and reconstruction with free-tissue transfer from a part of the body unaffected by radiation.Trauma-Induced InjuriesMechanical Injury. Physical disruption of the skin can occur via numerous mechanisms. Treatment of the wound is depen-dent on the size of the defect left behind by the insult, any exposed structures that remain in the wound bed, and the pres-ence of contaminating debris or infection. Clean, simple lacera-tions can be irrigated, debrided, and closed primarily. There is no systematic evidence to guide the optimal timing of closure within 24 hours,55 but many surgeons will close primarily within 6 hours of injury. Grossly contaminated or infected wounds should be allowed to heal by secondary intention or delayed primary closure.56 In wounds allowed to heal secondarily, nega-tive pressure wound therapy can increase the rate of granu-lation tissue formation.57 Tangential abrasions are treated similarly to burn wounds, with depth of injury dictating man-agement. Partial thickness injuries with preservation of the regenerative pilosebaceous units can be allowed to heal on their own while maintaining a moist, antimicrobial wound environ-ment. Full thickness wounds may require reconstruction with splitor full-thickness skin grafting depending on the size of the defect and the need for future cosmesis and durability. In the setting of devitalization of full thickness tissue, the damaged tissue may be used as a full thickness graft, provided the wound is appropriately cleaned.Bite Wounds. Dog bites alone recently accounted for 4.5 million bites to humans in a single year. Bites from dogs, humans, and other animals can quickly lead to severe deep-tissue infections if not properly recognized and treated.58 The most com-mon location of bite wounds is the hand. This area is of particular importance, as the anatomy of the hand allows for rapid pro-gression of deep infection long relatively avascular structures and can lead to long term morbidity if not adequately treated.59 Bite bacteriology is influenced by normal mouth flora, as well as the content of the offending animal’s diet. Early presentation bite wounds yield polymicrobial cultures, while cultures from a late infection will typically exhibit one dominant pathogen. Common aerobic bacteria include Pasteurella multocida, Streptococcus, Staphylococcus, Neisseria, and Corynebacterium; anaerobic organisms include Fusobacterium, Porphyromonas, Prevotella, Propionibacterium, Bacteroides, and Peptostreptococcus. Capnocytophaga canimorsus bacteria after a dog bite are rare, and it appears that immunocompromised patients are most susceptible to this type of infection and its complications. The bacterial load in dog bites is heavily influenced by the last meal of the animal, increasing with wet food and shorter time since the last meal60 (Fig. 16-3). Cat bite bacteriology is similar, with slightly higher prevalence of Pasturella species. Infections from Francisella tularensis (tularemia) and Yersinia pestis (human plague) have been reported.Bacteria colonizing human bites are those present on the skin or in the mouth. These include the gram-positive aerobic organisms Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus species, and anaerobes including Peptococ-cus species, Peptostreptococcus species, Bacteroides species, and Eikenella corrodens (facultative anaerobe). Human bites are characterized by a higher bacterial load (>105). Antibiotic prophylaxis after a human bite is recommended as it has been shown to significantly decrease the rate of infection.61 A course of 3 to 7 days of amoxicillin/clavulanate is typically used. Alter-natives are doxycycline or clindamycin with ciprofloxacin.There is controversy over the closure of bite wounds. Typically, in areas of aesthetic importance, the wound is thor-oughly irrigated and debrided and primarily closed with a short course of antibiotics and close follow-up to monitor for signs of infection. In areas that are less cosmetically sensitive and bites that look grossly contaminated or infected, the wounds 5Brunicardi_Ch16_p0511-p0540.indd 51919/02/19 3:08 PM 520SPECIFIC CONSIDERATIONSPART IIABCFigure 16-3. A. Dog bite to the face involving the lip. B. Primary multilayer closure following debridement and irrigation. Closure was performed due to aesthetic and functional considerations. C. Follow up 1 week after injury following suture removal.are allowed to close secondarily. Special consideration should be paid to puncture wounds in areas like the hands, which have multiple small compartments. Some groups have found that as long as wounds are properly irrigated and cleansed with povidone iodine solution while a short course of antibiotics is prescribed, there is no difference in infection rates in dog bite wounds closed primarily.62Rabies in domestic animals in the United States is rare, and most cases are contracted from bat bites. In developing countries, dog bites remain the most common source of rabies. Management of this is beyond the scope of this chapter.Caustic InjuryChemical burns make up to 10.7% of all burns but account for up to 30% of all burn-related deaths.63 The number of cases of industrial chemical burns is declining while chemical burns in the domestic setting is on the rise. The extent of tissue destruc-tion from a chemical burn is dependent on type of chemical agent, concentration, volume, and time of exposure, among other variables.Injuries from acidic solutions are typically not as severe as those from basic solutions. This is due to the mechanism of injury of each. Acidic injuries typically result in superficial eschar formation because the coagulative necrosis caused by acids limits tissue penetration. Acids can cause thermal injury in addition to the coagulative necrosis due to exothermic reactions. Without treatment, acid injuries will progress to erythema and ulcers through the subcutaneous tissue. Injuries from basic solu-tions undergo liquefactive necrosis, unlike acids, and thus have no barrier preventing them from causing deeper tissue injury. Brunicardi_Ch16_p0511-p0540.indd 52019/02/19 3:08 PM 521THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16Figure 16-4. Self-inflicted alkali burn with cleaner fluid.(Fig. 16-4). Common examples of agents that often cause alka-line chemical burns are sodium hydroxide (drain decloggers and paint removers) and calcium hydroxide (cement).Treatment for acidic or alkaline chemical burns is first and foremost centered around dilution of the offending agent, typically using distilled water or saline for 30 minutes for acidic burns and 2 hours for alkaline injuries. Attempting to neutralize the offending agent is typically discouraged, as it does not offer an advantage over dilution and the neutralization reaction could be exothermic, increasing the amount of tissue damage. After removal of the caustic agent, the burn is treated like other burns and is based on the depth of tissue injury. Topical antimicrobials and nonadherent dressings are used for partial-thickness wounds with surgical debridement and reconstruction if needed for full-thickness injuries. Liposuction and saline dilution have been used in cases were injury to deeper structures was suspected.64 Prophylactic use of antibiotics is generally avoided.There are several chemical agents that have specific treat-ments, including the use of calcium gluconate for hydrofluoric acid burns and polyethylene glycol for phenol burns. These types of treatments are specific to the offending agent and out-side of the scope of this chapter.One type of caustic injury that is commonly seen in the hos-pital is extravasation injury, especially in the setting of chemo-therapeutic administration. Extravasation is estimated to occur in 0.1% to 0.7% of all cytotoxic drug administrations. Like other chemical burns, extravasation injuries depend on properties of the offending agent, time of exposure, concentration, and volume of drug delivered to the tissues. Extravasation injuries typically cause little damage, but they can cause significant morbidity in those with thin skin, fragile veins, and poor tissue perfusion, like neonates and the critically ill. (Fig. 16-5).Initial presentation of extravasation injuries usually involves swelling, pain, erythema, and blistering. It may take days or longer for the extent of tissue damage to demarcate. Thorough evaluation to rule out injury to deeper tissues should be conducted. The treatment for extravasation injuries is usu-ally conservative management with limb elevation, but saline aspiration with a liposuction cannula in an effort to dilute and remove the offending agent has been used soon after injury pre-sentation.65 Infiltration of specific antidotes directed toward the offending agent has been described, but it lacks the support of randomized controlled trials, and no consensus in treatment has been reached.66 It is best to avoid cold or warm compression because the impaired temperature regulation of the damaged tissue may lead to thermal injury. After the wound demarcates, full-thickness skin death should be surgically debrided and man-aged like other wounds based on depth of injury.Thermal InjuryThermal injury involves the damage or destruction of the soft tissue due to extremes of temperature, and the extent of injury is dependent on the degree temperature to which the tissue is exposed and the duration of exposure. The pathophysiology and management are discussed in detail in a separate chapter. Briefly, the management of thermal wounds is initially guided by the concept of three distinct zones of injury. The focus of thermal injury that has already undergone necrosis is known as the zone of coagulation. Well outside the zone of coagulation is the zone of hyperemia, which exhibits signs of inflammation but Brunicardi_Ch16_p0511-p0540.indd 52119/02/19 3:08 PM 522SPECIFIC CONSIDERATIONSPART IIABCFigure 16-5. A. Potassium chloride intravenous infiltrate in a critically ill patient on multiple vasopressors. B. Following operative debride-ment to paratenon layer. C. Temporary coverage with Integra skin substitute.will likely remain viable. In between these two zones is a zone of stasis with questionable tissue viability, and it is this area at which proper burn care can salvage viable tissue and decrease the extent of injury67 (Fig. 16-6).The mechanisms of injury in hypothermic situation dif-fer. Direct cellular damage can occur as a result of the crys-tallization of intracellular and extracellular components with resultant dehydration of the cell and disruption of lipid protein Brunicardi_Ch16_p0511-p0540.indd 52219/02/19 3:08 PM 523THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16complexes. During rewarming, further damage occurs because of the shifts of fluid in response to melting ice. Indirect effects of hypothermic injury include microvascular thrombosis and tis-sue ischemia. This, together with subsequent edema and inflam-mation upon rewarming, propagates tissue injury even further.68 Even so, the standard treatment of frostbite injury begins with rapid rewarming to 40°C to 42°C. In addition, further treatment includes debridement of all devitalized tissue, hydrotherapy, elevation, topical antimicrobials, topical antithromboxanes (aloe vera), and systemic antiprostaglandins (aspirin).Pressure InjuryA problem that all surgeons will encounter very early in their careers is pressure necrosis. The development of pressure ulcers is increasingly being regarded as a marker of quality of care, and strategies aimed at prevention have been the source of recent study. Pressure ulcers are known to affect the critically ill (22% to 49% of all critically ill patients are affected), but pressure sources can also affect the chronically bedor wheelchair-bound, patients undergoing surgical procedures, and those with Foley catheters, artificial airways, or other medical equipment (Fig. 16-7).Pressure ulcers can present in several ways depending on the stage at presentation. They are typically grouped into 4 stages: stage 1, nonblanching erythema over intact skin; stage 2, partial-thickness injury with blistering or exposed dermis; stage 3, full-thickness injury extending down to, but not including, fascia and without undermining of adjacent tissue; and stage 4, full-thickness skin injury with destruction Figure 16-6. Scald burn of upper arm, back, and buttock. Pink areas are superficial partial-thickness burn, whereas whiter areas are deeper burns in the dermis.ABFigure 16-7. A. Pressure wound after removal of a poorly padded cast. Stage cannot be determined until debridement but is at least a grade 2 lesion. B. Decubitus ulcer of the sacral region, stage 4, to the tendinous and bone layers.or necrosis of muscle, bone, tendon, or joint capsule. Tissue destruction occurs most easily at bony prominences due to the inability to redistribute forces along a greater surface area. The average perfusion pressure of the microcirculation is about 30 mmHg, and pressures greater than that cause local tissue isch-emia. In animal models, pressure greater than twice the capillary perfusion pressure produces irreversible tissue necrosis in just 2 hours. The most common areas affected are the ischial tuber-osity (28%), greater trochanter (19%), sacrum (17%), and heel (9%). Tissue pressures can measure up to 300 mmHg in the ischial region during sitting and 150 mmHg over the sacrum while lying supine.69 Tissues with a higher metabolic demand are Brunicardi_Ch16_p0511-p0540.indd 52319/02/19 3:09 PM 524SPECIFIC CONSIDERATIONSPART IItypically susceptible to insult from tissue hypoperfusion more rapidly than tissues with a lower metabolic demand. Because of this, it is possible to have muscle necrosis beneath cutaneous tis-sue that has yet to develop signs of irreversible damage.Management of pressure sores first and foremost involves avoidance of prolonged pressure to at-risk areas. Strategies typically employed are pressure-offloading hospital beds or assist devices, patient repositioning every 2 hours, early mobilization, prophylactic silicone dressings, and nurs-ing education.70 From a wound healing perspective, patients should be nutritionally optimized and surgically debrided as appropriate.71,72 The presence of stage III or IV pressure ulcers is not necessarily an indication for surgery, and fevers in a patient with chronic pressure ulcers are often from a urinary or pulmonary source.73-75 Goals of surgical intervention are drain-age of fluid collections, wide debridement of devitalized and scarred tissue, excision of pseudobursa, ostectomy of involved bones, hemostasis, and tension-free closure of dead space with well-vascularized tissue (muscle, musculocutaneous, or fasciocutaneous flaps). Stage 2 and 3 ulcers may be left to heal secondarily after debridement. Subatmospheric pressure wound therapy devices (vacuum-assisted closure) play a role in wound management by removing excess interstitial fluid, promoting capillary circulation, decreasing bacterial coloniza-tion, increasing vascularity and granulation tissue formation, and contributing to wound size reduction.57BIOENGINEERED SKIN SUBSTITUTESThe management of soft tissue defects is more commonly including the use of bioengineered skin substitutes. These products are typically derived from or designed to imitate dermal tissue, providing a regenerative matrix or stimulating autogenous dermal regeneration while protecting the underly-ing soft tissue and structures. There are generally four types of skin substitutes: (a) autografts, which are taken from the patient and placed over a soft tissue defect (split-thickness and full-thickness skin grafts); (b) allografts, which are taken from human organ donors; (c) xenografts, which are taken from members of other animal species; and (d) synthetic and semisynthetic biomaterials that are constructed de novo and may be combined with biologic materials.76 Acellular dermal matrices are one type of skin substitute and are used quite often for wound healing and support of soft tissue reconstruction. They are from allogenic or xenogeneic sources and are com-posed of collagen, elastin, laminin, and glycosaminoglycans. Tissue incorporation generally occurs within 1 to 2 weeks.77 Dermal matrices have been shown to be an effective bridge to split-thickness skin grafting for wounds that have exposed nerves, vessels, tendons, bones, or cartilage.78 Bilayered matri-ces can also be used to promote dermal regeneration in acute or chronic wounds. These products can be temporary, needing to be removed prior to grafting, or permanent, integrating into the host tissue and being grafted directly.BACTERIAL INFECTIONS OF THE SKIN AND SUBCUTANEOUS TISSUEIntroductionIn 1998, the Food and Drug Administration (FDA) categorized infections of the skin and skin structures for the purpose of clini-cal trials. A revision of this categorization in 2010 excluded spe-cific diagnoses such as bite wounds, decubitus ulcers, diabetic foot ulcers, perirectal abscesses, and necrotizing fasciitis. The general division into “uncomplicated” and “complicated” skin infections can be applied to help guide management.79 The agent most commonly responsible for skin and soft tissue infections is S aureus and is isolated in 44% of spec-imens.80 Less common isolates include other gram-positive bacteria such as Enterococcus species (9%), β-hemolytic strep-tococci (4%), and coagulase-negative staphylococci (3%). S aureus is more commonly responsible for causing abscesses. Patients with an impaired immune system (diabetic, cirrhotic, or neutropenic patients) are at higher risk of infection from gram-negative species like Pseudomonas aeruginosa (11%), Esche-richia coli (7.2%), Enterobacter (5%), Klebsiella (4%), and Serratia (2%), among others.Uncomplicated Skin InfectionsUncomplicated infections involve relatively small surface area (<75 cm2) and bacterial invasion limited to the skin and its appendages. Impetigo, erysipelas, cellulitis, folliculitis, and simple abscess fall into this category. Impetigo is a superficial infection, typically of the face, that occurs most frequently in infants or children, resulting in honey-colored crusting. Erysip-elas is a cutaneous infection localized to the upper layers of the dermis, while cellulitis is a deeper infection, affecting the deeper dermis and subcutaneous tissue. Folliculitis describes inflammation of the hair follicle, and a furuncle describes a fol-licle with swelling and a collection of purulent material. These lesions can sometimes coalesce into a carbuncle, an abscess with multiple different draining sinus tracts.It is recommended to culture infectious lesions to help identify the causative agent, but treatment without these studies is reasonable in typical cases. Minor infections can be safely treated with topical antimicrobials like 2% mupirocin to pro-vide coverage for methicillin-resistant S aureus (MRSA). Fol-liculitis generally resolves with adequate hygiene and warm soaks. Furuncles, carbuncles and other simple abscesses can be incised, drained, and packed, typically without the use of systemic antibiotics. The decision to use systemic antibiotics after incision and drainage of abscess should be made based upon presence or absence of systemic inflammatory response syndrome (SIRS) criteria.81For nonpurulent, uncomplicated cellulitis in which there is no drainable collection, systemic antibiotic coverage for β-hemolytic streptococcus is recommended. If there is no improvement in 48 to 72 hours or worsening of symptoms, antibiotic coverage should be added for MRSA. Systemic therapy for purulent cellulitis, which includes cutaneous abscesses, should cover MRSA, and empiric coverage for streptococcus is likely unnecessary. Antibiotic coverage for streptococcus is generally accomplished with β-lactam antibi-otics like penicillins or first-generation cephalosporins. MRSA coverage is accomplished with clindamycin, trimethoprim-sulfamethoxazole, linezolid, and tetracyclines. Clindamycin, trimethoprim-sulfamethoxazole, linezolid, or tetracycline combined with a β-lactam can all be used for dual coverage of streptococcus and MRSA.Complicated Skin InfectionsComplicated skin infections include superficial cellulitis encompassing a large surface area (>75 cm2) or deeper infec-tions extending below the dermis. Necrotizing soft tissue infec-tions (NSTIs), including necrotizing fasciitis, can rapidly cause extensive morbidity and mortality, thus their prompt diagnosis and appropriate management is crucial. A thorough history and 6Brunicardi_Ch16_p0511-p0540.indd 52419/02/19 3:09 PM 525THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16exam should be performed to elicit information (e.g., history of trauma, diabetes mellitus, cirrhosis, neutropenia, bites, IV or subcutaneous drug abuse) as well as physical findings such as crepitus (gas-forming organism), fluctuance (abscess), purpura (sepsis in streptococcal infections), bullae (streptococci, Vibrio vulnificus), lymphangitis, and signs of a systemic inflammatory response.Extensive cellulitis is managed in a similar fashion as simple cellulitis. Initial treatment consists of intravenous anti-biotics that cover β-hemolytic streptococcus, such as ceph-alosporins, with the addition of MRSA coverage if there is no improvement in symptoms. Vancomycin is typically the first choice for MRSA coverage, but this drug is inferior to β-lactams for coverage of MSSA. Alternative antibiotics that are typically effective against MRSA are linezolid, daptomy-cin, tigecycline, and telavancin. Clindamycin is approved for use against MRSA, but resistance rates are increasing, and its use is discouraged if institutional rates of clindamycin resis-tance are >15%.81Necrotizing soft tissue infections occur 500 to 1500 times a year in the United States82 and are frequently asso-ciated with diabetes mellitus, intravenous drug abuse, obe-sity, alcohol abuse, immune suppression, and malnutrition.83 Because NSTIs can often present initially with nonspecific findings, the physician should always have a high index of suspicion when evaluating a patient. The threshold for surgi-cal exploration and debridement should be low, particularly in a weakened host. Occasionally an inciting event or point of entry can be identified, but in 20% to 50% of cases, the exact cause is unknown. These infections are associated with a high mortality, ranging from 25% to 40%, with higher rates in the truncal and perineal cases.NSTIs are classified based on anatomic site, involved tis-sues, and the offending organisms. NSTIs commonly originate at the genitalia, perineum (Fournier’s gangrene), and abdomi-nal wall. Subcutaneous tissue, fascia and muscle can all be affected. Necrotizing fasciitis involves infection of the fascia, and the infection can quickly travel along the easily separable, avascular planes. There are three types of NSTIs when clas-sified by the offending agent. The most common is type 1, which is caused by a polymicrobial source including gram-positive cocci, gram-negative rods, and anaerobic bacteria, specifically Clostridium perfringens and C septicum. Type 2 is caused by a monomicrobial source of β-hemolytic Strepto-coccus or Staphylococcus species, with MRSA contributing to the increasing number of community-acquired NSTIs.84 A his-tory of trauma is often elicited and can be associated with toxic shock syndrome. Type 3 is a rare but fulminant subset result-ing from a V vulnificus infection of traumatized skin exposed to a body of salt-water.In addition to signs of SIRS, patients can present with skin changes like erythema, bullae, necrosis, pain, and crepitus. (Fig. 16-8). They may exhibit signs of hemodynamic instability, and gas within the soft tissues on imaging is pathognomonic. Patients can present with a range of symptoms, from minimal skin change to frank necrosis, and the time of progression to fulminant disease varies in each patient. Laboratory values are nonspecific and resemble values seen in sepsis. There have been attempts at creating scoring systems to assist in the diagnosis of NSTI. One study in 2000 used the criteria of a white blood cell count >15,400 and a serum sodium level <135 mmol/L. This test was found to have a negative predictive value of 99%, but a positive predictive value of only 26%.85 In 2004, six criteria ABFigure 16-8. A. Initial presentation of necrotizing soft issue infec-tion in an obese, diabetic patient. B. Following operative debride-ment to muscle layer.were used and referred to as the Laboratory Risk Indicator for Necrotizing Fasciitis, or LRINEC, and included C-reactive protein (CRP), white blood cell (WBC) count, hemoglobin, plasma sodium, creatinine, and glucose.86 A score of 8 or greater Brunicardi_Ch16_p0511-p0540.indd 52519/02/19 3:09 PM 526SPECIFIC CONSIDERATIONSPART IIsuggested a high probability of NSTI, 6 or 7 an intermediate probability, and <5 a low probability. This test was internally validated and found to have a PPV of 92% and an NPV of 96%. However, some have criticized this study because of its small sample size and over-reliance on CRP, which can be elevated in multiple other conditions. Blood cultures are not always posi-tive, and tissue samples will demonstrate necrosis, white blood cell infiltration, thrombosis, angiitis, and microorganisms. The use of cross-sectional imaging in the diagnosis of NSTI is lim-ited, and it should not delay appropriate surgical treatment.Three principles form the foundation of the management of NSTIs: (a) source control with wide surgical debridement, (b) broad-spectrum intravenous antibiotics, and (c) supportive care and resuscitation. As soon as the diagnosis is clear or the sus-picion is high, the patient should be taken for operative explo-ration and debridement. Incisions should be made parallel to neurovascular structures and through the fascial plane, removing any purulent or devitalized tissue until viable, bleeding tissue is encountered. On inspection, the tissue will appear necrotic with dead muscle, thrombosed vessels, the classic “dishwater” fluid, and a positive finger test, in which the tissue layers can be easily separated from one another. In Fournier’s gangrene, one should aim to preserve the anal sphincter as well as the testicles (blood supply is independent of the overlying tissue and is usually not infected). Return to the OR should be planned for the next 24 to 48 hours to verify source control and the extent of damage. Broad spectrum antibiotic therapy should be initiated as soon as possible, with the intent of covering gram positives (including MRSA), gram negatives, and anaerobic organisms. The Infec-tious Diseases Society of America recommends initiating ther-apy with intravenous vancomycin and piperacillin/tazobactam, unless a monomicrobial agent is identified, in which case more directed therapy would be appropriate.81 Antibiotic therapy should continue until the patient requires no further debride-ment, is clinically improving, and has been afebrile for 48 to 72 hours.Adjuncts to surgery include topical antimicrobial creams, subatmospheric pressure wound dressings, and optimization of nutrition. Controversial topics include the role of hyperbaric oxygen87 (may inhibit infection by creating an oxidative burst, with anecdotally fewer debridements required and improved survival, but limited availability) and IVIG (may modulate the immune response to streptococcal superantigens). Wound clo-sure is performed once bacteriologic, metabolic, and nutritional balances are obtained.ActinomycosisActinomycetes is a genus of gram positive rods that inhabit the oropharynx, gastrointestinal tract, and female genital tract. The most commonly isolated species causing disease in humans is A isrealii. The cervicofacial form of Actinomycetes infection is the most common presentation, representing 55% of cases, and typically presenting as an acute pyogenic infection in the submandibular or paramandibular area. Patients can also exhibit chronic soft tissue swelling, fibrosis, and sinus discharge of sulfur granules.88 Demonstration of gram-positive filamentous organisms and sulfur granules on histological examination is strongly supportive of a diagnosis of actinomycosis.89 These infections are typically treated with high doses of intravenous followed by oral penicillin therapy. Surgical treatment is uti-lized if there is extensive necrotic tissue, poor response to anti-biotics, or the need for tissue biopsy to rule out malignancy.VIRAL INFECTIONS WITH SURGICAL IMPLICATIONSHuman Papillomavirus InfectionsHuman papillomaviruses represent a group of over 100 iso-lated types of small DNA viruses of the Papovavirus fam-ily that is highly host-specific to humans.90 These viruses are transmitted via cutaneous contact with individuals who have clinical or subclinical infection and occur more fre-quently in immunocompromised individuals. The viruses are responsible for the development of verrucae, or warts. These are histologically characterized by nonspecific findings of hyperkeratosis, papillomatosis, and acanthosis, as well as the hallmark koilocytes (clear halo around nucleus). Clinically, these generally arise as slow-growing papules on the skin or mucosal surfaces. Regression of HPV lesions is frequently an immune-mediated, spontaneous event that is exemplified by the persistent and extensive manifestation of this virus in the immune-compromised patient.The subtypes are generally grouped, based on their pre-sentation, as cutaneous or mucosal. Cutaneous types most com-monly affect the hands and fingers. Verruca vulgaris, or common warts, are caused by HPV types 1, 2, and 4, with a prevalence of up to 33% in school children and 3.5% in adults, and a higher prevalence in the immunosuppressed population.91 Plantar and palmar warts (HPV-1 and -4) typically occur at points of pres-sure and are characterized by a keratotic plug surrounded by a hyperkeratotic ring with black dots (thrombosed capillaries) on the surface. Plane warts occur on the face, dorsum of hands, and shins. They are caused by HPV-3 and -10 and tend to be multiple, flat-topped lesions with a smooth surface and light brown color. Cutaneous warts typically regress spontaneously in the immunocompetent patient. Epidermodysplasia verruci-formis is a rare, autosomal recessive inherited genetic skin dis-order that confers increased susceptibility to certain types of HPV. This presents with difficult-to-treat and often widespread verrucae that carry a higher risk of malignant transformation (30%–50% risk of squamous cell carcinoma), especially when caused by HPV types 5 and 8.92 A similar clinical picture has been described in human immunodeficiency virus (HIV) and transplant patients.93,94Mucosal HPV types cause lesions in the mucosal or geni-tal areas and behave like sexually transmitted infections. The most common mucosal types are HPV-6, -11, -16, -18, -31 and -33. These lesions present as condylomata acuminata, genital or veneral warts, papules that occur on the perineum, external genitalia, anus, and can extend into the mucosal surfaces of the vagina, urethra and rectum. These lesions are at risk for malig-nant transformation, with types 6 and 11 conferring low risk, and types 16, 18, 31 and 33 conferring a high risk. The recently developed quadrivalent HPV vaccine, targeting HPV types -6, -11, -16, and -18, is now available to both males and females age 9 to 26 and is associated with an up to 90% reduction of infections from those HPV types.95Treatment is aimed at physical destruction of the affected cells. Children often require no treatment as spontaneous regres-sion is common. In cases causing physical or emotional discom-fort, or in cases of immunocompromise or risk of transmission, treatment may be indicated. Cryotherapy using liquid nitrogen is an effective treatment for most warts, but care must be taken not to damage underlying structures.96 Topical preparations of salicylic acid, silver nitrate, and glutaraldehyde may also be Brunicardi_Ch16_p0511-p0540.indd 52619/02/19 3:09 PM 527THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16used. Treatment of recalcitrant lesions includes a variety of ther-apeutic options aimed at physically destroying the lesions by electrodessication, cryoablation, and pulsed dye laser therapy. Additional modalities such as H2-antagonists and zinc sulfate may have a role in augmenting the immune response and reduc-ing recurrence rates.Cutaneous Manifestations of Human Immunodeficiency VirusThe HIV-infected patient is significantly more susceptible to infectious and inflammatory skin conditions than the rest of the population.97 These skin disorders may be due to the HIV infection itself or from opportunistic infections secondary to immunosuppression. During early stages, nonspecific cutane-ous manifestations may occur. Acute retroviral syndrome occurs following inoculation in one-half to two-thirds of patients, and 30% to 50% of these patients can present with an acute viral exanthem.98 This is usually a morbilliform rash affecting the face, trunk, and upper extremities. Other skin changes, as well as common skin disorders with atypical features, can occur, including recurrent varicella zoster, hyperkeratotic warts, and seborrheic dermatitis. Condylomata acuminate and verrucae appear early; however, their frequency and severity do not change with disease progression.Late-presenting cutaneous manifestations include chronic herpes simplex virus (HSV), cytomegalovirus, and, to a lesser extent, molluscum contagiousum, which is typically treatable with imiquimod. HSV is the most common viral infection in the patient with HIV, and is more likely to display atypical fea-tures and less likely to spontaneously resolve in these patients.99 Mycobacterial infections and mucocutaneous candidiasis also occur. Bacterial infections such as impetigo and folliculitis may be more persistent and widespread.Malignant lesions such as Kaposi’s sarcoma occur in less than 5% of HIV-infected patients in the United States, although the worldwide prevalence in acquired immunodeficiency syn-drome (AIDS) patients exceeds 30%. Kaposi’s sarcoma is a vas-cular neoplasm that can affect cutaneous and visceral tissues. While the rates of Kaposi’s sarcoma development have sharply declined since the widespread use of antiretroviral therapy, the rates of other cutaneous malignancies have remained stable. The risk of an HIV-infected patient developing a cutaneous malig-nancy is about 5.7%, with basal cell carcinoma being the most common type encountered.100With regard to general surgical considerations in HIV patients, contributing related morbidities such as malnutrition, decreased CD4 count, and presence of opportunistic infection may result in delayed and attenuated wound healing capacity.101BENIGN TUMORSHemangiomaHemangiomas are benign vascular tumors that arise from the proliferation of endothelial cells that surround blood-filled cavities. They occur in about 4% of children by 1 year of age. Their natural history is typically presentation shortly after birth, a period of rapid growth during the first year, and then gradual involution over childhood in more than 90% of cases. These hemangiomas are generally managed nonsurgically prior to involution. Occasionally, during the rapid growth phase, the lesions can obstruct the airway, GI tract, vision, and musculo-skeletal function. In these cases, surgical resection is indicated prior to the involution phase. Hemangiomas can sometimes con-sume a large percentage of cardiac output, resulting in high-output heart failure or a consumptive coagulopathy, which may also necessitate resection. These lesions characteristically express the GLUT-1 glucose transporter protein, which is absent in cells of the normal cutaneous vasculature.102 First-line ther-apy for these infantile hemangiomas is propranolol, which causes cessation of growth and, in most cases, actual regression of the lesions.103,104 Systemic corticosteroids and interferon-α can impede tumor progression, and laser therapy has been used as well. If tumors persist into adolescence leaving a cosmeti-cally undesirable defect, surgical resection may be considered. When surgical resection or debulking is considered, upfront selective embolization can help with planned resection.NeviNevi (singular, nevus) are areas of melanocytic hyperplasia or neoplasia. These collections can be found in the epidermis (junctional), partially in the dermis (compound), or completely within the dermis (dermal). They commonly develop in child-hood and young adulthood, and will sometimes spontaneously regress. Exposure to UV radiation is associated with increased density of these lesions.105 Nevi are typically symmetric and small. Congenital nevi are the result of abnormal development of melanocytes. The events leading to this abnormal develop-ment may also affect the surrounding cells, resulting in longer, darker hair. Congenital nevi are found in less than 1% of neo-nates, and when characterized as giant congenital nevi, they have up to a 5% chance of developing into a malignant mela-noma, and may do so even in the first years of childhood.106,107 Treatment, therefore, consists of surgical excision of the lesion as early as is feasible. For larger lesions, serial excision and tissue expansion may be required, with the goal of lesion exci-sion being maintenance of function and form while decreasing oncologic risk.Cystic LesionsCutaneous cysts are benign lesions that are characterized by overgrowth of epidermis towards the center of the lesion, resulting in keratin accumulation. Epidermoid cysts (often mistakenly referred to as sebaceous cysts) are classically the result of keratin-plugged pilosebaceous units. They commonly affect adult men and women, and present as a dermal or sub-cutaneous cyst with a single, keratin-plugged punctum at the skin surface, often at or above the upper chest and back. Epi-dermoid cysts are the most common cutaneous cyst and are histologically characterized by mature epidermis complete with granular layer. Another type of cystic lesion is known as a trichilemmal cyst. These cysts are derived from the outer sheath of hair follicles, and, in contrast to epidermoid cysts, lack a granular layer. They are almost always found on the scalp and more commonly in women. A third type of cutaneous cyst is a dermoid cyst. Dermoid cysts are congenital variants that occur as the result of persistent epithelium within embry-onic lines of fusion. They occur most commonly between the forehead and nose tip, and the most frequent site is the eye-brow. They can lie in the subcutaneous tissue or intracranially, and often communicate with the skin surface via a small fis-tula. These cystic structures contain epithelial tissue, hair, and a variety of epidermal appendages. Treatment for these cystic structures includes surgical excision with care taken to remove the cyst lining to prevent recurrence.7Brunicardi_Ch16_p0511-p0540.indd 52719/02/19 3:09 PM 528SPECIFIC CONSIDERATIONSPART IIKeratosisActinic Keratosis. Actinic keratoses are neoplasms of epi-dermal keratinocytes that represent a range in a spectrum of disease from sun damage to squamous cell carcinoma. They typically occur in fair-skinned, elderly individuals in primarily sun-exposed areas, and UV radiation exposure is the greatest risk factor. There are multiple variants, and they can present as erythematous and scaly to hypertrophic, keratinized lesions. They can become symptomatic, causing bleeding, pruritis and pain. They can regress spontaneously, persist without change, and transform into invasive squamous cell carcinoma. It is estimated that approximately 10% of actinic keratoses will transform into invasive squamous cell carcinoma, and that pro-gression takes about 2 years on average.108 About 60% to 65% of squamous cell carcinomas are believed to originate from actinic keratoses. The presence of actinic keratoses also serves as a predictor of development of other squamous cell and basal cell carcinomas.109 Treatment options are excision, fluorouracil, cautery and destruction, and dermabrasion.110,111Seborrheic Keratosis. Seborrheic keratoses are benign lesions of the epidermis that typically present as well-demarcated, “stuck on” appearing papules or plaques over elderly individu-als. Clonal expansion of keratinocytes and melanocytes make up the substance of these lesions. They carry no malignant potential and treatment is primarily for cosmetic purposes.Soft Tissue TumorsAcrochordons. Acrochordons, also known as skin tags, are benign, pedunculated lesions on the skin made up of epider-mal keratinocytes surrounding a collagenous core. Although they can become irritated or necrotic, their removal is generally cosmetic.Dermatofibromas. Dermatofibromas are benign cutaneous proliferations that appear most commonly on the lower extremi-ties of women. They appear as pink to brown papules that pucker or dimple in the center when the lesion is pinched. It remains unclear whether these lesions have a neoplastic etiology or if they are the result of minor trauma or infection.112 These lesions are typically asymptomatic, and treatment is only indicated for cosmetic concerns or when a histologic diagnosis is required. Surgical excision is the recommended treatment, although cryo-therapy and laser treatment may be used.113 In rare cases, a basal cell carcinoma may develop within a dermatofibroma.Lipomas. Lipomas are the most common subcutaneous neo-plasm and have no malignant potential.114 They present as a painless, slow-growing, mobile mass of the subcutaneous tissue. Usually less than 5 cm in diameter, these neoplasms can reach much larger sizes. Lipomas are largely asymptomatic but may cause pain due to regional nerve deformation. Surgical resection is indicated in cases of local pain, mass effect, or cosmetically sensitive areas. The tumors are usually well circumscribed and amenable to surgical resection. Liposarcoma is a malignant fatty tumor that can mimic a lipoma, but is often deep-seated, rapidly growing, painful, and invasive. In these cases, cross-sectional imaging is recommended prior to any surgical resection.Neural TumorsNeuromas. Neuromas do not represent a true clonal prolifera-tion of neural tissue, but rather disordered growth of Schwann cells and nerve axons, often at the site of previous trauma. They can present within surgical scar lines or at the site of previous trauma as flesh-colored papules or nodules and are typically painful.Schwannomas. A schwannoma is a benign proliferation of the Schwann cells of the peripheral nerve sheath, and can arise sporadically or in association with type 2 neurofibromatosis. It contains no axons, but may displace the affected nerve and cause pain along the distribution of the nerve.Neurofibromas. Neurofibromas, in contrast, are benign prolif-erations that are made up of all nerve elements, and arise as fleshy and nontender, sessile or pedunculated masses on the skin. They can arise sporadically or in association with type 1 neurofibroma-tosis, and in these cases, are associated with café-au-lait spots and Lisch nodules. They are often asymptomatic, but may be pruritic. The development of pain at the site of a previously asymptomatic neurofibroma may indicate a rare malignant transformation and requires surgical excision and biopsy.MALIGNANT TUMORSBasal Cell CarcinomaBasal cell carcinoma (BCC) is the most common tumor diag-nosed in the United States, with an estimated one million new cases occurring each year. It represents 75% of non-melanoma skin cancers and 25% of all cancers diagnosed each year.115 BCC is seen slightly more commonly in males and indi-viduals over the age of 60, though the incidence in younger age groups is increasing. The primary risk factor for disease devel-opment is sun exposure (UVB rays more than UVA rays), par-ticularly during adolescence. The pathogenesis of BCC stems from mutations of genes involved in tumor suppression, often caused by ionizing radiation. The p53 tumor suppressor gene is defective in approximately 50% of cases.116 There is a latency period of 20 to 50 years.BCC tends to occur on sun-exposed areas of the skin, most commonly the nose and other parts of the face. A malignant lesion on the upper lip is almost always BCC, and BCC is the most common malignant eyelid tumor. Because of the photo-protective effect of melanin, dark-skinned individuals are far less commonly affected. Other risk factors for development of BCC include immune suppression, chemical exposure, and ion-izing radiation exposure. There are also genetic susceptibilities to development of BCC in conditions such as xeroderma pig-mentosa, unilateral basal cell nevus syndrome, and nevoid BCC syndrome.115 The natural history of BCC is typically one of local invasion rather than distant metastasis, but untreated BCC can often result in significant morbidity.There are multiple variants of BCC, and presentation can range from red, flesh-colored, or white macule or papule, to nodules and ulcerated lesions. Growth patterns of these lesions can either be well-circumscribed or diffuse and the most com-mon types of BCC are nodular and micronodular, superficial spreading, and infiltrative.117 The most common subtype is the nodular variant, characterized by raised, pearly pink papules with telangiectasias and occasionally a depressed tumor center with raised borders giving the classic “rodent ulcer” appearance. Superficial spreading BCC is confined to the epidermis as a flat, pink, scaling or crusting lesion, often mistaken for eczema, actinic keratosis, fungal infection, or psoriasis. This subtype typically appears on the trunk or extremities and the mean age of diagnosis is 57 years. The infiltrative form appears on the 8Brunicardi_Ch16_p0511-p0540.indd 52819/02/19 3:09 PM 529THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16head and neck in the late 60s, often at embryonic fusion lines,117 with an opaque yellow-white color that blends with surrounding skin and has no raised edges.118 The morpheaform subtype rep-resents 2% to 3% of all BCC and is the most aggressive subtype. It usually presents as an indurated macule or papule with the appearance of an enlarging scar. The clinical margins are often indistinct, and the rate of positive margins after excision is high. There is also a pigmented variant of BCC that can be difficult to distinguish from certain melanoma subtypes.Treatment of BCC varies according to size, location, type, and highor low-risk. Treatment options include surgical exci-sion, medical, or destructive therapies. Surgical excision should include 4 mm margins for small, primary BCC on cosmetically sensitive areas, and 10 mm margins otherwise.119 Mohs micro-surgical excision is sequential horizontal excision and has been shown to be cost-effective and associated with low recurrence rates for BCC (1%).120,121 It is the treatment of choice for mor-pheaform or other BCC with aggressive features, poorly delin-eated margins, recurrent tumors, or cosmetically sensitive areas, especially in the midface. A common approach used by derma-tologists for very small (<2 mm) and low risk lesions is cau-tery and destruction, although it should be kept in mind that the local cure rates can be operator and institution dependent. Other destructive techniques include cryosurgery and laser ablation. Radiation therapy can be used as adjuvant therapy following surgery, or as primary therapy in poor surgical candidates with low-risk lesions. The practitioner must be aware of the poten-tial consequences of radiation therapy, including poor cosmetic outcomes and future cancer risk.Superficial medical therapies are generally reserved for patients in whom surgical and radiation treatment is not an option. Topical imiquimod or 5-fluorouracil have been used for periods of 6 to 16 weeks for small, superficial BCC of the neck, trunk or extremities.122-126 Lastly, topical photodynamic therapy has shown some benefit in treatment of premalignant or super-ficial low-risk lesions as well.Patients with BCC need to have regular follow-up with full skin examinations every 6 to 12 months. Sixty-six percent of recurrences develop within 3 years, and with a few excep-tions occurring decades after initial treatment, the remaining recur within 5 years of initial treatment.121,127 A second primary BCC may develop after treatment and, in 40% of cases, presents within the first 3 years after treatment.Squamous Cell CarcinomaSquamous cell carcinoma (SCC) is the second most common skin cancer and accounts for approximately 100,000 cases each year. The primary risk factor for the development of SCC is UV radiation exposure128; however, other risks include light Fitzpatrick skin type (I or II), environmental factors such as chemical agents, physical agents (ionizing radiation), pso-ralen, HPV-16 and -18 infections, immunosuppression, smok-ing, chronic wounds, burn scars, and chronic dermatoses. Heritable risk factors include xeroderma pigmentosum, epider-molysis bullosa, and oculocutaneous albinism.SCC classically appears as a scaly or ulcerated papule or plaque, and bleeding of the lesion with minimal trauma is not uncommon, but pain is rare. It can exhibit in situ (confined to the epidermis) or invasive subtypes. The most common in situ variant of SCC is actinic keratosis, described previously in this chapter. Invasive squamous cell carcinomas may arise de novo, but more commonly evolve from these precursors. Another in 9Figure 16-9. Squamous cell carcinoma forming in a chronic wound.situ variant is known as Bowen disease. This is characterized by full-thickness epidermal dysplasia and clinically appears as a scaly, erythematous patch often with pigmentation and fis-suring. When it occurs on the glans penis, it is known as eryth-roplasia of Queyrat. Ten percent of these cases will eventually become invasive.129 Outside of these instances, most in situ cases grow slowly and do not progress to invasive disease.Invasive SCC is characterized by invasion through the basement membrane into the dermis of the skin. It usually arises from an actinic keratosis precursor, but de novo varieties do occur and are higher risk. De novo invasive SCC commonly occurs in organ transplant and immunocompromised patients, and has a metastatic rate as high as 14%.130 De novo invasive SCC arising in areas of chronic wounds or burn scars are known as Marjolin’s ulcers, and have a higher metastatic potential (Fig. 16-9). Keratoacanthoma is now being accepted as a sub-type of SCC that is characterized by a rapidly growing nodule with a central keratin plug.131 The natural history of invasive disease depends on location and inherent tumor characteristics. Clinical risk factors for recurrence include presentation with neurologic symptoms, immunosuppression, tumor with poorly defined borders, and tumor that arises at a site of prior radiation. Perineural involvement also has a poorer survival with increased local recurrence and lymph node metastasis. Grades of differen-tiation are based on the ratio of differentiated to undifferentiated cells, with a lower ratio associated with a greater metastatic and recurrent potential. Large (>2 cm) lesions, depth of invasion >4 mm, rapid growth, and location on the ear, lips, nose, scalp, or genitals are all also indicators of worse prognosis.When feasible, wide surgical excision including subcuta-neous fat is the treatment of choice for SCC. Margins of 4 mm are recommended for low-risk lesions and 6 mm for high-risk lesions.128 Mohs microsurgical excision is indicated for posi-tive margins, recurrent tumors, sites where cosmesis or function preservation is critical, poorly differentiated tumors, invasive lesions, and verrucous tumors. Using this modality often results in lower recurrence rates.127,130 It has also found use in nail bed lesions and in those arising in a background of osteomyelitis. The role of lymph node dissection in the setting of SCC contin-ues to evolve. Lymphadenectomy is indicated following fine-needle aspiration or core biopsy for clinically palpable lymph nodes or nodes detected on cross-sectional imaging. Nodes Brunicardi_Ch16_p0511-p0540.indd 52919/02/19 3:09 PM 530SPECIFIC CONSIDERATIONSPART IIshould also be removed from susceptible regional lymph node basins in patients with SCC in the setting of chronic wounds. Patients with parotid disease benefit from a superficial or total parotidectomy (with facial nerve preservation) and adjuvant radiotherapy. Sentinel lymph node dissection may be used in high risk cases with clinically negative nodal disease. Radiation therapy is typically reserved as primary therapy for those who are poor surgical candidates, and as adjuvant therapy after surgi-cal resection for large, high-risk tumors. When used as primary therapy, cure rates may approach 90%.121MelanomaBackground. In 2017, an estimated 87,110 new cases of melanoma were diagnosed, as well as 9730 melanoma-related deaths. The incidence of melanoma is rising faster than most other solid malignancies, and these numbers likely represent an underestimation given the many in situ and thin melanoma cases that are underreported. These tumors primarily arise from mela-nocytes at the epidermal-dermal junction but may also originate from mucosal surfaces of the oropharynx, nasopharynx, eyes, proximal esophagus, anorectum, and female genitalia. Mela-noma characteristically metastasizes quite often, and can travel to most other tissues in the body. This metastasis confers a poor prognosis in patients, with a median life span of 6 to 8 months after diagnosis.132The most important risk factor for the development of melanoma is exposure to UV radiation. It was recently reported that greater than 10 tanning bed sessions by adolescents and young adults increased their relative risk of developing mela-noma twofold,133 and there is a positive association with inter-mittent childhood sunburns and melanoma development.134 There is also an association with residence at high altitudes or in close proximity to the equator. Both personal and family history of melanomas increase the risk of primary melanoma develop-ment. Individuals with dysplastic nevi have a 6% to10% overall lifetime risk of melanoma, with tumors arising from preexisting nevi or de novo. Individuals with familial atypical multiple-mole melanoma syndrome have numerous melanocytic nevi and a greatly increased risk of cutaneous melanoma. Congenital nevi increase the risk for melanoma proportionally with size, and giant congenital nevi (generally considered >20 cm in diameter) are associated with a 5% to 8% lifetime risk. Melanoma development is strongly associated with the p16/CDK4,6/Rb and p14ARF/HMD2/p53 tumor suppressor pathways and the RAF-MEK-ERK and PI3K-Akt oncogenic pathways.135Clinical Presentation. The presentation of melanoma is com-monly used to determine subtype but often starts as a localized, radial growth phase followed by a more aggressive, vertical growth phase. Approximately 30% of melanoma lesions arise from a preexisting melanocytic nevus. The most common sub-type of melanoma is superficial spreading (Fig. 16-10). This accounts for 50% to 70% of melanomas and typically arises from a precursor melanocytic nevus. Nodular subtype accounts for 15% to 30% of melanomas, and typically arises de novo, most commonly in men and on the trunk (Figs. 16-11 and 16-12). This subtype is aggressive with an early vertical growth pat-tern and is often diagnosed at a later stage. Up to 5% of these lesions will lack melanin and can be mistaken for other cutane-ous lesions. Lentigo maligna represents 10% of melanoma cases and is a less aggressive subtype of melanoma in situ that typi-cally arises on sun-exposed areas of the head and neck. Acral Figure 16-10. Primary cutaneous melanoma seen in the scalp of a 61-year-old male.Figure 16-11. Nodular melanoma seen in the leg of a 55-year-old male.lentiginous melanoma accounts for 29% to 72% of melanomas in dark-skinned individuals, is occasionally seen in Caucasians, and is found on palmar, plantar, and subungual surfaces. This subtype is not thought to be due to sun exposure.Melanoma most commonly manifests as cutaneous dis-ease, and clinical characteristics of malignant transformation are often remembered by the initialism ABCDE. These lesions are typically Asymmetric with irregular Borders, Color variations, a Diameter greater than 6 mm, and are undergoing some sort of Evolution or change. Other key clinical characteristics include a pigmented lesion that has enlarged, ulcerated, or bled. Amela-notic lesions appear as raised pink, purple, or flesh-colored skin papules and are often diagnosed late.Diagnosis and Staging. Workup should begin with a his-tory and physical exam. The entire skin should be checked for synchronous primaries, satellite lesions, and in-transit metas-tases, and all nodal basins should be examined for lymphade-nopathy. Suspicious lesions should undergo excisional biopsy with 1to 3-mm margins; however, tumors that are large or are in a cosmetically or anatomically challenging area can be approached by incisional biopsy, including punch biopsy.136 Brunicardi_Ch16_p0511-p0540.indd 53019/02/19 3:09 PM 531THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16ABCFigure 16-12. A. AP view of advanced melanoma in a 59-year-old male. B. Lateral view C. After resection and reconstruction with skin grafting.Tissue specimen should include full thickness of the lesion and a small section of normal adjacent skin to aid the pathologist in diagnosis. Clinically suspicious lymph nodes should undergo fine-needle aspiration (FNA), as this has been shown to have a high sensitivity and specificity for detection of melanoma in large lymph nodes.136-139Melanoma is characterized according to the American Joint Committee on Cancer (AJCC) as localized disease (stage I and II), regional disease (stage III), or distant metastatic disease (stage IV). The Breslow tumor thickness replaced the Clark’s level as the most important prognostic indicator for melanoma stag-ing.132,140 The Breslow tumor thickness measures the depth of penetration of the lesions from the top of the granular layer of the epidermis into the dermal layer and is directly related to the risk of disease progression. Tumor ulceration, mitotic rate ≥1 per mm2, and metastasis are all also associated with worse prognosis. In the presence of regional node metastasis, the num-ber of nodes affected is the most important prognostic indicator. For stage IV disease, the site of metastasis is strongly associated with prognosis, and elevated lactate dehydrogenase (LDH) is associated with a worse prognosis.141There is no supportive evidence for chest X-ray or com-puted tomography (CT) in the staging of patients unless there is positive regional lymph node disease, although it can be used to work up specific signs and symptoms when metastatic disease is suspected.136 In patients with stage III or greater disease, there is a high risk for distant metastasis, and imaging is recommended for baseline staging. These patients should receive additional imaging that includes CT of the chest, abdomen, and pelvis; whole-body positon emission tomography (PET)-CT; or brain magnetic resonance imaging (MRI).136The sentinel lymph node biopsy (SLNB) technique for melanoma was introduced in 1992 and has become a corner-stone in the management of melanoma, although its role in man-agement continues to be refined. SLNB is a standard staging procedure to evaluate the regional nodes for patients with clini-cally node-negative malignant melanoma. Detecting subclinical nodal metastasis in may benefit from lymphadenectomy or adju-vant therapy. This technique identifies the first draining lymph node from the primary lesion and has shown excellent accuracy and significantly less morbidity compared to complete resection of nodal basins. It is almost always performed at the time of initial wide excision, as SLN mapping after lymphatic violation from surgical excision could decrease the accuracy of the test. Recently, the results of MSLT-1, an international, multicenter, phase III trial were published. This study randomized clinically node negative patients to either SLNB at the time of primary melanoma excision (and completion lymphadenectomy if posi-tive) or nodal basin monitoring (and delayed complete lymph-adenectomy for recurrent lymph node disease).142 The results of this study demonstrated that SLNB, with immediate lymphad-enectomy if positive, improved disease-free survival by 7% and 10% in patients with intermediate thickness (1.2–3.5 mm) and thick (>3.5 mm) lesions respectively. The use of SLNB in lesions <1.2 mm thick did not affect disease-free survival. SLNB should also be offered to thin lesions with high-risk features (thickness >0.75, ulceration, mitoses ≥1 per mm2.136 The SLNB involves preoperative lymphoscintigraphy with intradermal injections of technetium-sulfur colloid to delineate lymphatic drainage and intraoperative intradermal injection of 1 mL of isosulfan or methylene blue dye near the tumor or biopsy site. (Figs. 16-13 and 16-14). The radioactive tracer-dye combination allows the sentinel node to be identified in 98% of cases. An incision over the lymph node basin of interest allows nodes to be excised and studied with hematoxylin and eosin and immunohistochemistry (S100, HMB45, and MART-1/Melan-A) staining (Fig. 16-15). 10Brunicardi_Ch16_p0511-p0540.indd 53119/02/19 3:09 PM 532SPECIFIC CONSIDERATIONSPART IIABSentinellymph nodeInjection siteSurgical exposure of sentinel lymph nodeAfferent lymphaticchannelsSentinellymph nodePrimary melanomaSentinellymphnodeInguinal nodesABCFLOWINJ SITEAxillaryNODEANTFLOWPOSTTymphoMelanoma Primary Injection SiteSubmanibular Lymph nodesPopliteal nodesFigure 16-13. After injection of radioactive technetium-99–labeled sulfur colloid tracer at the primary cutaneous melanoma site, sentinel lymph node basins are identified. A. Lymphoscintig-raphy of 67-year-old male with a malignant melanoma of the right heel; sentinel lymph nodes in both the right popliteal fossa and inguinal region. B. Lymphoscintigraphy of 52-year-old male with a malignant melanoma of the posterior right upper arm; sentinel lymph node in the right axillary region. C. Lymphoscintigraphy of 69-year-old male with a facial melanoma; sentinel lymph nodes in the submandibular region. ANT = anterior; INJ = injection; POST = posterior.Risks of this technique are uncommon but include skin necrosis near the site of injection, anaphylactic shock, lymphedema, sur-gical site infections, seromas, and hematomas.Surgical Management of the Primary Tumors and Lymph Nodes. The appropriate excision margin is based on primary tumor thickness. Several retrospective studies suggest that for melanoma in situ, 0.5 to 1 cm margins are sufficient.143-145 We believe that 1-cm margins should be obtained in anatomically fea-sible areas given the possibility of an incidental finding of a small invasive component in permanent sections. Several studies com-pared 1to 3-cm margins and 2to 5-cm margins in melanoma <2 mm thick, and 2to 4-cm margins in melanoma lesions 1 to 4 mm thick and found no difference. 146-149 A British trial suggested that there is a limit to how narrow margins can be for melanomas >2 mm thick by showing that 1-cm margins provide worse outcomes compared to 3-cm margins.150 Tumors <1 mm thick require 0.5 to 1 cm margins. Tumors 1 to 2 mm thick require 1 to 2 cm margins, and tumors >2 mm thick require 2-cm margins.Completion lymphadenectomy is commonly performed in cases of sentinel nodes with metastatic disease, but it has been shown that most of these nodal basins do not have addi-tional disease. Thus, many surgeons do not perform routine completion lymphadenectomy for positive nodes, and data from the MSLT-2 may provide guidance. It has been shown that those patients with nonsentinel lymph node positivity found on completion lymph node dissection after a positive SLN have higher rates of recurrence and lower rates of sur-vival. The therapeutic value, however, has not been clearly demonstrated. In patients with clinically positive lymph nodes but absent signs of distant metastasis on PET-CT, therapeu-tic lymph node dissection is associated with 5-year survival rates of 30% to 50%. In these cases, resection of the primary melanoma lesion and a completion lymphadenectomy should be performed.Individuals with face, anterior scalp, and ear prima-ries who have a positive SLNB should undergo a superficial parotidectomy in addition to a modified radical neck dissection. Figure 16-14. Technique of sentinel lymph node biopsy for cutaneous melanoma. A. After injection of radioactive technetium-99–labeled sulfur colloid tracer at a lower abdominal wall primary cutaneous melanoma site, B. sentinel lymph node basins are identified. (Reproduced with permission from Gershenwald JE, Ross MI: Sentinel-lymph-node biopsy for cutane-ous melanoma, N Engl J Med. 2011 May 5;364(18):1738-1745.)Brunicardi_Ch16_p0511-p0540.indd 53219/02/19 3:09 PM 533THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16ABFigure 16-15. Operation of sentinel lymph node biopsy for cutaneous melanoma. After preoperative injection of radioactive technetium-99–labeled sulfur colloid tracer and intraoperative injection of Lymphazurin blue dye around the primary melanoma excision site, the nodal basin of interest is identified. An incision is made directly overlying the lymph node basin in the posterior axillary space. The sentinel lymph nodes are identified and excised.Patients with positive sentinel nodes in the inguino-femoral nodal basin should undergo an inguino-femoral lymphadenec-tomy that includes removal of Cloquet’s node. If Cloquet’s node is positive or the patient has three or more nodes that contain melanoma metastases the probability of clinically occult posi-tive pelvic nodes is increased. The effect of ileo-obturator lymph node dissection on the survival of these patients is unknown.Surgery for Regional and Distant Metastasis. Nonmeta-static, in-transit disease should undergo excision to clear mar-gins when feasible. However, disease not amenable to complete excision derives benefit from isolated limb perfusion (ILP) and isolated limb infusion (ILI) (Fig. 16-16). These two modali-ties are used to treat regional disease, and their purpose is to administer high doses of chemotherapy, commonly melphalan, to an affected limb while avoiding systemic drug toxicity. ILI was shown to provide a 31% response rate in one study, while hyperthermic ILP provided a 63% complete response rate in an independent study.151-154The most common sites of metastasis of melanoma are the lung and liver. These are followed by the brain, gastroin-testinal tract, distant skin, and subcutaneous tissue. A limited subset of patients with small-volume, limited distant metastases to the brain, gastrointestinal tract, or distant skin can be treated with surgical resection or directed radiation. Liver metastases are better dealt without surgical resection unless they arise from an ocular primary. Adjuvant therapy after resection of meta-static lesions is not standard of care. However, there are ongo-ing clinical trials addressing whether drugs and vaccines will be beneficial in this setting.115 Surgery may provide palliation for patients with gastrointestinal obstruction, gastrointestinal hem-orrhage, and nongastrointestinal hemorrhage. Radiotherapy for symptomatic bony or brain metastases provides palliation in dif-fuse disease.Adjuvant and Palliative Therapies. Eastern Cooperative Oncology Group (ECOG) Trials 1684, 1690, and 1694 were prospective randomized controlled trials that demonstrated Overhead heaterHot air blanketVenouscatheterArterialcatheterPneumatictourniquetPumpchamber25cc SyringeWarmingcoilEsmarchbandageDrug inpre-warmedsalineFigure 16-16. Isolated limb infusion. Schematic of isolated limb infusion of lower extremity. (Adapted with permis-sion from Testori A, Verhoef C, Kroon HM, et al: Treatment of melanoma metas-tases in a limb by isolated limb perfusion and isolated limb infusion, J Surg Oncol. 2011 Sep;104(4):397-404.)Brunicardi_Ch16_p0511-p0540.indd 53319/02/19 3:09 PM 534SPECIFIC CONSIDERATIONSPART IIdisease-free survival advantages in patients with melanoma >4 mm in thickness with or without lymph node involvement if they received adjuvant treatment with high-dose interferon (IFN).155-157 A European Organization for Research and Treat-ment of Cancer (EORTC) trial also showed recurrence-free survival benefit with pegylated IFN.158 It is important to note that IFN therapy is not well tolerated and the pooled analysis of these trials did not show an improvement in overall survival benefit.Most patients with melanoma will not be surgical candi-dates. Although medical options for melanoma have historically been poor, several recent studies have shown promise in drug therapy for metastatic melanoma. BRAF inhibitors (sorafenib), anti-PD1 antibodies, CTLA antibodies (ipilimumab), and high-dose interleukin-2 (IL-2) with and without vaccines have been shown in randomized studies to provide survival benefit in metastatic disease.159-165 Despite the excitement of recent drugs, surgery will likely play an adjunct role in treating individuals who develop resistance to these drugs over time.Special Circumstances. Special circumstances of note are melanoma in pregnant women, melanoma of unknown prima-ries, and noncutaneous melanomas. The prognosis of pregnant patients is similar to women who are not pregnant. Extrapo-lation of studies examining the SLNB technique in pregnant women with breast cancer suggests lymphoscintigraphy may be done safely during pregnancy without risk to the fetus (blue dye is contraindicated). General anesthesia should be avoided during the first trimester, and local anesthetics should be used during this time. It has been suggested by some that after excising the primary tumor during pregnancy, the SLNB may be performed after delivery.Unknown primary melanoma occurs in 2% to 5% of cases and most commonly occurs in the lymph nodes. In these cases, a thorough search for the primary lesion should be sought, includ-ing eliciting a history about prior skin lesions, skin procedures (e.g., curettage and electrodessication, excision, laser), and review of any prior “benign” pathology. The surgeon should be aware that melanoma is known to spontaneously regress because of an immune response. Melanoma of unknown pri-mary has survival rates comparable to melanoma diagnosed with a known primary of the same stage.The most common noncutaneous disease site is ocular melanoma, and treatment of this condition includes photocoag-ulation, partial resection, radiation, or enucleation.166-168 Ocular melanomas exclusively metastasize to the liver and not regional lymph nodes, and some patients benefit from liver resection. Melanoma of the mucous membranes most commonly presents in the oral cavity, oropharynx, nasopharynx, paranasal sinus, anus, rectum, and female genitalia. Patients with this presenta-tion have a worse prognosis (10% 5-year survival) than patients with cutaneous melanomas. Management should be excision to negative margins, and radical resections should be avoided because the role of surgery is locoregional control, not cure. Generally speaking, lymph node dissection should be avoided because the benefit is unclear.Merkel Cell CarcinomaMerkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin whose incidence has been rapidly increas-ing. Although it is a much rarer malignancy than melanoma, the prognosis is much worse, with a 5-year survival of 46%.169 Merkel cells are epidermal appendages involved in the sensation Figure 16-17. Merkel cell carcinoma seen just above the left knee in a 44-year-old female.of light touch, and along with Merkel cell carcinoma, are cyto-keratin-20 positive. This stain is now used to confirm the diag-nosis. Other risk factors include age >65 years (the median age of diagnosis is 70 years), UV exposure, Merkel cell polyoma virus, and immunosuppression. MCC typically presents as a rapidly growing, flesh-colored to red or purple papule or plaque (Fig. 16-17). Regional nodes are involved in 30% of patients at diagnosis, and 50% will develop systemic disease (skin, lymph nodes, liver, lung, bone, and brain).170,171 There are no standard-ized diagnostic imaging studies for staging, but CT of the chest, abdomen, pelvis and octreotide scans may provide useful infor-mation when clinically indicated.After a thorough skin examination, treatment should begin by evaluating nodal basins. Patients without clinical nodal dis-ease should undergo an SLNB prior to wide local excision because studies suggest a benefit.172 In patients with sentinel lymph nodes with metastatic disease, completion lymphad-enectomy and/or radiation therapy may follow, and in patients with node-negative disease, observation or radiation therapy should be considered.172 SLNB is important for staging and treatment, and the literature suggests that it predicts recurrenceand relapse-free survival. Elective lymph node dissection may decrease regional nodal recurrence and in-transit metastases. Patients with clinically positive nodes should have an FNA to confirm disease. If positive, a metastatic staging workup should follow, and, if negative, treatment of the primary and nodal basin as managed for sentinel lymph node-positive disease should be considered. A negative FNA and open biopsy-negative disease should be managed by treatment of the primary disease alone. Brunicardi_Ch16_p0511-p0540.indd 53419/02/19 3:09 PM 535THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16Patients with metastatic disease should be managed according to consensus from a multidisciplinary tumor board.Important surgical principles for excision of the primary lesion are to excise with wide margins down to fascia and com-plete circumferential and peripheral deep-margin assessment. Recommended management for margins is 1 to 3 cm, but there are no randomized trials defining these margins. Chemotherapy and adjuvant radiation are commonly used, but there are no data to support a specific regimen or that demonstrate a definitive survival benefit.Recurrence of MCC is common. One study of 95 patients showed a 47% recurrence, with 80% of recurrences occurring within 2 years and 96% occurring within 5 years.173,174 Regional lymph node disease is common, and 70% of patients will have nodal spread within 2 years of disease presentation. Five-year overall survival of head and neck disease in surgically treated patients is between 40% and 68%.Kaposi’s SarcomaKaposi’s sarcoma is characterized by the proliferation and inflammation of endothelial-derived spindle cell lesions. There are five major forms of this angioproliferative disorder: classic (Mediterranean), African endemic, HIV-negative men having sex with men (MSM)-associated, and immunosuppression-associated. They are all driven by the human herpesvirus (HHV-8).175 Kaposi’s sarcoma is diagnosed after the fifth decade of life and predominantly found on the skin but can occur anywhere in the body. In North America, the Kaposi’s sarcoma herpes virus is transmitted via sexual and nonsexual routes and predominantly affects individuals with compromised immune systems such as those with HIV and transplant recipients on immune-suppressing medications. Clinically, Kaposi’s sarcoma appears as multifocal, rubbery blue-red nodules. Treatment of AIDS-associated Kaposi’s sarcoma is with antiviral therapy, and many patients experience a dramatic treatment response.176,177 Those individuals who do not respond and have limited muco-cutaneous disease may benefit from cryotherapy, photodynamic therapy, radiation therapy, intralesional injections, and topical therapy. Surgical biopsy is important for disease diagnosis, but given the high local recurrence and the fact that Kaposi’s sar-coma represents more of a systemic rather than local disease, the benefit of surgery is limited and generally should not be pursued except for palliation.Dermatofibrosarcoma ProtuberansThis rare, low-grade sarcoma of fibroblast origin commonly afflicts individuals during their third decade of life. It has low distant metastatic potential, but it behaves aggressively locally with finger-like extensions. Tumor depth is the most important prognostic variable. Presentation is characteristically a slow-growing, asymptomatic, violaceous plaque involving the trunk, head, neck, or extremities (Fig. 16-18). Nearly all cases are posi-tive for CD34 and negative for factor XIIIa.178,179 Treatment is wide local excision with 3-cm margins down to deep underly-ing fascia or Mohs microsurgery in cosmetically sensitive areas where maximum tissue preservation will benefit.180 No nodal dissection is needed, and both approaches provide similar local control.181 Some clinicians have used radiation therapy and bio-logic agents (imatinib) as adjuvant therapy with some success in patients with advanced disease. Local recurrence occurs in 50% to 75% of cases, usually within 3 years of treatment. Thus, clini-cal follow-up is important. Recurrent tumors should be resected whenever possible.Figure 16-18. Dermatofibrosarcoma protuberans of the left flank.Malignant Fibrous Histiocytoma (Undifferentiated Pleomorphic Sarcoma and Myxofibrosarcoma)This uncommon, cutaneous, spindle-cell, soft tissue sarcoma occurs in the extremities, head, and neck of elderly patients. They present as solitary, soft to firm, skin-colored subcutane-ous nodules. Complete surgical resection is the treatment of choice, and adjuvant radiation therapy provides local control; patients with positive margins benefit most from this combina-tion. Nevertheless, patients undergoing complete gross resection will experience recurrence in 30% to 35% of cases.135 Up to 50% of patients may present with distant metastasis, and this is a contraindication to surgical resection.AngiosarcomaAngiosarcoma is an uncommon, aggressive cancer that arises from vascular endothelial cells and occurs in four variants, all of which have a poor prognosis.182 The 5-year survival estimate is 15%.183 The head and neck variant presents in individuals older than 40 years as an ill-defined red patch on the face or scalp, often with satellite lesions and distant metastasis, and has a median survival of 18 to 28 months. Lymphedema-associated angiosarcoma (Stewart-Treves) develops on an extremity ipsi-lateral to an axillary lymphadenectomy. It appears on the upper, medial arm as a violaceous plaque in an individual with nonpit-ting edema and has a poor survival. Radiation-induced angio-sarcoma occurs 4 to 25 years after radiation therapy for benign and malignant conditions. Finally, the epithelioid variant of angiosarcoma involves the lower extremities and also has a poor prognosis. Surgical excision with wide margins is the treatment Brunicardi_Ch16_p0511-p0540.indd 53519/02/19 3:09 PM 536SPECIFIC CONSIDERATIONSPART IIof choice for localized disease, but the rate of recurrence is high. Adjuvant radiation therapy can be considered in a multidisci-plinary fashion. Cases of extremity disease can be considered for amputation. For widely metastatic disease, chemotherapy and radiation may provide palliation, but these modalities do not prolong overall survival.115Extramammary Paget’s DiseaseThis rare adenocarcinoma of apocrine glands arises in axillary, perianal, and genital regions of men and women.184 Clinical pre-sentation is that of erythematous or nonpigmented plaques with an eczema-like appearance that often persist after failed treat-ment from other therapies. An important characteristic and one that the surgeon must be acutely aware of is the high incidence of concomitant other malignancies with this cutaneous disease. Forty percent of cases are associated with primary gastrointesti-nal and genitourinary malignancies, and a diligent search should be made after a diagnosis of extramammary Paget’s disease is made. Treatment is surgical resection with negative microscopic margins, and adjuvant radiation may provide additional locore-gional control.CONCLUSIONThe skin is the largest organ in the human body and is com-posed of three organized layers that are the source of numer-ous pathologies. Recognition and management of cutaneous and subcutaneous diseases require an astute clinician to opti-mize clinical outcomes. Improvements in drugs, therapies, and healthcare practices have helped recovery from skin injuries. Skin and subcutaneous diseases are often managed medically, although surgery frequently complements treatment. Benign tumors are surgical diseases, while malignant tumors are pri-marily treated surgically, and additional modalities including chemotherapy and radiation therapy are sometimes required. 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A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372(8):735-746. A multi-center, randomized, double-blind, adaptive, phase 2 and 3 trial that showed propranolol is a very effective treatment for infantile hemangioma. 105. Kelly JW, Rivers JK, MacLennan R, Harrison S, Lewis AE, Tate BJ. Sunlight: a major factor associated with the develop-ment of melanocytic nevi in Australian schoolchildren. J Am Acad Dermatol. 1994;30(1):40-48. 106. Krengel S, Hauschild A, Schafer T. Melanoma risk in con-genital melanocytic naevi: a systematic review. Br J Dermatol. 2006;155(1):1-8. 107. Schaffer J V. Pigmented lesions in children: when to worry. Curr Opin Pediatr. 2007;19(4):430-440. 108. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg. 2007;33(9):1099-1101. 109. Marks R, Rennie G, Selwood T. The relationship of basal cell carcinomas and squamous cell carcinomas to solar keratoses. Arch Dermatol. 1988;124(7):1039-1042. 110. Robins P, Gupta AK. The use of topical fluorouracil to treat actinic keratosis. Cutis. 2002;70(2 suppl):4-7. 111. Fu W, Cockerell CJ. The actinic (solar) keratosis: a 21st-century perspective. Arch Dermatol. 2003;139(1):66-70. 112. Pariser RJ. Benign neoplasms of the skin. Med Clin North Am. 1998;82(6):1285-307, v-vi. 113. Lee EH, Nehal KS, Disa JJ. Benign and premalignant skin lesions. Plast Reconstr Surg. 2010;125(5):188e-198e. 114. Mentzel T. Cutaneous lipomatous neoplasms. Semin Diagn Pathol. 2001;18(4):250-257. 115. Reszko A, Wilson L, Leffell D. Devita, Hellman, Rosenberg’s Cancer: Principles and Practice. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 116. Benjamin CL, Ananthaswamy HN. p53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol. 2007;224(3):241-248. 117. Netscher DT, Leong M, Orengo I, Yang D, Berg C, Krishnan B. Cutaneous malignancies: melanoma and nonmelanoma types. Plast Reconstr Surg. 2011;127(3):37e-56e.Brunicardi_Ch16_p0511-p0540.indd 53819/02/19 3:09 PM 539THE SKIN AND SUBCUTANEOUS TISSUECHAPTER 16 118. Siegle RJ, MacMillan J, Pollack S V. Infiltrative basal cell carcinoma: a nonsclerosing subtype. J Dermatol Surg Oncol. 1986;12(8):830-836. 119. Kimyai-Asadi A, Alam M, Goldberg LH, et al. Efficacy of narrowmargin excision of well-demarcated primary facial basal cell carcinomas. J Am Acad Dermatol. 2005;53(3):464-468. 120. Rowe DE, Carroll RJ, Day CL. Mohs surgery is the treat-ment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol. 1989;15(4):424-431. A heavily referenced paper from 1989 demonstrating the effectiveness of Mohs micrographic surgery in local control of recurrent basal cell carcinoma. 121. Rowe DE, Carroll RJ, Day CL. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol. 1989;15(3):315-328. 122. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, random-ized, vehicle-controlled studies. J Am Acad Dermatol. 2004;50(5):722-733. A multicenter, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study which showed that 5% imiquimod cream was an effective treatment for superficial BCC. 123. Marks R, Gebauer K, Shumack S, et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol. 2001;44(5):807-813. 124. Schulze HJ, Cribier B, Requena L, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol. 2005;152(5):939-947. 125. Shumack S, Robinson J, Kossard S, et al. Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol. 2002;138(9):1165-1171. 126. Vidal D, Matías-Guiu X, Alomar A. Open study of the efficacy and mechanism of action of topical imiquimod in basal cell carcinoma. Clin Exp Dermatol. 2004;29(5):518-525. 127. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26(6):976-990. 128. National Comprehensive Cancer Network. Squamous cell carcinoma, National Comprehensive Cancer Network clini-cal practice guidelines in oncology, squamous cell carcinoma, version 1.2018. In: National Comprehensive Cancer Network. Fort Washington, PA; 2017. 129. Kao GF. Carcinoma arising in Bowen’s disease. Arch Derma-tol. 1986;122(10):1124-1126. 130. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classifica-tion. Part one. J Cutan Pathol. 2006;33(3):191-206. 131. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol. 1994;30(1):1-19. 132. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622-3634. This paper looked at over 17,000 melanoma patients in 2001, validating the AJCC TNM staging system for melanoma. 133. Cust AE, Armstrong BK, Goumas C, et al. Sunbed use dur-ing adolescence and early adulthood is associated with increased risk of early-onset melanoma. Int J Cancer. 2011;128(10):2425-2435. 134. Elwood JM, Jopson J. Melanoma and sun exposure: an over-view of published studies. Int J Cancer. 1997;73(2):198-203. 135. Chudnovsky Y, Khavari PA, Adams AE. 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Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206. 141. Weide B, Elsässer M, Büttner P, et al. Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer. 2012;107(3):422-428. 142. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. This was a phase 3 trial evaluating outcomes in 2001 patients with primary cutaneous melanoma that demonstrated the use-fulness of SLN biopsy in patients with thick and interme-diate-thickness melanoma. 143. Duffy KL, Truong A, Bowen GM, et al. Adequacy of 5-mm surgical excision margins for non-lentiginous melanoma in situ. J Am Acad Dermatol. 2014;71(4):835-838. 144. Akhtar S, Bhat W, Magdum A, Stanley PR. Surgical excision margins for melanoma in situ. J Plast Reconstr Aesthetic Surg. 2014;67(3):320-323. 145. Felton S, Taylor RS, Srivastava D. Excision margins for melanoma in situ on the head and neck. Dermatologic Surg. 2016;42(3):327-334. 146. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. N Engl J Med. 1988;318(18):1159-1162. 147. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer. 2000;89(7):1495-1501. 148. Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8(2):101-108. 149. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. 1993;218(3):262-269. 150. Hayes AJ, Maynard L, Coombes G, et al. Wide versus nar-row excision margins for high-risk, primary cutaneous mela-nomas: long-term follow-up of survival in a randomised trial. Lancet Oncol. 2016;17(2):184-192. A multicenter random-ized trial that demonstrated superiority of 3 cm margins over 1 cm margins for cutaneous melanoma >2 mm in thickness. 151. Beasley GM, Caudle A, Petersen RP, et al. A multi-institu-tional experience of isolated limb infusion: defining response and toxicity in the US. J Am Coll Surg. 2009;208(5):706-715.Brunicardi_Ch16_p0511-p0540.indd 53919/02/19 3:09 PM 540SPECIFIC CONSIDERATIONSPART II 152. Boesch CE, Meyer T, Waschke L, et al. Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treat-ment of locoregionally metastasised malignant melanoma of the extremities. Int J Hyperthermia. 2010;26(1):16-20. 153. Lindnér P, Doubrovsky A, Kam PCA, Thompson JF. Prognos-tic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol. 2002;9(2):127-136. 154. Lens MB, Dawes M. Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Lancet Oncol. 2003;4(6):359-364. 155. Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analy-sis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10(5):1670-1677. A multicenter, random-ized trial that demonstrated high-dose interferon may be effective as an adjuvant treatment for melanoma. 156. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17. 157. Kirkwood JM, Ibrahim JG, Sondak VK, et al. Highand low-dose interferon alfa-2b in high-risk melanoma: first analy-sis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444-2458. 158. Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant ther-apy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet (London, England). 2008;372(9633):117-126. 159. Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group S0008: A phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleu-kin-2 and interferon in patients with high-risk melanoma— an Intergroup Study of Cancer and Leukemia Group B, Children’s Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014; 32(33):3771-3778. 160. Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, doubleblind, phase 3 trial. Lancet Oncol. 2015;16(5):522-530. 161. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombi-nant interleukin 2 therapy for patients with metastatic mela-noma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105-2116. 162. Chapman PB, Hauschild A, Robert C, et al. Improved sur-vival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516. A phase 3 clinical trial demonstrating effectiveness of vemurafenib in melanoma patients with BRAF V600E mutations. 163. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. A phase III clinical trial demonstrating some improvement in survival with the use of ipilimumab in the treatment of recalcitrant metastatic melanoma. 164. Smith FO, Downey SG, Klapper JA, et al. Treatment of meta-static melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14(17):5610-5618. 165. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 271(12):907-913. 166. Albert DM, Ryan LM, Borden EC. Metastatic ocular and cutaneous melanoma: a comparison of patient characteris-tics and prognosis. Arch Ophthalmol (Chicago, Ill 1960). 1996;114(1):107-108. 167. Inskip PD, Devesa SS, Fraumeni JF. Trends in the incidence of ocular melanoma in the United States, 1974-1998. Cancer Causes Control. 2003;14(3):251-257. 168. Starr OD, Patel D V, Allen JP, McGhee CN. Iris melanoma: pathology, prognosis and surgical intervention. Clin Exp Ophthalmol. 2004;32(3):294-296. 169. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evalu-ation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus stag-ing system. J Am Acad Dermatol. 2010;63(5):751-761. 170. Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol. 2000;43(5):755-767. 171. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carci-noma: case series and literature review of 1024 cases. Ann Surg Oncol. 2001;8(3):204-208. 172. National Comprehensive Cancer Network. Merkel cell carcinoma. In: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Merkel Cell Carcinoma Version 1.2018. Fort Washington, PA; 2017. 173. Bichakjian CK, Lowe L, Lao CD, et al. Merkel cell carcinoma: critical review with guidelines for multidisciplinary manage-ment. Cancer. 2007;110(1):1-12. 174. Ott MJ, Tanabe KK, Gadd MA, et al. Multimodal-ity management of Merkel cell carcinoma. Arch Surg. 1999;134(4):388-393. 175. Ramírez-Amador V, Anaya-Saavedra G, Martínez-Mata G. Kaposi’s sarcoma of the head and neck: a review. Oral Oncol. 2010;46(3):135-145. 176. 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The BreastCatherine C. Parker, Senthil Damodaran, Kirby I. Bland, and Kelly K. Hunt 17chapterA BRIEF HISTORY OF BREAST CANCER THERAPYBreast cancer has captured the attention of surgeons throughout the ages. The Smith Surgical Papyrus (3000–2500 b.c.) is the earliest known document to refer to breast cancer. The cancer was in a man, but the description encompassed most of the common clinical features. In reference to this cancer, the author concluded, “There is no treatment.”1 There were few other historical references to breast cancer until the first century. In De Medicina, Celsus commented on the value of operations for early breast cancer: “None of these may be removed but the cacoethes (early cancer), the rest are irritated by every method of cure. The more violent the operations are, the more angry they grow.”2 In the second century, Galen inscribed his classical clinical observation: “We have often seen in the breast a tumor exactly resembling the animal the crab. Just as the crab has legs on both sides of his body, so in this disease the veins extending out from the unnatural growth take the shape of a crab’s legs. We have often cured this disease in its early stages, but after it has reached a large size, no one has cured it. In all operations we attempt to excise the tumor in a circle where it borders on the healthy tissue.”3The Galenic system of medicine ascribed cancers to an excess of black bile and concluded that excision of a local bodily outbreak could not cure the systemic imbalance. Theories espoused by Galen dominated medicine until the Renaissance. In 1652, Tulp introduced the idea that cancer was contagious when he reported an elderly woman and her housemaid who both developed breast cancer (N. Tulp, Observationes medi-cae 1652). This single incidence was accepted as conclusive A Brief History of Breast Cancer Therapy541Embryology and Functional Anatomy of the Breast543Embryology / 543Functional Anatomy / 544Physiology of the Breast547Breast Development and Function / 547Pregnancy, Lactation, and Senescence / 548Gynecomastia / 549Infectious and Inflammatory Disorders of the Breast550Bacterial Infection / 550Mycotic Infections / 550Hidradenitis Suppurativa / 550Mondor’s Disease / 550Common Benign Disorders and Diseases of the Breast551Aberrations of Normal Development and Involution / 551Pathology of Nonproliferative Disorders / 552Pathology of Proliferative Disorders Without Atypia / 553Pathology of Atypical Proliferative Diseases / 553Treatment of Selected Benign Breast Disorders and Diseases / 554Risk Factors for Breast Cancer555Hormonal and Nonhormonal Risk Factors / 555Risk Assessment Models / 555Risk Management / 556BRCA Mutations / 558Epidemiology and Natural History of Breast Cancer561Epidemiology / 561Natural History / 562Histopathology of Breast Cancer563Carcinoma In Situ / 563Invasive Breast Carcinoma / 565Diagnosis of Breast Cancer567Examination / 567Imaging Techniques / 567Breast Biopsy / 574Breast Cancer Staging and Biomarkers575Breast Cancer Staging / 575Biomarkers / 575Overview of Breast Cancer Therapy580In Situ Breast Cancer (Stage 0) / 580Early Invasive Breast Cancer (Stage I, IIA, or IIB) / 582Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB) / 585Internal Mammary Lymph Nodes / 587Distant Metastases (Stage IV) / 587Local-Regional Recurrence / 587Breast Cancer Prognosis / 587Surgical Techniques in Breast Cancer Therapy588Excisional Biopsy With Needle Localization / 588Sentinel Lymph Node Dissection / 590Breast Conservation / 591Mastectomy and Axillary Dissection / 591Modified Radical Mastectomy / 592Reconstruction of the Breast and Chest Wall / 593Nonsurgical Breast Cancer Therapies594Radiation Therapy / 594Chemotherapy Adjuvant / 594Antiestrogen Therapy / 597Ablative Endocrine Therapy / 598Anti-HER2 Therapy / 598Special Clinical Situations599Nipple Discharge / 599Axillary Lymph Node Metastases in the Setting of an Unknown Primary Cancer / 600Breast Cancer During Pregnancy / 600Male Breast Cancer / 600Phyllodes Tumors / 600Inflammatory Breast Carcinoma / 601Rare Breast Cancers / 602Brunicardi_Ch17_p0541-p0612.indd 54101/03/19 5:04 PM 542evidence and started an idea which persisted into the 20th century among some lay people. The majority of respected sur-geons considered operative intervention to be a futile and ill-advised endeavor. The Renaissance and the wars of the 16th and 17th centuries brought developments in surgery, particularly in anatomical understanding. However, there were no new theories espoused in relation to cancer. Beginning with Morgagni, surgi-cal resections were more frequently undertaken, including some early attempts at mastectomy and axillary dissection. The 17th century saw the start of the Age of Enlightenment, which lasted until the 19th century. In terms of medicine, this resulted in the abandonment of Galen’s humoral pathology, which was repudi-ated by Le Dran, and the subsequent rise in cellular pathology as espoused by Virchow. Le Dran stated that breast cancer was a local disease that spread by way of lymph vessels to axillary lymph nodes. When operating on a woman with breast cancer, he routinely removed any enlarged axillary lymph nodes.4In the 19th century, Moore, of the Middlesex Hospital, London, emphasized complete resection of the breast for cancer and stated that palpable axillary lymph nodes also should be removed.5 In a presentation before the British Medical Asso-ciation in 1877, Banks supported Moore’s concepts and advo-cated the resection of axillary lymph nodes even when palpable lymphadenopathy was not evident, recognizing that occult involvement of axillary lymph nodes was frequently present. In 1894, Halsted and Meyer reported their operations for treatment of breast cancer.6 By demonstrating superior local-regional con-trol rates after radical resection, these surgeons established radi-cal mastectomy as state-of-the-art treatment for that era. Halsted and Meyer advocated complete dissection of axillary lymph node levels I to III. Both routinely resected the long thoracic nerve and the thoracodorsal neurovascular bundle with the axil-lary contents. In 1943, Haagensen and Stout described the grave signs of breast cancer, which included: (a) edema of the skin of the breast, (b) skin ulceration, (c) chest wall fixation, (d) an axillary lymph node >2.5 cm in diameter, and (e) fixed axillary lymph nodes. Women with two or more signs had a 42% local recurrence rate and only a 2% 5-year disease-free survival rate.7 Based on these findings, they declared that women with grave signs were beyond cure by radical surgery. In 1948, Patey and Dyson of the Middlesex Hospital, London, advocated a modi-fied radical mastectomy for the management of advanced oper-able breast cancer, explaining, “Until an effective general agent for treatment of carcinoma of the breast is developed, a high proportion of these cases are doomed to die.”8 Their technique included removal of the breast and axillary lymph nodes with preservation of the pectoralis major muscle. They showed that removal of the pectoralis minor muscle allowed access to and clearance of axillary lymph node levels I to III.During the 1970s, there was a transition from the Halsted radical mastectomy to the modified radical mastectomy as the surgical procedure most frequently used by American surgeons to treat breast cancer. This transition acknowledged that: (a) fewer patients were presenting with advanced local disease with or without the grave signs described by Haagensen, (b) extirpation of the pectoralis major muscle was not essential for local-regional control in stages I and II breast cancer, and (c) neither the modified radical mastectomy nor the Halsted radi-cal mastectomy consistently achieved local-regional control of stage III breast cancer. Radiation therapy was incorporated into the management of advanced breast cancer and demonstrated improvements in local-regional control. The National Surgical Key Points1 The breast receives its principal blood supply from per-forating branches of the internal mammary artery, lateral branches of the posterior intercostal arteries, and branches from the axillary artery, including the highest thoracic, lat-eral thoracic, and pectoral branches of the thoracoacromial artery.2 The axillary lymph nodes usually receive >75% of the lymph drainage from the breast, and the rest flows through the lymph vessels that accompany the perforating branches of the internal mammary artery and enters the parasternal (internal mammary) group of lymph nodes.3 Breast development and function are initiated by a variety of hormonal stimuli, with the major trophic effects being modulated by estrogen, progesterone, and prolactin.4 Benign breast disorders and diseases are related to the nor-mal processes of reproductive life and to involution, and there is a spectrum of breast conditions that ranges from normal to disorder to disease (aberrations of normal devel-opment and involution classification).5 To calculate breast cancer risk using the Gail model, a woman’s risk factors are translated into an overall risk score by multiplying her relative risks from several cat-egories. This risk score is then compared with an adjusted population risk of breast cancer to determine the wom-an’s individual risk. This model is not appropriate for use in women with a known BRCA1 or BRCA2 mutation or women with lobular or ductal carcinoma in situ.6 Routine use of screening mammography in women ≥50 years of age reduces mortality from breast cancer by 25%. Magnetic resonance imaging (MRI) screening is recom-mended in women with BRCA mutations and may be con-sidered in women with a greater than 20% to 25% lifetime risk of developing breast cancer.7 Core-needle biopsy is the preferred method for diagnosis of palpable or nonpalpable breast abnormalities.8 When a diagnosis of breast cancer is made, the surgeon should determine the clinical stage, histologic characteris-tics, and appropriate biomarker levels before initiating local therapy.9 Sentinel node dissection is the preferred method for stag-ing of the regional lymph nodes in women with clinically node-negative invasive breast cancer. Axillary dissection may be avoided in women with one to two positive senti-nel nodes who are treated with breast conserving surgery, whole breast radiation, and systemic therapy.10 Local-regional and systemic therapy decisions for an indi-vidual patient with breast cancer are best made using a multidisciplinary treatment approach. The sequencing of therapies is dependent on patient and tumor related factors including breast cancer subtype.Brunicardi_Ch17_p0541-p0612.indd 54201/03/19 5:04 PM 543THE BREASTCHAPTER 17Adjuvant Breast and Bowel Project (NSABP) conducted a ran-domized trial in the early 1970s to determine the impact of local and regional treatments on survival in operable breast cancer. In the B-04 trial, 1665 women were enrolled and stratified by clinical assessment of the axillary lymph nodes. The clinically node-negative women were randomized into three treatment groups: (a) Halsted radical mastectomy; (b) total mastectomy plus radiation therapy; and (c) total mastectomy alone. Clini-cally node-positive women were randomized to Halsted radical mastectomy or total mastectomy plus radiation therapy. This trial accrued patients between 1971 and 1974, an era that pre-dated widespread availability of effective systemic therapy for breast cancer and therefore reflect survival associated with local-regional therapy alone. There were no differences in survival between the three groups of node-negative women or between the two groups of node-positive women. These overall survival equivalence patterns persisted at 25 years of follow-up.9The next major advance in the surgical management of breast cancer was the development of breast conserving surgery. Breast conserving surgery and radium treatment was first reported by Geoffrey Keynes of St Bartholomew’s Hospital, London in the British Medical Journal in 1937.10 Several decades later, the NSABP launched the B-06 trial, a phase 3 study that randomized 1851 patients to total mastec-tomy, lumpectomy alone, or lumpectomy with breast irradia-tion. The results showed no difference in disease-free, distant disease-free, and overall survival among the three groups; how-ever, the omission of radiation therapy resulted in significantly higher rates of ipsilateral breast tumor recurrence in those who received lumpectomy alone.11 The B-06 trial excluded patients who had palpable axillary lymph nodes, and those patients randomized to breast conserving surgery had frozen sections performed. If on frozen section the margins were involved, the surgeon proceeded to perform a mastectomy, but the patient was included in the analysis as having had a breast conserv-ing operation. Furthermore, in B-06, local in-breast recurrences were regarded as “nonevents” in terms of disease-free survival. Both the NSABP B-04 and B-06 trials were taken to refute the Halstedian concept that cancer spread throughout a region of the breast to lymphatics and then on to distant sites. Bernard Fisher proposed the “alternative hypothesis” that breast cancer was a systemic disease at diagnosis and that tumor cells had access to both the blood and lymphatic systems and that regional lymph nodes were a marker of systemic disease and not a barrier to the dissemination of cancer cells. He proposed that host factors were important in the development of metastasis and that varia-tions in the local-regional approach to breast cancer treatment were not likely to substantially impact survival. This idea was dominant for a number of years but has been challenged by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview analysis, which reported that “the avoidance of recur-rence in a conserved breast . . . avoids about one breast cancer death over the next 15 years for every four such recurrences avoided,”12 indicating that not all breast cancer is a systemic disease at presentation.During the 1970s, clinical trials were initiated to determine the value of systemic therapy in the postoperative setting as an adjuvant to surgery. The EBCTCG was established in 1985 to coordinate the meta-analysis of data from randomized clinical trials in order to examine the impact of adjuvant treatments for breast cancer on recurrence and mortality. The EBCTCG overview has demonstrated that anthracycline containing regimens are superior to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and more recently, that the addition of a taxane to an anthracycline-based regimen reduces breast cancer mortality by one-third.11 The overview has also demonstrated that tamoxifen is of benefit only in patients with estrogen recep-tor (ER) positive breast cancer and that tamoxifen may decrease mortality from breast cancer by as much as 30%.13 Importantly, the EBCTCG data have shown that proportional reduction in risk was not significantly affected by standard clinical and pathologic factors such as tumor size, ER status, and nodal status.14 This underscores the importance of stratification of risk in determining adjuvant therapy decisions in order to minimize the toxicities of therapies in those unlikely to benefit, yet real-ize the substantial benefits gained in local-regional control and survival in those at higher risk.Many early randomized clinical trials considered all patients similarly in terms of treatment viewing breast cancer as more of a homogeneous disease. Breast cancer has traditionally been defined by pathologic determinants using conventional light microscopy and basic histologic techniques. In the 1980s, immunohistochemistry allowed assessment of the expression of individual tumor markers (most commonly proteins) while DNA was initially assessed in terms of its ploidy status. Sub-sequently, breast cancer specimens have been interrogated at the level of the DNA by labeling genes of interest and allow-ing fluorescent dyes to quantify the abundance of a particular gene and comparing a large number of genes simultaneously in a single breast cancer specimen. Gene expression arrays have shown that breast cancers cluster according to their intrinsic gene expression patterns into at least five intrinsic subtypes and these intrinsic subtypes correlate with breast cancer outcomes.15 Breast cancers are now classified by molecular subtypes and these are being used for risk stratification and decision making in terms of local-regional and systemic therapies.Currently, 50% of American women will consult a sur-geon regarding breast disease, 25% will undergo breast biopsy for diagnosis of an abnormality, and 12% will develop some variant of breast cancer. Considerable progress has been made in the integration of surgery, radiation therapy, and systemic therapy to control local-regional disease, enhance survival, and improve the quality of life of breast cancer survivors. Surgeons are traditionally the first physician consulted for breast care, and it is critical for them to be well trained in all aspects of the breast from embryologic development, to growth and development, to benign and malignant disease processes. This will allow the greatest opportunity to achieve optimal outcomes for patients and their families.EMBRYOLOGY AND FUNCTIONAL ANATOMY OF THE BREASTEmbryologyAt the fifth or sixth week of fetal development, two ventral bands of thickened ectoderm (mammary ridges, milk lines) are evident in the embryo.16 In most mammals, paired breasts develop along these ridges, which extend from the base of the forelimb (future axilla) to the region of the hind limb (inguinal area). These ridges are not prominent in the human embryo and disappear after a short time, except for small portions that may persist in the pectoral region. Accessory breasts (polymastia) or accessory nipples (polythelia) may Brunicardi_Ch17_p0541-p0612.indd 54301/03/19 5:04 PM 544SPECIFIC CONSIDERATIONSPART IIFigure 17-1. The mammary milk line. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Figure 17-2. Anatomy of the breast. Tangential and cross-sectional (sagittal) views of the breast and associated chest wall. (Reproduced with permission from Bland KI, Copeland EMI: The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)occur along the milk line (Fig. 17-1) when normal regression fails. Each breast develops when an ingrowth of ectoderm forms a primary tissue bud in the mesenchyme. The primary bud, in turn, initiates the development of 15 to 20 secondary buds. Epithelial cords develop from the secondary buds and extend into the surrounding mesenchyme. Major (lactiferous) ducts develop, which open into a shallow mammary pit. Dur-ing infancy, a proliferation of mesenchyme transforms the mammary pit into a nipple. If there is failure of a pit to elevate above skin level, an inverted nipple results. This congenital malformation occurs in 4% of infants. At birth, the breasts are identical in males and females, demonstrating only the pres-ence of major ducts. Enlargement of the breast may be evi-dent, and a secretion, historically referred to as witch’s milk, may be produced. These transitory events occur in response to maternal hormones that cross the placenta.The breast remains undeveloped in the female until puberty, when it enlarges in response to ovarian estrogen and progesterone, which initiate proliferation of the epithelial and connective tissue elements. However, the breasts remain incompletely developed until pregnancy occurs. Absence of the breast (amastia) is rare and results from an arrest in mam-mary ridge development that occurs during the sixth fetal week. Poland’s syndrome consists of hypoplasia or complete absence of the breast, costal cartilage and rib defects, hypoplasia of the subcutaneous tissues of the chest wall, and brachysyndactyly. Breast hypoplasia also may be iatrogenically induced before puberty by trauma, infection, or radiation therapy. Symmastia is a rare anomaly recognized as webbing between the breasts across the midline. Accessory nipples (polythelia) occur in <1% of infants and may be associated with abnormalities of the urinary and cardiovascular systems. Supernumerary breasts may occur in any configuration along the mammary milk line but most frequently occur between the normal nipple location and the symphysis pubis. Turner’s syndrome (ovarian agenesis and dysgenesis) and Fleischer’s syndrome (displacement of the nipples and bilateral renal hypoplasia) may have polymastia as a component. Accessory axillary breast tissue is uncommon and usually is bilateral.Functional AnatomyThe breast is composed of 15 to 20 lobes (Fig. 17-2), which are each composed of several lobules.17 Fibrous bands of con-nective tissue travel through the breast (Cooper’s suspensory ligaments), insert perpendicularly into the dermis, and provide structural support. The mature female breast extends from the level of the second or third rib to the inframammary fold at the sixth or seventh rib. It extends transversely from the lateral border of the sternum to the anterior axillary line. The deep or posterior surface of the breast rests on the fascia of the pecto-ralis major, serratus anterior, and external oblique abdominal muscles, and the upper extent of the rectus sheath. The retro-mammary bursa may be identified on the posterior aspect of the breast between the investing fascia of the breast and the fascia of the pectoralis major muscles. The axillary tail of Spence extends laterally across the anterior axillary fold. The upper outer quad-rant of the breast contains a greater volume of tissue than do the other quadrants. The breast has a protuberant conical form. The base of the cone is roughly circular, measuring 10 to 12 cm in diameter. Considerable variations in the size, contour, and den-sity of the breast are evident among individuals. The nulliparous breast has a hemispheric configuration with distinct flattening above the nipple. With the hormonal stimulation that accom-panies pregnancy and lactation, the breast becomes larger and increases in volume and density, whereas with senescence, it assumes a flattened, flaccid, and more pendulous configuration with decreased volume.Nipple-Areola Complex. The epidermis of the nipple-are-ola complex is pigmented and is variably corrugated. During puberty, the pigment becomes darker and the nipple assumes an elevated configuration. Throughout pregnancy, the areola Brunicardi_Ch17_p0541-p0612.indd 54401/03/19 5:04 PM 545THE BREASTCHAPTER 17Figure 17-3. Inactive human breast (100x). The epithelium, which is primarily ductal, is embedded in loose connective tissue. Dense connective tissue surrounds the terminal duct lobular units (TDLU). (Used with permission from Dr. Sindhu Menon, Consultant Histo-pathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)Figure 17-4. Active human breast: pregnancy and lactation (160x). The alveolar epithelium becomes conspicuous during the early pro-liferative period. The alveolus is surrounded by cellular connective tissue. (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)enlarges and pigmentation is further enhanced. The areola con-tains sebaceous glands, sweat glands, and accessory glands, which produce small elevations on the surface of the areola (Montgomery’s tubercles). Smooth muscle bundle fibers, which lie circumferentially in the dense connective tissue and longi-tudinally along the major ducts, extend upward into the nipple, where they are responsible for the nipple erection that occurs with various sensory stimuli. The dermal papilla at the tip of the nipple contains numerous sensory nerve endings and Meiss-ner’s corpuscles. This rich sensory innervation is of functional importance because the sucking of the infant initiates a chain of neurohumoral events that results in milk letdown.Inactive and Active Breast. Each lobe of the breast termi-nates in a major (lactiferous) duct (2–4 mm in diameter), which opens through a constricted orifice (0.4–0.7 mm in diameter) into the ampulla of the nipple (see Fig. 17-2). Immediately below the nipple-areola complex, each major duct has a dilated portion (lactiferous sinus), which is lined with stratified squa-mous epithelium. Major ducts are lined with two layers of cuboidal cells, whereas minor ducts are lined with a single layer of columnar or cuboidal cells. Myoepithelial cells of ectoder-mal origin reside between the epithelial cells in the basal lamina and contain myofibrils. In the inactive breast, the epithelium is sparse and consists primarily of ductal epithelium (Fig. 17-3). In the early phase of the menstrual cycle, minor ducts are cord-like with small lumina. With estrogen stimulation at the time of ovulation, alveolar epithelium increases in height, duct lumina become more prominent, and some secretions accumulate. When the hormonal stimulation decreases, the alveolar epithe-lium regresses.With pregnancy, the breast undergoes proliferative and developmental maturation. As the breast enlarges in response to hormonal stimulation, lymphocytes, plasma cells, and eosin-ophils accumulate within the connective tissues. The minor ducts branch and alveoli develop. Development of the alveoli is asymmetric, and variations in the degree of development may occur within a single lobule (Fig. 17-4). With parturition, enlargement of the breasts occurs via hypertrophy of alveolar epithelium and accumulation of secretory products in the lumina of the minor ducts. Alveolar epithelium contains abundant endo-plasmic reticulum, large mitochondria, Golgi complexes, and dense lysosomes. Two distinct substances are produced by the alveolar epithelium: (a) the protein component of milk, which is synthesized in the endoplasmic reticulum (merocrine secretion); and (b) the lipid component of milk (apocrine secretion), which forms as free lipid droplets in the cytoplasm. Milk released in the first few days after parturition is called colostrum and has low lipid content but contains considerable quantities of anti-bodies. The lymphocytes and plasma cells that accumulate within the connective tissues of the breast are the source of the antibody component. With subsequent reduction in the number of these cells, the production of colostrum decreases and lipid-rich milk is released.Blood Supply, Innervation, and Lymphatics. The breast receives its principal blood supply from: (a) perforating branches of the internal mammary artery; (b) lateral branches of the poste-rior intercostal arteries; and (c) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery (Fig. 17-5). The second, third, and fourth anterior intercostal perforators and branches of the internal mammary artery arborize in the breast as the medial mammary arteries. The lateral thoracic artery gives off branches to the serratus anterior, pectoralis major and pectoralis minor, and subscapularis muscles. It also gives rise to lateral mammary branches. The veins of the breast and chest wall follow the course of the arteries, with venous drainage being toward the axilla. The three principal groups of veins are: (a) per-forating branches of the internal thoracic vein, (b) perforating branches of the posterior intercostal veins, and (c) tributaries of the axillary vein. Batson’s vertebral venous plexus, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system. Lymph vessels generally parallel the course of blood vessels.1Brunicardi_Ch17_p0541-p0612.indd 54501/03/19 5:04 PM 546SPECIFIC CONSIDERATIONSPART IIFigure 17-5. Arterial supply to the breast, axilla, and chest wall. (Reproduced with permission from Bland KI, Copeland EMI: The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)Figure 17-6. Lymphatic pathways of the breast. Arrows indicate the direction of lymph flow. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Figure 17-7. Axillary lymph node groups. Level I includes lymph nodes located lateral to the pectoralis minor muscle; level II includes lymph nodes located deep to the pectoralis minor; and level III includes lymph nodes located medial to the pectoralis minor. The axillary vein with its major tributaries and the supracla-vicular lymph node group are also illustrated. (Visual Art: © 2013.The University of Texas MD Anderson Cancer Center.)Lateral cutaneous branches of the third through sixth inter-costal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. These branches exit the intercostal spaces between slips of the serratus anterior muscle. Cutaneous branches that arise from the cervical plexus, specifically the anterior branches of the supraclavicular nerve, supply a limited area of skin over the upper portion of the breast. The intercostobrachial nerve is the lateral cutane-ous branch of the second intercostal nerve and may be visual-ized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm.The boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the posi-tion of the axillary lymph nodes. The six axillary lymph node groups recognized by surgeons (Figs. 17-6 and 17-7) are: (a) the axillary vein group (lateral), which consists of four to six lymph nodes that lie medial or posterior to the vein and receive most of the lymph drainage from the upper extremity; (b) the external mammary group (anterior or pectoral group), which consists of five to six lymph nodes that lie along the lower border of the pectoralis minor muscle contiguous with the lateral thoracic vessels and receive most of the lymph drainage from the lat-eral aspect of the breast; (c) the scapular group (posterior or subscapular), which consists of five to seven lymph nodes that lie along the posterior wall of the axilla at the lateral border of the scapula contiguous with the subscapular vessels and receive lymph drainage principally from the lower posterior neck, the posterior trunk, and the posterior shoulder; (d) the central group, which consists of three or four sets of lymph nodes that are embedded in the fat of the axilla lying immediately posterior to the pectoralis minor muscle and receive lymph drainage both from the axillary vein, external mammary, and scapular groups of lymph nodes, and directly from the breast; (e) the subcla-vicular group (apical), which consists of six to twelve sets of lymph nodes that lie posterior and superior to the upper bor-der of the pectoralis minor muscle and receive lymph drainage from all of the other groups of axillary lymph nodes; and (f) the interpectoral group (Rotter’s lymph nodes), which consists of one to four lymph nodes that are interposed between the pec-toralis major and pectoralis minor muscles and receive lymph drainage directly from the breast. The lymph fluid that passes Brunicardi_Ch17_p0541-p0612.indd 54601/03/19 5:04 PM 547THE BREASTCHAPTER 17through the interpectoral group of lymph nodes passes directly into the central and subclavicular groups.As indicated in Fig. 17-7, the lymph node groups are assigned levels according to their anatomic relationship to the pectoralis minor muscle. Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral groups. Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which consist of the subclavicular group. The plexus of lymph vessels in the breast arises in the interlobular connective tissue and in the walls of the lactiferous ducts and communicates with the subareolar plexus of lymph vessels. Efferent lymph vessels from the breast pass around the lateral edge of the pectoralis major muscle and pierce the clavipectoral fascia, ending in the external mammary (anterior, pectoral) group of lymph nodes. Some lymph vessels may travel directly to the subscapular (pos-terior, scapular) group of lymph nodes. From the upper part of the breast, a few lymph vessels pass directly to the subclavicular (api-cal) group of lymph nodes. The axillary lymph nodes usually receive >75% of the lymph drainage from the breast. The rest is derived primarily from the medial aspect of the breast, flows through the lymph vessels that accompany the per-forating branches of the internal mammary artery, and enters the parasternal (internal mammary) group of lymph nodes.PHYSIOLOGY OF THE BREASTBreast Development and FunctionBreast development and function are initiated by a variety of hormonal stimuli, including estrogen, progesterone, prolactin, oxytocin, thyroid hormone, cortisol, and growth hormone.17,18 Estrogen, progesterone, and prolactin especially have profound trophic effects that are essential to normal breast develop-ment and function. Estrogen initiates ductal development, whereas progesterone is responsible for differentiation of epithe-lium and for lobular development. Prolactin is the primary hor-monal stimulus for lactogenesis in late pregnancy and the postpartum period. It upregulates hormone receptors and stimu-lates epithelial development. Fig. 17-8 depicts the secretion of neurotrophic hormones from the hypothalamus, which is respon-sible for regulation of the secretion of the hormones that affect the breast tissues. The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate the release of estrogen and progesterone from the ovaries. In turn, the release of LH and FSH from the basophilic cells of the anterior pituitary is regulated by the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Positive and negative feedback effects of circulating estrogen and progesterone regulate the secretion of LH, FSH, and GnRH. These hormones are respon-sible for the development, function, and maintenance of breast tissues (Fig. 17-9A). In the female neonate, circulating estrogen and progesterone levels decrease after birth and remain low throughout childhood because of the sensitivity of 23GRFLH-RHDopamineOxy/ADHTRHCRF-Figure 17-8. Overview of the neuroendocrine con-trol of breast development and function. ADH = antidiuretic hormone; CRF = corticotropin-releasing factor; GRF = growth hormone releasing factor; LH-RH = luteinizing hormone–releasing hormone; Oxy = oxytocin; TRH = thyrotropin-releasing hor-mone. (Reproduced with permission from Bland KI, Copeland EMI: The Breast: Comprehensive Man-agement of Benign and Malignant Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)Brunicardi_Ch17_p0541-p0612.indd 54701/03/19 5:04 PM 548SPECIFIC CONSIDERATIONSPART IIABCDFigure 17-9. The breast at different physi-ologic stages. The central column contains three-dimensional depictions of microscopic structures. A. Adolescence. B. Pregnancy. C. Lactation. D. Senescence.the hypothalamic-pituitary axis to negative feedback from these hormones. With the onset of puberty, there is a decrease in the sensitivity of the hypothalamic-pituitary axis to negative feed-back and an increase in its sensitivity to positive feedback from estrogen. These physiologic events initiate an increase in GnRH, FSH, and LH secretion and ultimately an increase in estrogen and progesterone secretion by the ovaries, leading to establish-ment of the menstrual cycle. At the beginning of the menstrual cycle, there is an increase in the size and density of the breasts, which is followed by engorgement of the breast tissues and epi-thelial proliferation. With the onset of menstruation, the breast engorgement subsides and epithelial proliferation decreases.Pregnancy, Lactation, and SenescenceA dramatic increase in circulating ovarian and placental estro-gens and progestins is evident during pregnancy, which initiates striking alterations in the form and substance of the breast (see Fig. 17-9B).17-19 The breast enlarges as the ductal and lobular epithelium proliferates, the areolar skin darkens, and the acces-sory areolar glands (Montgomery’s glands) become prominent. In the first and second trimesters, the minor ducts branch and develop. During the third trimester, fat droplets accumulate in the alveolar epithelium, and colostrum fills the alveolar and duc-tal spaces. In late pregnancy, prolactin stimulates the synthesis of milk fats and proteins.After delivery of the placenta, circulating progesterone and estrogen levels decrease, permitting full expression of the lactogenic action of prolactin. Milk production and release are controlled by neural reflex arcs that originate in nerve endings of the nipple-areola complex. Maintenance of lactation requires regular stimulation of these neural reflexes, which results in prolactin secretion and milk letdown. Oxytocin release results from the auditory, visual, and olfactory stimuli associated with nursing. Oxytocin initiates contraction of the myoepithelial cells, which results in compression of alveoli and expulsion of milk into the lactiferous sinuses. After weaning of the infant, prolactin and oxytocin release decreases. Dormant milk causes increased pressure within the ducts and alveoli, which results in atrophy of the epithelium (Fig. 17-9C). With menopause, there is a decrease in the secretion of estrogen and progesterone by Brunicardi_Ch17_p0541-p0612.indd 54801/03/19 5:04 PM 549THE BREASTCHAPTER 17Table 17-1Pathophysiologic mechanisms of gynecomastia I. Estrogen excess states A. Gonadal origin 1. True hermaphroditism 2. Gonadal stromal (nongerminal) neoplasms of the testis a. Leydig cell (interstitial) b. Sertoli cell c. Granulosa-theca cell 3. Germ cell tumors a. Choriocarcinoma b. Seminoma, teratoma c. Embryonal carcinoma B. Nontesticular tumors 1. Adrenal cortical neoplasms 2. Lung carcinoma 3. Hepatocellular carcinoma C. Endocrine disorders D. Diseases of the liver—nonalcoholic and alcoholic cirrhosis E. Nutrition alteration states II. Androgen deficiency states A. Senescence B. Hypoandrogenic states (hypogonadism) 1. Primary testicular failure a. Klinefelter’s syndrome (XXY) b. Reifenstein’s syndrome c. Rosewater-Gwinup-Hamwi familial gynecomastia d. Kallmann syndrome e. Kennedy’s disease with associated gynecomastia f. Eunuchoidal state (congenital anorchia) g. Hereditary defects of androgen biosynthesis h. Adrenocorticotropic hormone deficiency 2. Secondary testicular failure a. Trauma b. Orchitis c. Cryptorchidism d. Irradiation C. Renal failure III. Pharmacologic causes IV. Systemic diseases with idiopathic mechanismsthe ovaries and involution of the ducts and alveoli of the breast. The surrounding fibrous connective tissue increases in density, and breast tissues are replaced by adipose tissues (Fig. 17-9D).GynecomastiaGynecomastia refers to an enlarged breast in the male.20 Physi-ologic gynecomastia usually occurs during three phases of life: the neonatal period, adolescence, and senescence. Common to each of these phases is an excess of circulating estrogens in relation to circulating testosterone. Neonatal gynecomastia is caused by the action of placental estrogens on neonatal breast tissues, whereas in adolescence, there is an excess of estradiol relative to testosterone, and with senescence, the circulating testosterone level falls, which results in relative hyperestrin-ism. In gynecomastia, the ductal structures of the male breast enlarge, elongate, and branch with a concomitant increase in epithelium. During puberty, the condition often is unilateral and typically occurs between ages 12 and 15 years. In contrast, senescent gynecomastia is usually bilateral. In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be made. Mammography and ultrasonography are used to differentiate breast tissues. Dominant masses or areas of firmness, irregular-ity, and asymmetry suggest the possibility of a breast cancer, particularly in the older male. Gynecomastia generally does not predispose the male breast to cancer. However, the hypoandro-genic state of Klinefelter’s syndrome (XXY), in which gyneco-mastia is usually evident, is associated with an increased risk of breast cancer. Gynecomastia is graded based on the degree of breast enlargement, the position of the nipple with reference to the inframammary fold, and the degree of breast ptosis and skin redundancy: Grade I—mild breast enlargement without skin redundancy; Grade IIa—moderate breast enlargement without skin redundancy; Grade IIb—moderate breast enlargement with skin redundancy; and Grade III—marked breast enlargement with skin redundancy and ptosis.Table 17-1 identifies the pathophysiologic mechanisms that may initiate gynecomastia: estrogen excess states; andro-gen deficiency states; pharmacologic causes; and idiopathic causes. Estrogen excess results from an increase in the secretion of estradiol by the testicles or by nontesticular tumors, nutri-tional alterations such as protein and fat deprivation, endocrine disorders (hyperthyroidism, hypothyroidism), and hepatic dis-ease (nonalcoholic and alcoholic cirrhosis). Refeeding gyne-comastia is related to the resumption of pituitary gonadotropin secretion after pituitary shutdown. Androgen deficiency may initiate gynecomastia. Concurrently occurring with decreased circulating testosterone levels is an elevated level of circulating testosterone-binding globulin, which results in a reduction of free testosterone. This senescent gynecomastia usually occurs in men age 50 to 70 years. Hypoandrogenic states can be from primary testicular failure or secondary testicular failure. Kline-felter’s syndrome (XXY) is an example of primary testicular failure that is manifested by gynecomastia, hypergonadotropic hypogonadism, and azoospermia. Secondary testicular failure may result from trauma, orchitis, and cryptorchidism. Renal failure, regardless of cause, also may initiate gynecomastia.Pharmacologic causes of gynecomastia include drugs with estrogenic activity (digitalis, estrogens, anabolic steroids, marijuana) or drugs that enhance estrogen synthesis (human chorionic gonadotropin). Drugs that inhibit the action or syn-thesis of testosterone (cimetidine, ketoconazole, phenytoin, spironolactone, antineoplastic agents, diazepam) also have been implicated. Drugs such as reserpine, theophylline, verapamil, tricyclic antidepressants, and furosemide induce gynecomastia through idiopathic mechanisms.When gynecomastia is caused by androgen deficiency, then testosterone administration may cause regression. When it is caused by medications, then these are discontinued if possi-ble. When endocrine defects are responsible, then these receive specific therapy. As soon as gynecomastia is progressive and does not respond to other treatments, surgical therapy is con-sidered. Techniques include local excision, liposuction or sub-cutaneous mastectomy. Attempts to reverse gynecomastia with danazol have been successful, but the androgenic side effects of the drug are considerable.Brunicardi_Ch17_p0541-p0612.indd 54901/03/19 5:04 PM 550SPECIFIC CONSIDERATIONSPART IIINFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREASTInfections in the postpartum period remain proportionately the most common time for breast infections to occur. Infections of the breast unrelated to lactation are proportionately less com-mon, however, are still a relatively common presentation to breast specialists. The latter are classified as intrinsic (second-ary to abnormalities in the breast) or extrinsic (secondary to an infection in an adjacent structure, e.g., skin, thoracic cavity) the most common being probably periductal mastitis and infected sebaceous cysts, respectively.Bacterial InfectionStaphylococcus aureus and Streptococcus species are the organisms most frequently recovered from nipple discharge from an infected breast.17 Typically breast abscesses are seen in staphylococcal infections and present with point tenderness, erythema, and hyperthermia. When these abscesses are related to lactation they usually occur within the first few weeks of breastfeeding. If there is progression of a staphylococcal infec-tion, this may result in subcutaneous, subareolar, interlobular (periductal), and retromammary abscesses (unicentric or multi-centric). Previously almost all breast abscesses were treated by operative incision and drainage, but now the initial approach is antibiotics and repeated aspiration of the abscess, usually ultra-sound-guided aspiration.21 Operative drainage is now reserved for those cases that do not resolve with repeated aspiration and antibiotic therapy or cases in which there is some other indica-tion for incision and drainage (e.g., thinning or necrosis of the overlying skin). Preoperative ultrasonography is effective in delineating the required extent of the drainage procedure. While staphylococcal infections tend to be more localized and may be situated deep in the breast tissues, streptococcal infections usually present with diffuse superficial involvement. They are treated with local wound care, including application of warm compresses, and the administration of IV antibiotics (penicillins or cephalosporins). Breast infections may be chronic, possibly with recurrent abscess formation. In this situation, cultures are performed to identify acid-fast bacilli, anaerobic and aerobic bacteria, and fungi. Uncommon organisms may be encountered, and long-term antibiotic therapy may be required.Biopsy of the abscess cavity wall should be considered at the time of incision and drainage to rule out underlying breast cancer in patients where antibiotics and drainage have been ineffective.Nowadays hospital-acquired puerperal infections of the breast are much less common, but nursing women who pres-ent with milk stasis or noninfectious inflammation may still develop this problem. Epidemic puerperal mastitis is initiated by highly virulent strains of methicillin-resistant S aureus that are transmitted via the suckling neonate and may result in sub-stantial morbidity and occasional mortality. Purulent fluid may be expressed from the nipple. In this circumstance, breastfeed-ing is stopped, antibiotics are started, and surgical therapy is initiated. Nonepidemic (sporadic) puerperal mastitis refers to involvement of the interlobular connective tissue of the breast by an infectious process. The patient develops nipple fissuring and milk stasis, which initiates a retrograde bacterial infection. Emptying of the breast using breast suction pumps shortens the duration of symptoms and reduces the incidence of recurrences. The addition of antibiotic therapy results in a satisfactory out-come in >95% of cases.Zuska’s disease, also called recurrent periductal mastitis, is a condition of recurrent retroareolar infections and abscesses.22,23 Smoking has been implicated as a risk factor for this condition.24,25 This syndrome is managed symptomatically by antibiotics coupled with incision and drainage as necessary. Attempts to obtain durable long-term control by wide debride-ment of chronically infected tissue and/or terminal duct resec-tion have been reported and can be curative, but they can also be frustrated by postoperative infections.26Mycotic InfectionsFungal infections of the breast are rare and usually involve blas-tomycosis or sporotrichosis.27 Intraoral fungi that are inoculated into the breast tissue by the suckling infant initiate these infec-tions, which present as mammary abscesses in close proxim-ity to the nipple-areola complex. Pus mixed with blood may be expressed from sinus tracts. Antifungal agents can be adminis-tered for the treatment of systemic (noncutaneous) infections. This therapy generally eliminates the necessity of surgical inter-vention, but occasionally drainage of an abscess, or even partial mastectomy, may be necessary to eradicate a persistent fungal infection. Candida albicans affecting the skin of the breast presents as erythematous, scaly lesions of the inframammary or axillary folds. Scrapings from the lesions demonstrate fungal elements (filaments and binding cells). Therapy involves the removal of predisposing factors such as maceration and the topi-cal application of nystatin.Hidradenitis SuppurativaHidradenitis suppurativa of the nipple-areola complex or axilla is a chronic inflammatory condition that originates within the accessory areolar glands of Montgomery or within the axillary sebaceous glands.27 Women with chronic acne are predisposed to developing hidradenitis. When located in and about the nipple-areola complex, this disease may mimic other chronic inflammatory states, Paget’s disease of the nipple, or invasive breast cancer. Involvement of the axillary skin is often multifo-cal and contiguous. Antibiotic therapy with incision and drain-age of fluctuant areas is appropriate treatment. Excision of the involved areas may be required. Large areas of skin loss may necessitate coverage with advancement flaps or split-thickness skin grafts.Mondor’s DiseaseMondor’s disease is a variant of thrombophlebitis that involves the superficial veins of the anterior chest wall and breast.28 In 1939, Mondor described the condition as “string phlebitis,” a thrombosed vein presenting as a tender, cord-like structure.29 Frequently involved veins include the lateral thoracic vein, the thoracoepigastric vein, and, less commonly, the superficial epi-gastric vein. Typically, a woman presents with acute pain in the lateral aspect of the breast or the anterior chest wall. A ten-der, firm cord is found to follow the distribution of one of the major superficial veins. Rarely, the presentation is bilateral, and most women have no evidence of thrombophlebitis in other ana-tomic sites. This benign, self-limited disorder is not indicative of a cancer. When the diagnosis is uncertain, or when a mass is present near the tender cord, biopsy is indicated. Therapy for Mondor’s disease includes the liberal use of anti-inflammatory medications and application of warm compresses along the symptomatic vein. The process usually resolves within 4 to 6 weeks. When symptoms persist or are refractory to therapy, excision of the involved vein segment may be considered.Brunicardi_Ch17_p0541-p0612.indd 55001/03/19 5:04 PM 551THE BREASTCHAPTER 17COMMON BENIGN DISORDERS AND DISEASES OF THE BREASTBenign breast disorders and diseases encompass a wide range of clinical and pathologic entities. Surgeons require an in-depth understanding of benign breast disorders and diseases so that clear explanations may be given to affected women, appropriate treat-ment is instituted, and unnecessary long-term follow up is avoided.Aberrations of Normal Development and InvolutionThe basic principles underlying the aberrations of normal devel-opment and involution (ANDI) classification of benign breast conditions are the following: (a) benign breast disorders and diseases are related to the normal processes of reproductive life and to involution; (b) there is a spectrum of breast conditions that ranges from normal to disorder to disease; and (c) the ANDI classification encompasses all aspects of the breast condition, including pathogenesis and the degree of abnormality.30 The horizontal component of Table 17-2 defines ANDI along a spectrum from normal, to mild abnormality (disorder), to severe abnormality (disease). The vertical component indi-cates the period during which the condition develops.Early Reproductive Years. Fibroadenomas are seen and pres-ent symptomatically predominantly in younger women age 15 to 25 years (Fig. 17-10).31 Fibroadenomas usually grow to 1 or 2 cm in diameter and then are stable but may grow to a larger size. Small fibroadenomas (≤1 cm in size) are considered nor-mal, whereas larger fibroadenomas (≤3 cm) are disorders, and giant fibroadenomas (>3 cm) are disease. Similarly, multiple fibroadenomas (more than five lesions in one breast) are very uncommon and are considered disease. It is noted that with the introduction of mammographic screening, asymptomatic 4Table 17-2ANDI classification of benign breast disorders NORMALDISORDERDISEASEEarly reproductive years (age 15–25 y) Lobular developmentStromal developmentFibroadenomaAdolescent hypertrophyGiant fibroadenomaGigantomastia Nipple eversionNipple inversionSubareolar abscess   Mammary duct fistulaLater reproductive years (age 25–40 y)Cyclical changes of menstruationCyclical mastalgiaIncapacitating mastalgia  Nodularity  Epithelial hyperplasia of pregnancyBloody nipple discharge Involution (age 35–55 y)Lobular involutionMacrocysts—  Sclerosing lesions  Duct involution    DilatationDuct ectasiaPeriductal mastitis  SclerosisNipple retraction— Epithelial turnoverEpithelial hyperplasiaEpithelial hyperplasia with atypiaANDI = aberrations of normal development and involution.Reproduced with permission from Mansel RE, Webster D, Sweetland H: Hughes, Mansel & Webster’s Benign Disorders and Diseases of the Breast, 3rd ed. London: Elsevier/Saunders; 2009.Figure 17-10. Fibroadenoma (40x). These benign tumors are typi-cally well circumscribed and are comprised of both stromal and glandular elements. (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)fibroadenomas are sometimes found in an older screened popu-lation. The precise etiology of adolescent breast hypertrophy is unknown. A spectrum of changes from limited to massive stro-mal hyperplasia (gigantomastia) is seen. Nipple inversion is a disorder of development of the major ducts, which prevents nor-mal protrusion of the nipple. Mammary duct fistulas arise when nipple inversion predisposes to major duct obstruction, leading to recurrent subareolar abscess and mammary duct fistula.Brunicardi_Ch17_p0541-p0612.indd 55101/03/19 5:04 PM 552SPECIFIC CONSIDERATIONSPART IIABFigure 17-11. A. Ductal epithelial hyperplasia. The irregular intra-cellular spaces and variable cell nuclei distinguish this process from carcinoma in situ. B. Lobular hyperplasia. The presence of alveo-lar lumina and incomplete distention distinguish this process from carcinoma in situ. (Used with permission from Dr. R.L. Hackett.)Table 17-3Cancer risk associated with benign breast disorders and in situ carcinoma of the breastABNORMALITYRELATIVE RISKNonproliferative lesions of the breastNo increased riskSclerosing adenosisNo increased riskIntraductal papillomaNo increased riskFlorid hyperplasia1.5 to 2-foldAtypical lobular hyperplasia4-foldAtypical ductal hyperplasia4-foldDuctal involvement by cells of atypical ductal hyperplasia7-foldLobular carcinoma in situ10-foldDuctal carcinoma in situ10-foldData from Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease, N Engl J Med. 1985 Jan 17; 312(3):146-151.Table 17-4Classification of benign breast disordersNonproliferative disorders of the breast Cysts and apocrine metaplasia Duct ectasia Mild ductal epithelial hyperplasia Calcifications Fibroadenoma and related lesionsProliferative breast disorders without atypia Sclerosing adenosis Radial and complex sclerosing lesions Ductal epithelial hyperplasia Intraductal papillomasAtypical proliferative lesions Atypical lobular hyperplasia Atypical ductal hyperplasiaData from Godfrey SE: Is fibrocystic disease of the breast precancerous? Arch Pathol Lab Med. 1986 Nov;110(11):991.include ductal and lobular hyperplasia, both of which display some features of carcinoma in situ. Women with atypical ductal or lobular hyperplasia have a fourfold increase in breast cancer risk (Table 17-3).Pathology of Nonproliferative DisordersOf paramount importance for the optimal management of benign breast disorders and diseases is the histologic differentia-tion of benign, atypical, and malignant changes.32,33 Determin-ing the clinical significance of these changes is a problem that is compounded by inconsistent nomenclature. The classifica-tion system originally developed by Page separates the various types of benign breast disorders and diseases into three clini-cally relevant groups: nonproliferative disorders, proliferative disorders without atypia, and proliferative disorders with atypia (Table 17-4). Nonproliferative disorders of the breast account for 70% of benign breast conditions and carry no increased risk Later Reproductive Years. Cyclical mastalgia and nodular-ity usually are associated with premenstrual enlargement of the breast and are regarded as normal. Cyclical pronounced mastal-gia and severe painful nodularity are viewed differently than are physiologic discomfort and lumpiness. Painful nodularity that persists for >1 week of the menstrual cycle is considered a disor-der. In epithelial hyperplasia of pregnancy, papillary projections sometimes give rise to bilateral bloody nipple discharge.Involution. Involution of lobular epithelium is dependent on the specialized stroma around it. However, an integrated invo-lution of breast stroma and epithelium is not always seen, and disorders of the process are common. When the stroma invo-lutes too quickly, alveoli remain and form microcysts, which are precursors of macrocysts. The macrocysts are common, often subclinical, and do not require specific treatment. Sclerosing adenosis is considered a disorder of both the proliferative and the involutional phases of the breast cycle. Duct ectasia (dilated ducts) and periductal mastitis are other important components of the ANDI classification. Periductal fibrosis is a sequela of periductal mastitis and may result in nipple retraction. About 60% of women ≥70 years of age exhibit some degree of epi-thelial hyperplasia (Fig. 17-11). Atypical proliferative diseases Brunicardi_Ch17_p0541-p0612.indd 55201/03/19 5:04 PM 553THE BREASTCHAPTER 17for the development of breast cancer. This category includes cysts, duct ectasia, periductal mastitis, calcifications, fibroad-enomas, and related disorders.Breast macrocysts are an involutional disorder, have a high frequency of occurrence, and are often multiple. Duct ecta-sia is a clinical syndrome characterized by dilated subareolar ducts that are palpable and often associated with thick nipple discharge. Haagensen regarded duct ectasia as a primary event that led to stagnation of secretions, epithelial ulceration, and leakage of duct secretions (containing chemically irritating fatty acids) into periductal tissue.34 This sequence was thought to pro-duce a local inflammatory process with periductal fibrosis and subsequent nipple retraction. An alternative theory considers periductal mastitis to be the primary process, which leads to weakening of the ducts and secondary dilatation. It is possible that both processes occur and together explain the wide spec-trum of problems seen, which include nipple discharge, nipple retraction, inflammatory masses, and abscesses.Calcium deposits are frequently encountered in the breast. Most are benign and are caused by cellular secretions and debris or by trauma and inflammation. Calcifications that are associated with cancer include microcalcifications, which vary in shape and density and are <0.5 mm in size, and fine, linear calcifications, which may show branching. Fibroadenomas have abundant stroma with histologically normal cellular elements. They show hormonal dependence similar to that of normal breast lobules in that they lactate during pregnancy and invo-lute in the postmenopausal period. Adenomas of the breast are well circumscribed and are composed of benign epithelium with sparse stroma, which is the histologic feature that differentiates them from fibroadenomas. They may be divided into tubular adenomas and lactating adenomas. Tubular adenomas are seen in young nonpregnant women, whereas lactating adenomas are seen during pregnancy or during the postpartum period. Ham-artomas are discrete breast tumors that are usually 2 to 4 cm in diameter, firm, and sharply circumscribed. Adenolipomas con-sist of sharply circumscribed nodules of fatty tissue that contain normal breast lobules and ducts.Fibrocystic Disease. The term fibrocystic disease is nonspe-cific. Too frequently, it is used as a diagnostic term to describe symptoms, to rationalize the need for breast biopsy, and to explain biopsy results. Synonyms include fibrocystic changes, cystic mastopathy, chronic cystic disease, chronic cystic mas-titis, Schimmelbusch’s disease, mazoplasia, Cooper’s disease, Reclus’ disease, and fibroadenomatosis. Fibrocystic disease refers to a spectrum of histopathologic changes that are best diagnosed and treated specifically.Pathology of Proliferative Disorders Without AtypiaProliferative breast disorders without atypia include sclerosing adenosis, radial scars, complex sclerosing lesions, ductal epithe-lial hyperplasia, and intraductal papillomas.32,33 Sclerosing ade-nosis is prevalent during the childbearing and perimenopausal years and has no malignant potential. Histologic changes are both proliferative (ductal proliferation) and involutional (stro-mal fibrosis, epithelial regression). Sclerosing adenosis is char-acterized by distorted breast lobules and usually occurs in the context of multiple microcysts, but occasionally presents as a palpable mass. Benign calcifications are often associated with this disorder. Sclerosing adenosis can be managed by observa-tion as long as the imaging features and pathologic findings are concordant. Central sclerosis and various degrees of epithelial proliferation, apocrine metaplasia, and papilloma formation characterize radial scars and complex sclerosing lesions of the breast. Lesions up to 1 cm in diameter are called radial scars, whereas larger lesions are called complex sclerosing lesions. Radial scars originate at sites of terminal duct branching where the characteristic histologic changes radiate from a central area of fibrosis. All of the histologic features of a radial scar are seen in the larger complex sclerosing lesions, but there is a greater disturbance of structure with papilloma formation, apocrine metaplasia, and occasionally sclerosing adenosis. Distinguish-ing between a radial scar and invasive breast carcinoma can be challenging based on core-needle biopsy sampling. Often the imaging features of a radial scar (which can be quite similar to an invasive cancer) will dictate the need for either a vacuum-assisted biopsy or surgical excision in order to exclude the pos-sibility of carcinoma.Mild ductal hyperplasia is characterized by the presence of three or four cell layers above the basement membrane. Moder-ate ductal hyperplasia is characterized by the presence of five or more cell layers above the basement membrane. Florid duc-tal epithelial hyperplasia occupies at least 70% of a minor duct lumen. It is found in >20% of breast tissue specimens, is either solid or papillary, and is associated with an increased cancer risk (see Table 17-3). Intraductal papillomas arise in the major ducts, usually in premenopausal women. They generally are <0.5 cm in diameter but may be as large as 5 cm. A common presenting symptom is nipple discharge, which may be serous or bloody. Grossly, intraductal papillomas are pinkish tan, fri-able, and usually attached to the wall of the involved duct by a stalk. They rarely undergo malignant transformation, and their presence does not increase a woman’s risk of developing breast cancer (unless accompanied by atypia). However, multiple intraductal papillomas, which occur in younger women and are less frequently associated with nipple discharge, are susceptible to malignant transformation.Pathology of Atypical Proliferative DiseasesThe atypical proliferative diseases have some of the features of carcinoma in situ but either lack a major defining feature of car-cinoma in situ or have the features in less than fully developed form.34 Atypical ductal hyperplasia (ADH) appears similar to low grade ductal carcinoma in situ (DCIS) histologically and is composed of monotonous round, cuboidal, or polygonal cells enclosed by basement membrane with rare mitoses. A lesion will be considered to be ADH if it is up to 2 or 3 mm in size but would be called DCIS if it is larger than 3 mm. The diagnosis can be difficult to establish with core-needle biopsy specimen alone and many cases will require excisional biopsy specimen for classification. Individuals with a diagnosis of ADH are at increased risk for development of breast cancer and should be counseled appropriately regarding risk reduction strategies.In 1978, Haagensen et al described lobular neoplasia, a spectrum of disorders ranging from atypical lobular hyperplasia to lobular carcinoma in situ (LCIS).35 Atypical lobular hyper-plasia (ALH) results in minimal distention of lobular units with cells that are similar to those seen in LCIS. The diagnosis of LCIS is made when small monomorphic cells that distend the terminal ductal lobular unit are noted. In cases of LCIS, the acini are full and distended while the overall lobular architec-ture is maintained (Fig. 17-12). Classic LCIS is not associated with a specific mammographic or palpable abnormality but is Brunicardi_Ch17_p0541-p0612.indd 55301/03/19 5:04 PM 554SPECIFIC CONSIDERATIONSPART IIFigure 17-12. Lobular carcinoma in situ (100x). There are small monomorphic cells that distend the terminal duct lobular unit, with-out necrosis or mitoses. (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consul-tant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)an incidental finding noted on breast biopsy. There is a variant of LCIS that has been termed pleomorphic LCIS. In the case of pleomorphic LCIS, there can be calcifications or other suspi-cious mammographic changes that dictate the need for biopsy. Classic LCIS is not treated with excision as the patient is at risk for developing invasive breast cancer in either breast and therefore the patient is counseled regarding appropriate risk reduction strategies. Pleomorphic LCIS can be difficult to dis-tinguish from high-grade DCIS and there are some proponents who have suggested that patients with pleomorphic LCIS be managed similar to those with DCIS with attention to margins and consideration for radiation therapy in the setting of breast conserving treatment. The use of immunohistochemical stain-ing for E-cadherin can help to discriminate between LCIS and DCIS. In lobular neoplasias, such as ALH and LCIS, there is a lack of E-cadherin expression, whereas the majority of ductal lesions will demonstrate E-cadherin reactivity.Treatment of Selected Benign Breast Disorders and DiseasesCysts. Because needle biopsy of breast masses may produce artifacts that make mammography assessment more difficult, many multidisciplinary teams prefer to image breast masses before performing either fine-needle aspiration or core-needle biopsy.36,37 In practice, however, the first investigation of pal-pable breast masses may be a needle biopsy, which allows for the early diagnosis of cysts. A 21-gauge needle attached to a 10-mL syringe is placed directly into the mass, which is fixed by fingers of the nondominant hand. The volume of a typical cyst is 5 to 10 mL, but it may be 75 mL or more. If the fluid that is aspirated is not bloodstained, then the cyst is aspirated to dryness, the needle is removed, and the fluid is discarded because cytologic examination of such fluid is not cost effec-tive. After aspiration, the breast is carefully palpated to exclude a residual mass. In most cases, however, imaging has been per-formed prior to a needle being introduced into the breast, and indeed the majority of cysts are now aspirated under ultrasound guidance. If a mass was noted on initial ultrasound or there is a residual mass post aspiration, then a tissue specimen is obtained, usually by core biopsy. When cystic fluid is bloodstained, fluid can be sent for cytologic examination. A simple cyst is rarely of concern, but a complex cyst may be the result of an underlying malignancy. A pneumocystogram can be obtained by injecting air into the cyst and then obtaining a repeat mammogram. When this technique is used, the wall of the cyst cavity can be more carefully assessed for any irregularities.Fibroadenomas. Most fibroadenomas are self-limiting and many go undiagnosed, so a more conservative approach is reasonable. Careful ultrasound examination with core-needle biopsy will provide for an accurate diagnosis. Ultrasonogra-phy may reveal specific features that are pathognomonic for fibroadenoma, and in a young woman (e.g., under 25 years) where the risk of breast cancer is already very low a core-needle biopsy may not be necessary. In patients where biopsy is performed, the patient is counseled concerning the ultra-sound and biopsy results, and surgical excision of the fibroad-enoma may be avoided. Cryoablation and ultrasound-guided vacuum-assisted biopsy are approved treatments for fibroad-enomas of the breast, especially lesions <3 cm. Larger lesions are often still best treated by excision. With short-term follow-up, a significant percentage of fibroadenomas will decrease in size and will no longer be palpable.38 However, many will remain palpable, especially those larger than 2 cm.39 There-fore, women should be counseled that the options for treat-ment include surgical removal, cryoablation, vacuum assisted biopsy, or observation.Sclerosing Disorders. The clinical significance of scleros-ing adenosis lies in its imitation of cancer. On physical exami-nation, it may be confused with cancer, by mammography, and at gross pathologic examination. Excisional biopsy and histologic examination are frequently necessary to exclude the diagnosis of cancer. The diagnostic work-up for radial scars and complex sclerosing lesions frequently involves stereo-tactic biopsy. It usually is not possible to differentiate these lesions with certainty from cancer by mammographic features, so a larger tissue biopsy is recommended either by way of vacuum-assisted biopsy or an open surgical excisional biopsy. The mammographic appearance of a radial scar or sclerosing adenosis (mass density with spiculated margins) will usually lead to an assessment that the results of a core-needle biopsy specimen showing benign disease are discordant with the radiographic findings.Periductal Mastitis. Painful and tender masses behind the nipple-areola complex are aspirated with a 21-gauge needle attached to a 10-mL syringe. Any fluid obtained is submitted for culture using a transport medium appropriate for the detec-tion of anaerobic organisms. In the absence of pus, women are started on a combination of antibiotics to cover polymicrobial infections while awaiting the results of culture. Antibiotics are then continued based on sensitivity tests. Many cases respond satisfactorily to antibiotics alone, but when considerable puru-lent material is present, repeated ultrasound guided aspiration is performed, and ultimately in a proportion of cases surgical treatment is required. Unlike puerperal abscesses, a subareo-lar abscess is usually unilocular and often is associated with a single duct system. Ultrasound will accurately delineate its extent. In those cases that come to surgery, the surgeon may either undertake simple drainage with a view toward formal Brunicardi_Ch17_p0541-p0612.indd 55401/03/19 5:04 PM 555THE BREASTCHAPTER 17Table 17-5Treatment of recurrent subareolar sepsisSUITABLE FOR FISTULECTOMYSUITABLE FOR TOTAL DUCT EXCISIONSmall abscess localized to one segmentLarge abscess affecting >50% of the areolar circumferenceRecurrence involving the same segmentRecurrence involving a different segmentMild or no nipple inversionMarked nipple inversionPatient unconcerned about nipple inversionPatient requests correction of nipple inversionYounger patientOlder patientNo discharge from other ductsPurulent discharge from other ductsNo prior fistulectomyRecurrence after fistulectomyModified with permission from Mansel RE, Webster DJT: Benign Disorders and Diseases of the Breast: Concepts and Clinical Management, 2nd ed. London: Elsevier/Saunders; 2000.surgery, should the problem recur, or proceed with definitive surgery. In a woman of childbearing age, simple drainage is preferred, but if there is an anaerobic infection, recurrent infection frequently develops. Recurrent abscess with fistula is a difficult problem. Treatment of periductal fistula was ini-tially recommended to be opening up of the fistulous track and allowing it to granulate.40 This approach may still be used, especially if the fistula is recurrent after previous attempts at fistulectomy. However, nowadays the preferred initial surgical treatment is by fistulectomy and primary closure with anti-biotic coverage.41 Excision of all the major ducts is an alter-native option depending on the circumstances (Table 17-5). When a localized periareolar abscess recurs at the previous site and a fistula is present, the preferred operation is fistulec-tomy, which has minimal complications and a high degree of success. However, when subareolar sepsis is diffused rather than localized to one segment or when more than one fistula is present, total duct excision is the most expeditious approach. The first circumstance is seen in young women with squamous metaplasia of a single duct, whereas the latter circumstance is seen in older women with multiple ectatic ducts. Age is not always a reliable guide, however, and fistula excision is the preferred initial procedure for localized sepsis irrespective of age. Antibiotic therapy is useful for recurrent infection after fistula excision, and a 2to 4-week course is recommended before total duct excision.Nipple Inversion. More women request correction of con-genital nipple inversion than request correction for the nipple inversion that occurs secondary to duct ectasia. Although the results are usually satisfactory, women seeking correction for cosmetic reasons should always be made aware of the surgi-cal complications of altered nipple sensation, nipple necrosis, and postoperative fibrosis with nipple retraction. Because nipple inversion is a result of shortening of the subareolar ducts, a com-plete division of these ducts is necessary for permanent correc-tion of the disorder.RISK FACTORS FOR BREAST CANCERHormonal and Nonhormonal Risk FactorsIncreased exposure to estrogen is associated with an increased risk for developing breast cancer, whereas reducing exposure is thought to be protective.42-48 Correspondingly, factors that increase the number of menstrual cycles, such as early men-arche, nulliparity, and late menopause, are associated with increased risk. Moderate levels of exercise and a longer lacta-tion period, factors that decrease the total number of menstrual cycles, are protective. The terminal differentiation of breast epi-thelium associated with a full-term pregnancy is also protective, so older age at first live birth is associated with an increased risk of breast cancer. Finally, there is an association between obesity and increased breast cancer risk. Because the major source of estrogen in postmenopausal women is the conversion of andro-stenedione to estrone by adipose tissue, obesity is associated with a long-term increase in estrogen exposure.Nonhormonal risk factors include radiation exposure. Young women who receive mantle radiation therapy for Hodg-kin’s lymphoma have a breast cancer risk that is 75 times greater than that of age-matched control subjects. Survivors of the atomic bomb blasts in Japan during World War II have a very high incidence of breast cancer, likely because of somatic muta-tions induced by the radiation exposure. In both circumstances, radiation exposure during adolescence, a period of active breast development, magnifies the deleterious effect. Studies also sug-gest that the risk of breast cancer increases as the amount of alcohol a woman consumes increases.49 Alcohol consumption is known to increase serum levels of estradiol. Finally, evidence suggests that long-term consumption of foods with a high fat content contributes to an increased risk of breast cancer by increasing serum estrogen levels.Risk Assessment ModelsThe average lifetime risk of breast cancer for newborn U.S. women is 12%.50,51 The longer a woman lives without cancer, the lower her risk of developing breast cancer. Thus, a woman age 50 years has an 11% lifetime risk of developing breast cancer, and a woman age 70 years has a 7% lifetime risk of developing breast cancer. Because risk factors for breast cancer interact, evaluating the risk conferred by combinations of risk factors is difficult. There are several risk assessment models available to predict the risk of breast cancer. From the Breast Cancer Detec-tion Demonstration Project, a mammography screening program conducted in the 1970s, Gail et al developed the model most frequently used in the United States, which incorporates age, age at menarche, age at first live birth, the number of breast biopsy specimens, any history of atypical hyperplasia, and number of first-degree relatives with breast cancer.52 It predicts the cumula-tive risk of breast cancer according to decade of life. To calculate breast cancer risk using the Gail model, a woman’s risk factors are translated into an overall risk score by multiplying her rela-tive risks from several categories (Table 17-6). This risk score is then compared to an adjusted population risk of breast cancer to determine a woman’s individual or absolute risk. The output is a 5-year risk and a lifetime risk of developing breast cancer. A software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc. This model was recently modified to more accu-rately assess risk in African American women.52,53 There have also been modifications that project individualized absolute 5Brunicardi_Ch17_p0541-p0612.indd 55501/03/19 5:04 PM 556SPECIFIC CONSIDERATIONSPART IITable 17-6Relative risk estimates for the Gail modelVARIABLERELATIVE RISKAge at menarche (years) ≥14 12–13 <12Number of biopsy specimens/history of benign breast disease, age <50 y 0 1 ≥2Number of biopsy specimens/history of benign breast disease, age ≥50 y 0 1 ≥2Age at first live birth (years) <20 y  Number of first-degree relatives with history of breast cancer  0  1  ≥2 20–24 y  Number of first-degree relatives with history of breast cancer  0  1  ≥2 25–29 y  Number of first-degree relatives with history of breast cancer  0  1  ≥2 ≥30 y  Number of first-degree relatives with history of breast cancer  0  1  ≥21.001.101.211.001.702.881.021.271.621.002.616.801.242.685.781.552.764.911.932.834.17Reproduced with permission from Armstrong K, Eisen A, Weber B: Assessing the risk of breast cancer, N Engl J Med. 2000 Feb 24;342(8):564-571.invasive breast cancer risk for Asian and Pacific Island American women. The Gail model is the most widely used model in the United States. Gail and colleagues have also described a revised model that includes body weight and mammographic density but excludes age at menarche.54Claus et al, using data from the Cancer and Steroid Hor-mone Study, a case-control study of breast cancer, developed the other frequently used risk assessment model, which is based on assumptions about the prevalence of high-penetrance breast cancer susceptibility genes.55 Compared with the Gail model, the Claus model incorporates more information about family his-tory but excludes other risk factors. The Claus model provides individual estimates of breast cancer risk according to decade of life based on presence of firstand second-degree relatives with breast cancer and their age at diagnosis. Risk factors that are less consistently associated with breast cancer (diet, use of oral contraceptives, lactation) or are rare in the general population (radiation exposure) are not included in either the Gail or Claus risk assessment model. Other models have been proposed that account for mammographic breast density in assessing breast cancer risk.54,56Neither the Gail model nor the Claus model accounts for the risk associated with mutations in the breast cancer suscepti-bility genes BRCA1 and BRCA2 (described in detail in the fol-lowing section). The BRCAPRO model is a Mendelian model that calculates the probability that an individual is a carrier of a mutation in one of the breast cancer susceptibility genes based on their family history of breast and ovarian cancer.57 The prob-ability that an individual will develop breast or ovarian cancer is derived from this mutation probability based on age-specific incidence curves for both mutation carriers and noncarriers.58 Use of the BRCAPRO model in the clinic is challenging since it requires input of all family history information regarding breast and ovarian cancer. The Tyrer-Cuzick model attempts to utilize both family history information and individual risk information. It uses the family history to calculate the probability that an individual carries a mutation in one of the breast cancer suscep-tibility genes, and then the risk is adjusted based on personal risk factors, including age at menarche, parity, age at first live birth, age at menopause, history of atypical hyperplasia or LCIS, height, and body mass index.59 Once a risk model has been uti-lized to assess breast cancer risk, this must be communicated to the individual and put into context with competing risk and medical comorbidities. This information can then be used to discuss options that are available to the individual for manag-ing risk.Risk ManagementSeveral important medical decisions may be affected by a wom-an’s underlying risk of developing breast cancer.60-68 These deci-sions include when to use postmenopausal hormone replacement therapy, at what age to begin mammography screening or incor-porate magnetic resonance imaging (MRI) screening, when to use tamoxifen to prevent breast cancer, and when to perform prophylactic mastectomy to prevent breast cancer. Postmeno-pausal hormone replacement therapy was widely prescribed in the 1980s and 1990s because of its effectiveness in controlling the symptoms of estrogen deficiency, namely vasomotor symp-toms such as hot flashes, night sweats and their associated sleep deprivation, osteoporosis, and cognitive changes. Furthermore, these hormone supplements were thought to reduce coronary artery disease as well. Use of combined estrogen and progester-one became standard for women who had not undergone hyster-ectomy because unopposed estrogen increases the risk of uterine cancer. Concerns of prolonging a woman’s lifetime exposure to estrogen, coupled with conflicting data regarding the impact of these hormones on cardiovascular health, motivated the imple-mentation of large-scale phase 3 clinical trials to definitively evaluate the risks vs. benefits of postmenopausal hormone replacement therapy. The Women’s Health Initiative (WHI) was therefore designed by the National Institutes of Health as a series of clinical trials to study the effects of diet, nutritional supplements, and hormones on the risk of cancer, cardiovascular disease, and bone health in postmenopausal women. Findings from primary studies of postmenopausal hormone replacement therapy were released in 2002, demonstrating conclusively that Brunicardi_Ch17_p0541-p0612.indd 55601/03/19 5:04 PM 557THE BREASTCHAPTER 17breast cancer risk is threefold to fourfold higher after >4 years of use and there is no significant reduction in coronary artery or cerebrovascular risks. The Collaborative Group on Hormonal Factors in Breast Cancer combined and reanalyzed data from a number of studies totaling 52,705 women with breast cancer and 108,411 women without breast cancer. They found an increased risk of breast cancer with every use of estrogen replacement therapy. They also reported increased risk among current users but not past users and risk increased with increasing duration of use of hormone replacement therapy.69 Cheblowski et al also reported from the WHI study that estrogen + progesterone increased the incidence of breast cancer.70 This was con-firmed by the Million Women study, which also showed that the increased risk was substantially greater for the combined estrogen + progesterone replacement therapy than other types of hormone replacement therapy.71Breast Cancer Screening. Routine use of screening mam-mography in women ≥50 years of age has been reported to reduce mortality from breast cancer by 25%.72 This reduc-tion comes at an acceptable economic cost. More recently, there has been debate over the potential harms associated with breast screening.73 Controversy over the age to initiate screening mammography is evident in the current recommendations. The U.S. Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), and the National Comprehensive Cancer Network (NCCN) are three organizations with differing recom-mendations for screening mammography in average risk women. The guidelines, however, similarly define high-risk women as those with personal history of breast cancer, history of chest radiation at young age, and confirmed or suspected genetic mutation known to increase risk for developing breast cancer. The USPSTF recommends biennial screening mammog-raphy for women age 50 to 74 years. The USPSTF applies these guidelines to asymptomatic women age >40 years who do not have a preexisting breast cancer or who were not previously diagnosed with a high-risk breast lesion, and who are not at high risk for breast cancer because of a known underlying genetic mutation or history of chest radiation at a young age.74-76 In October 2015, the ACS released updated guidelines stating average-risk women should start annual screening mammogra-phy at 45 years of age. Women age 45 to 54 years should be screened annually, and those 55 years and older should transi-tion to biennial screening or have the opportunity to continue annual screening. Women should have the opportunity to begin annual screening between the ages of 40 and 44 years and should continue screening as long as their overall health is good and have a life expectancy of 10 years or longer. The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age.77 The NCCN recommends that average-risk women begin annual screening mammograms at ≥40 years of age, along with annual clinical breast exams and breast awareness.78The United Kingdom recently established an independent expert panel to review the published literature and estimate the benefits and harms associated with screening women >50 years of age in its national screening program.79 The expert panel estimated that an invitation to breast screening delivers about a 20% reduction in breast cancer mortality. At the same time, however, the panel estimated that in women invited to the screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis. Despite the overdiagnosis, the panel concluded that breast screening confers significant benefit and should continue. The use of screening mammography in women <50 years of age is more controversial for several reasons: (a) breast density is greater, and screening mammography is less likely to detect early breast cancer (i.e., reduced sensitivity); (b) screening mammography results in more false-positive test findings (i.e., reduced specificity), which results in unneces-sary biopsy specimens; and (c) younger women are less likely to have breast cancer (i.e., lower incidence), so fewer young women will benefit from screening.80,81 In the United States, on a population basis, however, the benefits of screening mam-mography in women between the ages of 40 and 49 years is still felt to outweigh the risks; although targeting mammography to women at higher risk of breast cancer improves the balance of risks and benefits and is the approach some health care sys-tems have taken. In one study of women age 40 to 49 years, an abnormal mammography finding was three times more likely to be cancer in a woman with a family history of breast cancer than in a woman without such a history. Furthermore, as noted previously in the section Risk Assessment Models, mounting data regarding mammographic breast density demonstrate an independent correlation with breast cancer risk. Incorporation of breast density measurements into breast cancer risk assess-ment models appears to be a promising strategy for increasing the accuracy of these tools. Unfortunately, widespread applica-tion of these modified models is hampered by inconsistencies in the reporting of mammographic density. Ultrasonography can also be used for breast cancer screening in women with dense breasts, but there is no data available that the additional cancers detected with this modality reduce mortality from breast cancer.Current recommendations by the United States Preventive Services Task Force are that women undergo biennial mammo-graphic screening between the ages of 50 and 74 years.77 The use of MRI for breast cancer screening is recommended by the ACS for women with a 20% to 25% or greater lifetime risk using risk assessment tools based mainly on family history, BRCA mutation carriers, those individuals who have a family member with a BRCA mutation who have not been tested themselves, individuals who received radiation to the chest between the ages of 10 and 30 years, and those individuals with a history of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome or those who have a first-degree relative with one of these syndromes. MRI is an extremely sensitive screening tool that is not limited by the density of the breast tissue as mammography is; however, its specificity is moderate, leading to more false-positive events and the increased need for biopsy.Chemoprevention. Tamoxifen, a selective estrogen receptor modulator, was the first drug shown to reduce the incidence of breast cancer in healthy women. There have been four pro-spective studies published evaluating tamoxifen vs. placebo for reducing the incidence of invasive breast cancer for women at increased risk. The largest trial was the Breast Cancer Preven-tion Trial (NSABP P-01), which randomly assigned >13,000 women with a 5-year Gail relative risk of breast cancer of 1.66% or higher or LCIS to receive tamoxifen or placebo. After a mean follow-up period of 4 years, the incidence of breast cancer was reduced by 49% in the group receiving tamoxifen.60 The decrease was evident only in ER-positive breast cancers with no significant change in ER-negative tumors. The Royal Marsden Hospital Tamoxifen Chemoprevention Trial,78 the Italian Tamox-ifen Prevention Trial,82 and the International Breast Cancer Intervention Study I (IBIS-I) trial all83 showed a reduction in 6Brunicardi_Ch17_p0541-p0612.indd 55701/03/19 5:04 PM 558SPECIFIC CONSIDERATIONSPART IIER-positive breast cancers with the use of tamoxifen compared with placebo. There was no effect on mortality; however, the trials were not powered to assess either breast cancer mortality or all-cause mortality events. The adverse events were similar in all four randomized trials, including an increased risk of endo-metrial cancer, thromboembolic events, cataract formation, and vasomotor disturbances in individuals receiving tamoxifen.Tamoxifen therapy currently is recommended only for women who have a Gail relative risk of 1.66% or higher, who are age 35 to 59, women over the age of 60, or women with a diagnosis of LCIS or atypical ductal or lobular hyperplasia. In addition, deep vein thrombosis occurs 1.6 times as often, pulmonary emboli 3.0 times as often, and endometrial cancer 2.5 times as often in women taking tamoxifen. The increased risk for endometrial cancer is restricted to early stage cancers in postmenopausal women. Cataract surgery is required almost twice as often among women taking tamoxifen. Gail et al sub-sequently developed a model that accounts for underlying risk of breast cancer as well as comorbidities to determine the net risk-benefit ratio of tamoxifen use for chemoprevention.84The NSABP completed a second chemoprevention trial, designed to compare tamoxifen and raloxifene for breast cancer risk reduction in high-risk postmenopausal women. Raloxifene, another selective estrogen receptor modulator, was selected for the experimental arm in this follow-up prevention trial because its use in managing postmenopausal osteoporosis suggested that it might be even more effective at breast cancer risk reduc-tion, but without the adverse effects of tamoxifen on the uterus. The P-2 trial, the Study of Tamoxifen and Raloxifene (known as the STAR trial), randomly assigned 19,747 postmenopausal women at high-risk for breast cancer to receive either tamoxi-fen or raloxifene. The initial report of the P-2 trial showed the two agents were nearly identical in their ability to reduce breast cancer risk, but raloxifene was associated with a more favor-able adverse event profile.85 An updated analysis revealed that raloxifene maintained 76% of the efficacy of tamoxifen in pre-vention of invasive breast cancer with a more favorable side effect profile. The risk of developing endometrial cancer was significantly higher with tamoxifen use at longer follow-up.86 Although tamoxifen has been shown to reduce the incidence of LCIS and DCIS, raloxifene did not have an effect on the frequency of these diagnoses.Aromatase inhibitors (AIs) have been shown to be more effective than tamoxifen in reducing the incidence of contra-lateral breast cancers in postmenopausal women receiving AIs for adjuvant treatment of invasive breast cancer. The MAP.3 trial was the first study to evaluate an AI as a chemopreventive agent in postmenopausal women at high risk for breast cancer. The trial randomized 4560 women to exemestane 25 mg daily vs. placebo for 5 years. After a median follow-up of 35 months, exemestane was shown to reduce invasive breast cancer inci-dence by 65%. Side effect profiles demonstrated more grade II or higher arthritis and hot flashes in patients taking exemestane.87 The IBIS II trial on the other hand, randomized 3864 postmeno-pausal women to either anastrozole, a nonsteroidal aromatase inhibitor, vs. placebo with a further randomization to bisphospho-nate or not based on bone density.88,89 After a median follow-up of 5 years, anastrozole reduced the incidence of invasive breast cancer by about 50%. The trial also had an initial sub-study that looked at the effect of the aromatase inhibitor on cogni-tive function and reported no adverse effects.90 The American Society of Clinical Oncology recommends tamoxifen for chemoprevention in premenopausal or postmenopausal women and consideration for raloxifene or exemestane in postmeno-pausal women who are noted to be at increased risk of breast cancer.91,92 The discussion with an individual patient should include risk assessment and potential risks and benefits with each agent.Risk-Reducing Surgery. A retrospective study of women at high risk for breast cancer found that prophylactic mastectomy reduced their risk by >90%.62 However, the effects of prophylac-tic mastectomy on the long-term quality of life are poorly quan-tified. A study involving women who were carriers of a breast cancer susceptibility gene (BRCA) mutation found that the ben-efit of prophylactic mastectomy differed substantially according to the breast cancer risk conferred by the mutations. For women with an estimated lifetime risk of 40%, prophylactic mastec-tomy added almost 3 years of life, whereas for women with an estimated lifetime risk of 85%, prophylactic mastectomy added >5 years of life.66 Domchek et al evaluated a cohort of BRCA1 and 2 mutation carriers who were followed prospectively and reported on outcomes with risk-reducing surgery.93 They found that risk-reducing mastectomy was highly effective at preventing breast cancer in both BRCA1 and 2 mutation carriers. Risk-reducing salpingo-oophorectomy was highly effective at reducing the incidence of ovarian cancer and breast cancer in BRCA mutation carriers and was associated with a reduction in breast cancer-specific mortality, ovarian cancer-specific mor-tality, and all-cause mortality. While studies of bilateral pro-phylactic or risk-reducing mastectomy have reported dramatic reductions in breast cancer incidence among those without known BRCA mutations, there is little data to support a survival benefit. Another consideration is that while most patients are satisfied with their decision to pursue risk-reducing surgery, some are dissatisfied with the cosmetic outcomes mostly due to reconstructive issues.BRCA MutationsBRCA1. Up to 5% of breast cancers are caused by inheritance of germline mutations such as BRCA1 and BRCA2, which are inherited in an autosomal dominant fashion with varying degrees of penetrance (Table 17-7).94-100 BRCA1 is located on chromosome arm 17q, spans a genomic region of approximately 100 kilobases (kb) of DNA, and contains 22 coding exons for 1863 amino acids. Both BRCA1 and BRCA2 function as tumor-suppressor genes, and for each gene, loss of both alleles is required for the initiation of cancer. Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, cell-cycle control, and DNA damage repair pathways. More than 500 sequence variations in BRCA1 have been identified. It now is known that germline mutations in BRCA1 represent a predisposing genetic factor in as many as 45% of hereditary breast cancers and in at least 80% of hereditary ovarian cancers. Female mutation carriers have been reported to have up to an 85% lifetime risk (for some families) for developing breast cancer and up to a 40% lifetime risk for developing ovarian cancer. The initial families reported had high penetrance and subsequently the average lifetime risk has been reported to lie between 60% and 70%. Breast cancer susceptibility in these families appears as an autosomal dominant trait with high pen-etrance. Approximately 50% of children of carriers inherit the trait. In general, BRCA1-associated breast cancers are invasive ductal carcinomas, are poorly differentiated, are in the majority Brunicardi_Ch17_p0541-p0612.indd 55801/03/19 5:04 PM 559THE BREASTCHAPTER 17Table 17-7Incidence of sporadic, familial, and hereditary breast cancerSporadic breast cancer65%–75%Familial breast cancer20%–30%Hereditary breast cancer5%–10% BRCA1a45% BRCA235% p53a (Li-Fraumeni syndrome)1% STK11/LKB1a (Peutz-Jeghers syndrome)<1% PTENa (Cowden disease)<1% MSH2/MLH1a (Muir-Torre syndrome)<1% ATMa (Ataxia-telangiectasia)<1% Unknown20%aAffected gene.Data from Martin AM, Weber BL: Genetic and hormonal risk factors in breast cancer, J Natl Cancer Inst. 2000 Jul 19;92(14):1126-1135.hormone receptor negative, and have a triple receptor negative (immunohistochemical profile: ER-negative, PR-negative, and HER2-negative) or basal phenotype (based on gene expression profiling). BRCA1-associated breast cancers have a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases; a higher prevalence of bilateral breast cancer; and the presence of associated cancers in some affected individuals, specifically ovarian cancer and possibly colon and prostate cancers.Several founder mutations have been identified in BRCA1. The two most common mutations are 185delAG and 5382insC, which account for 10% of all the mutations seen in BRCA1. These two mutations occur at a 10-fold higher frequency in the Ashkenazi Jewish population than in non-Jewish Caucasians. The carrier frequency of the 185delAG mutation in the Ashkenazi Jewish population is 1% and, along with the 5382insC mutation, accounts for almost all BRCA1 mutations in this population. Analysis of germline mutations in Jewish and non-Jewish women with early-onset breast cancer indicates that 20% of Jewish women who develop breast cancer before age 40 years carry the 185delAG mutation. There are founder BRCA1 mutations in other populations including, among others, Dutch, Polish, Finnish, and Russian populations.101-105BRCA2. BRCA2 is located on chromosome arm 13q and spans a genomic region of approximately 70 kb of DNA. The 11.2-kb coding region contains 26 coding exons.94-100 It encodes a pro-tein of 3418 amino acids. The BRCA2 gene bears no homology to any previously described gene, and the protein contains no previously defined functional domains. The biologic function of BRCA2 is not well defined, but like BRCA1, it is postulated to play a role in DNA damage response pathways. BRCA2 mes-senger RNA also is expressed at high levels in the late G1 and S phases of the cell cycle. The kinetics of BRCA2 protein regu-lation in the cell cycle is similar to that of BRCA1 protein, which suggests that these genes are coregulated. The mutational spec-trum of BRCA2 is not as well established as that of BRCA1. To date, >250 mutations have been found. The breast cancer risk for BRCA2 mutation carriers is close to 85%, and the life-time ovarian cancer risk, while lower than for BRCA1, is still estimated to be close to 20%. Breast cancer susceptibility in BRCA2 families is an autosomal dominant trait and has a high penetrance. Approximately 50% of children of carriers inherit the trait. Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have an estimated breast cancer risk of 6%, which represents a 100-fold increase over the risk in the general male population. BRCA2-associated breast cancers are invasive ductal carcinomas, which are more likely to be well differentiated and to express hormone receptors than are BRCA1-associated breast cancers. BRCA2-associated breast cancer has a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases, a higher prevalence of bilateral breast cancer, and the presence of associ-ated cancers in some affected individuals, specifically ovarian, colon, prostate, pancreatic, gallbladder, bile duct, and stomach cancers, as well as melanoma. A number of founder mutations have been identified in BRCA2. The 6174delT mutation is found in Ashkenazi Jews with a prevalence of 1.2% and accounts for 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.106 Another BRCA2 founder mutation, 999del5, is observed in Icelandic and Finnish popula-tions, while more recently 3036delACAA has been observed in a number of Spanish families.107-109Identification of BRCA Mutation Carriers. Identifying hereditary risk for breast cancer is a four-step process that includes: (a) obtaining a complete, multigenerational family history, (b) assessing the appropriateness of genetic testing for a particular patient, (c) counseling the patient, and (d) interpret-ing the results of testing.110 Genetic testing should not be offered in isolation, but only in conjunction with patient education and counseling, including referral to a genetic counselor. Initial determinations include whether the individual is an appropriate candidate for genetic testing and whether genetic testing will be informative for personal and clinical decision-making. A thor-ough and accurate family history is essential to this process, and the maternal and paternal sides of the family are both assessed because 50% of the women with a BRCA mutation have inher-ited the mutation from their fathers. To help clinicians advise women about genetic testing, statistically based models that determine the probability that an individual carries a BRCA mutation have been developed. A method for calculating carrier probability that has been demonstrated to have acceptable per-formance (i.e., both in terms of calibration and discrimination) such as the Manchester scoring system and BODICEA should be used to offer referral to a specialist genetic clinic. A heredi-tary risk of breast cancer is considered if a family includes Ash-kenazi Jewish heritage; a first-degree relative with breast cancer before age 50; a history of ovarian cancer at any age in the patient or firstor second-degree relative with ovarian cancer; breast and ovarian cancer in the same individual; two or more firstor second-degree relatives with breast cancer at any age; patient or relative with bilateral breast cancer; and male breast cancer in a relative at any age.111 The threshold for genetic test-ing is lower in individuals who are members of ethnic groups in whom the mutation prevalence is increased.BRCA Mutation Testing. Appropriate counseling for the individual being tested for a BRCA mutation is strongly rec-ommended, and documentation of informed consent is required.110,112 The test that is clinically available for analyzing BRCA mutations is gene sequence analysis. In a family with a history suggestive of hereditary breast cancer and no previously Brunicardi_Ch17_p0541-p0612.indd 55901/03/19 5:04 PM 560SPECIFIC CONSIDERATIONSPART IItested member, the most informative strategy is first to test an affected family member. This person undergoes complete sequence analysis of both the BRCA1 and BRCA2 genes. If a mutation is identified, relatives are usually tested only for that specific mutation. An individual of Ashkenazi Jewish ancestry is tested initially for the three specific mutations that account for hereditary breast and ovarian cancer in that population. If results of that test are negative, it may then be appropriate to fully analyze the BRCA1 and BRCA2 genes.A positive test result is one that discloses the presence of a BRCA mutation that interferes with translation or function of the BRCA protein. A woman who carries a deleterious mutation has a breast cancer risk of up to 85% (in some families) as well as a greatly increased risk of ovarian cancer. A negative test result is interpreted according to the individual’s personal and family history, especially whether a mutation has been previously iden-tified in the family, in which case the woman is generally tested only for that specific mutation. If the mutation is not present, the woman’s risk of breast or ovarian cancer may be no greater than that of the general population. In addition, no BRCA muta-tion can be passed on to the woman’s children. In the absence of a previously identified mutation, a negative test result in an affected individual generally indicates that a BRCA mutation is not responsible for the familial cancer. However, the possibil-ity remains of an unusual abnormality in one of these genes that cannot yet be identified through clinical testing. It also is possible that the familial cancer is indeed caused by an identifi-able BRCA mutation but that the individual tested had sporadic cancer, a situation known as phenocopy. This is especially pos-sible if the individual tested developed breast cancer close to the age of onset of the general population (age 60 years or older) rather than before age 50 years, as is characteristic of BRCA mutation carriers. Overall, the false-negative rate for BRCA mutation testing is <5%. Some test results, especially when a single base-pair change (missense mutation) is identified, may be difficult to interpret. This is because single base-pair changes do not always result in a nonfunctional protein. Thus, missense mutations not located within critical functional domains, or those that cause only minimal changes in protein structure, may not be disease associated and are usually reported as indetermi-nate results. In communicating indeterminate results to women, care must be taken to relay the uncertain cancer risk associ-ated with this type of mutation and to emphasize that ongoing research might clarify its meaning. In addition, testing other family members with breast cancer to determine if a genetic variant tracks with their breast cancer may provide clarification as to its significance. Indeterminate genetic variance currently accounts for 12% of the test results.Concern has been expressed that the identification of hereditary risk for breast cancer may interfere with access to affordable health insurance. This concern refers to discrimina-tion directed against an individual or family based solely on an apparent or perceived genetic variation from the normal human genotype. The Health Insurance Portability and Accountability Act of 1996 (HIPAA) made it illegal in the United States for group health plans to consider genetic information as a preexist-ing condition or to use it to deny or limit coverage. Most states also have passed laws that prevent genetic discrimination in the provision of health insurance. In addition, individuals applying for health insurance are not required to report whether relatives have undergone genetic testing for cancer risk, only whether those relatives have actually been diagnosed with cancer. Currently, there is little documented evidence of genetic dis-crimination resulting from findings of available genetic tests.Cancer Prevention for BRCA Mutation Carriers. Risk man-agement strategies for BRCA1 and BRCA2 mutation carriers include the following:1. Risk-reducing mastectomy and reconstruction2. Risk-reducing salpingo-oophorectomy3. Intensive surveillance for breast and ovarian cancer4. ChemopreventionAlthough removal of breast tissue reduces the likeli-hood that BRCA1 and BRCA2 mutation carriers will develop breast cancer, mastectomy does not remove all breast tissue, and women continue to be at risk because a germline muta-tion is present in any remaining breast tissue. For postmeno-pausal BRCA1 and BRCA2 mutation carriers who have not had a mastectomy, it may be advisable to avoid hormone replace-ment therapy because no data exist regarding the effect of the therapy on the penetrance of breast cancer susceptibility genes. Because breast cancers in BRCA mutation carriers have the same mammographic appearance as breast cancers in noncarri-ers, a screening mammogram is likely to be effective in BRCA mutation carriers, provided it is performed and interpreted by an experienced radiologist with a high level of suspicion. Pres-ent screening recommendations for BRCA mutation carriers who do not undergo risk-reducing mastectomy include clinical breast examination every 6 months and mammography every 12 months beginning at age 25 years because the risk of breast cancer in BRCA mutation carriers increases after age 30 years. Recent attention has been focused on the use of MRI for breast cancer screening in high-risk individuals and known BRCA mutation carriers. MRI appears to be more sensitive at detect-ing breast cancer in younger women with dense breasts.113 How-ever, as noted previously, MRI does lead to the detection of benign breast lesions that cannot easily be distinguished from malignancy, and these false-positive events can result in more interventions, including biopsy specimens. The current recom-mendations from the American Cancer Society are for annual MRI in women with a 20% to 25% or greater lifetime risk of developing breast cancer (mainly based on family history), women with a known BRCA1 or BRCA2 mutation, those who have a first-degree relative with a BRCA1 or BRCA2 mutation and have not had genetic testing themselves, women who were treated with radiation therapy to the chest between the ages of 10 and 30 years, and those who have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or a first-degree relative with one of these syndromes.75,114 Despite a 49% reduction in the overall incidence of breast cancer and a 69% reduction in the incidence of estrogen receptor positive tumors in high-risk women taking tamoxifen reported in the NSABP P1 trial, there is insufficient evidence to recommend the use of tamoxifen uniformly for BRCA1 mutation carriers.60 Cancers arising in BRCA1 mutation carriers are usually high grade and are most often hormone receptor negative. Approxi-mately 66% of BRCA1-associated DCIS lesions are estrogen receptor negative, which suggests early acquisition of the hor-mone-independent phenotype. In the NSABP P1 trial there was a 62% reduction in the incidence of breast cancer in BRCA2 carriers, similar to the overall reduction seen in the P1 trial. In contrast, there was no reduction seen in breast cancer incidence in BRCA1 carriers who started tamoxifen in P1 age 35 years or Brunicardi_Ch17_p0541-p0612.indd 56001/03/19 5:04 PM 561THE BREASTCHAPTER 17older.115 Tamoxifen appears to be more effective at preventing estrogen receptor-positive breast cancers.The risk of ovarian cancer in BRCA1 and BRCA2 muta-tion carriers ranges from 20% to 40%, which is 10 times higher than that in the general population. Risk-reducing salpingo-oophorectomy is a reasonable prevention option in mutation carriers. In women with a documented BRCA1 or BRCA2 mutation, consideration for bilateral risk-reducing salpingo-oophorectomy should be between the ages of 35 and 40 years at the completion of childbearing. Removing the ovaries reduces the risk of ovarian cancer and breast cancer when per-formed in premenopausal BRCA mutation carriers. Hormone replacement therapy is discussed with the patient at the time of oophorectomy. The Cancer Genetics Studies Consortium recommends yearly transvaginal ultrasound timed to avoid ovulation and annual measurement of serum cancer antigen 125 levels beginning at age 25 years as the best screening modalities for ovarian carcinoma in BRCA mutation carriers who have opted to defer risk-reducing surgery.PALB2 (partner and localizer of BRCA2) has recently been characterized as a potential high-risk gene for breast cancer. PALB2 allows nuclear localization of BRCA2 and provides a scaffold for the BRCA1–PALB2–BRCA2 complex. Analysis by Antoniou et al has suggested that the risk of breast cancer for PALB2 mutation carriers is as high as that of BRCA2 mutation carriers.116 The absolute risk of breast cancer for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25–44) for those with no family history of breast cancer to 58% (95% CI, 50–66) for those with two or more first-degree relatives with breast cancer at 50 years of age. The risk of breast cancer for female PALB2 mutation carriers, depending on the age, was about five to nine times as high compared with the gen-eral population. While screening with mammogram along with MRI has been suggested for PALB2 mutation carriers starting at age 30 with consideration of risk-reducing mastectomy, there is currently insufficient evidence regarding the risk of ovarian cancer and its management.Other hereditary syndromes associated with an increased risk of breast cancer include Cowden disease (PTEN mutations, in which cancers of the thyroid, GI tract, and benign skin and subcutaneous nodules are also seen), Li-Fraumeni syndrome (TP53 mutations, also associated with sarcomas, lymphomas, and adrenocortical tumors), hereditary diffuse gastric cancer syndrome (CDH1 mutations, associated with diffuse gastric cancer and lobular breast cancers), and syndromes of breast and melanoma. With the discovery of additional genes related to breast cancer susceptibility, panel testing is available for a number of genes in addition to BRCA1 and BRCA2. The inter-pretation of results is complex and is best done with a genetic counselor.EPIDEMIOLOGY AND NATURAL HISTORY OF BREAST CANCEREpidemiologyBreast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for women age 20 to 59 years. Based on Surveillance, Epidemiology, and End Results registries (SEER) data, 266,120 new cases were esti-mated in 2018 with 40,920 estimated deaths attributed to breast cancers.117 It accounts for 30% of all newly diagnosed cancers in women and is responsible for 14% of the cancer-related deaths in women.Breast cancer was the leading cause of cancer-related mortality in women until 1987, when it was surpassed by lung cancer. In the 1970s, the probability that a woman in the United States would develop breast cancer at some point in her lifetime was estimated at 1 in 13; in 1980 it was 1 in 11; and in 2004 it was 1 in 8. Cancer registries in Connecticut and upper New York State document that the age-adjusted incidence of new breast cancer cases had steadily increased since the mid-1940s. The incidence in the United States, based on data from nine SEER registries, has been decreasing by 23% per year since 2000. The increase had been approximately 1% per year from 1973 to 1980, and there was an additional increase in inci-dence of 4% between 1980 and 1987, which was characterized by frequent detection of small primary cancers. The increase in breast cancer incidence occurred primarily in women age ≥55 years and paralleled a marked increase in the percentage of older women who had mammograms taken. At the same time, incidence rates for regional metastatic disease dropped and breast cancer mortality declined. From 1960 to 1963, 5-year overall survival rates for breast cancer were 63% and 46% in white and African American women, respectively, whereas the rates for 1981 to 1983 were 78% and 64%, respectively. For 2002 to 2008 rates were 92% and 78%, respectively.There is a 10-fold variation in breast cancer incidence among different countries worldwide. Cyprus and Malta have the highest age-adjusted mortality for breast cancer (29.6 per 100,000 population), whereas Haiti has the lowest (2.0 deaths per 100,000 population). The United States has an age-adjusted mortality for breast cancer of 19.0 cases per 100,000 population. Women living in less industrialized nations tend to have a lower incidence of breast cancer than women living in industrialized countries, although Japan is an exception. In the United States, Mormons, Seventh Day Adventists, American Indians, Alaska natives, Hispanic/Latina Americans, and Japanese and Filipino women living in Hawaii have a below-average incidence of breast cancer, whereas nuns (due to nulliparity) and Ashkenazi Jewish women have an above-average incidence.The incidence rates of breast cancer increased in most countries through the 1990s. Since the estimates for 1990, there was an overall increase in incidence rates of approximately 0.5% annually. It was predicted that there would be approxi-mately 1.4 million new cases in 2010. The cancer registries in China have noted annual increases in incidence of up to 3% to 4%, and in eastern Asia, increases are similar.Data from the SEER program reveal declines in breast cancer incidence over the past decade, and this is widely attrib-uted to decreased use of hormone replacement therapy as a con-sequence of the Women’s Health Initiative reports.118Breast cancer burden has well-defined variations by geog-raphy, regional lifestyle, and racial or ethnic background.119 In general, both breast cancer incidence and mortality are rela-tively lower among the female populations of Asia and Africa, relatively underdeveloped nations, and nations that have not adopted Westernized reproductive and dietary patterns. In contrast, European and North American women and women from heavily industrialized or Westernized countries have a substantially higher breast cancer burden. These international patterns are mirrored in breast cancer incidence and mortality rates observed for the racially, ethnically, and culturally diverse population of the United States.120Brunicardi_Ch17_p0541-p0612.indd 56101/03/19 5:04 PM 562SPECIFIC CONSIDERATIONSPART II10090807060504030201083%68%54%41%Middlesex Hospital 1805-1933 (250 cases)86%66%44%28%18%9%3.6%2%0.8%1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Median survival 2.7 years Natural survivalSurvival untreated casesDuration of life from onset of symptoms (years)% SurvivalFigure 17-13. Survival of women with untreated breast cancer compared with natural survival. (Reproduced with permission from Bloom HJG, Richardson WW, Harries EJ: Natural history of untreated breast cancer (1805-1933). Comparison of untreated and treated cases according to histological grade of malignancy, Br Med J. 1962 Jul 28;2(5299):213-221.)Although often related, the factors that influence breast cancer incidence may differ from those that affect mortality. Incidence rates are lower among populations that are heavily weighted with women who begin childbearing at young ages and who have multiple full-term pregnancies followed by pro-longed lactation. These are features that characterize many underdeveloped nations and also many eastern nations. Breast cancer mortality rates should be lower in populations that have a lower incidence, but the mortality burden will simultaneously be adversely affected by the absence of effective mammographic screening programs for early detection and diminished access to multidisciplinary cancer treatment programs. These features are likely to account for much of the disproportionate mortal-ity risks that are seen in underdeveloped nations. Similar fac-tors probably account for differences in breast cancer burden observed among the various racial and ethnic groups within the United States. Interestingly, breast cancer incidence and mortality rates rise among secondand third-generation Asian Americans as they adopt Western lifestyles.Disparities in breast cancer survival among subsets of the American population are generating increased publicity because they are closely linked to disparities in socioeconomic status. Poverty rates and proportions of the population that lack health care insurance are two to three times higher among minority racial and ethnic groups such as African Americans and His-panic/Latino Americans. These socioeconomic disadvantages create barriers to effective breast cancer screening and result in delayed breast cancer diagnosis, advanced stage distribu-tion, inadequacies in comprehensive treatment, and, ultimately, increased mortality rates. Furthermore, the rapid growth in the Hispanic population is accompanied by increasing problems in health education because of linguistic barriers between physi-cians and recently immigrated, non–English-speaking patients. Recent studies also are documenting inequities in the treatments delivered to minority breast cancer patients, such as increased rates of failure to provide systemic therapy, use of sentinel lymph node dissection, and breast reconstruction. Some of the treatment delivery disparities are related to inadequately con-trolled comorbidities (such as hypertension and diabetes), which are more prevalent in minority populations. However, some studies that adjust for these factors report persistent and unex-plained unevenness in treatment recommendations. It is clear that breast cancer disparities associated with racial or ethnic background have a multifactorial cause, and improvements in outcome will require correction of many public health problems at both the patient and provider levels.Advances in the ability to characterize breast cancer sub-types and the genetics of the disease are now provoking specula-tion regarding possible hereditary influences on breast cancer risk that are related to racial or ethnic ancestry.121 These questions become particularly compelling when one looks at disparities in breast cancer burden between African Americans and Cau-casians. Lifetime risk of breast cancer is lower for African Americans, yet a paradoxically increased breast cancer mortal-ity risk also is seen. African Americans also have a younger age distribution for breast cancer; among women <45 years of age, breast cancer incidence is highest among African Americans compared to other subsets of the American population. Lastly and most provocatively, African American women of all ages have notably higher incidence rates for estrogen receptor-negative tumors. These same patterns of disease are seen in con-temporary female populations of western, sub-Saharan Africa, who are likely to share ancestry with African American women as a consequence of the Colonial-era slave trade. Interestingly, male breast cancer also is seen with increased frequency among both African Americans and Africans.Natural HistoryBloom and colleagues described the natural history of breast cancer based on the records of 250 women with untreated breast cancers who were cared for on charity wards in the Middlesex Hospital, London, between 1805 and 1933. The median survival of this population was 2.7 years after initial diagnosis (Fig. 17-13).122 The 5and 10-year survival rates for these women were 18.0% and 3.6%, respectively. Only 0.8% survived for 15 years or longer. Autopsy data confirmed that 95% of these women died of breast cancer, whereas the remaining 5% died of other causes. Almost 75% of the women developed ulcer-ation of the breast during the course of the disease. The longest surviving patient died in the 19th year after diagnosis.Primary Breast Cancer. More than 80% of breast cancers show productive fibrosis that involves the epithelial and stro-mal tissues. With growth of the cancer and invasion of the surrounding breast tissues, the accompanying desmoplastic response entraps and shortens Cooper’s suspensory ligaments to produce a characteristic skin retraction. Localized edema (peau d’orange) develops when drainage of lymph fluid from the skin is disrupted. With continued growth, cancer cells invade the skin, and eventually ulceration occurs. As new areas of skin are invaded, small satellite nodules appear near the primary ulceration. The size of the primary breast cancer correlates with disease-free and overall survival, but there is a close associa-tion between cancer size and axillary lymph node involvement (Fig. 17-14). In general, up to 20% of breast cancer recurrences are local-regional, >60% are distant, and 20% are both local-regional and distant.Brunicardi_Ch17_p0541-p0612.indd 56201/03/19 5:04 PM 563THE BREASTCHAPTER 17xxxxxxxxxx**********Diameter (cm)0.980.950.900.800.700.600.500.400.300.20Proportion of patients with metastases10100Volume (ml)2345676891011100908070605040302010Percent survivors31529717363653126317714265321234909214425N + >3 (183)N + (381)N + 1 (198)N (335)Whole series (716)241068Years after mastectomyABFigure 17-14. A. Overall survival for women with breast cancer according to axillary lymph node status. The time periods are years after radical mastectomy. (Reproduced with permission from Vala-gussa P, Bonadonna G, Veronesi U, et al: Patterns of relapse and survival following radical mastectomy. Analysis of 716 consecutive patients, Cancer. 1978 Mar;41(3):1170-1178.) B. Risk of metasta-ses according to breast cancer volume and diameter. (Reproduced with permission from Koscielny S, Tubiana M, Lê MG, et al: Breast cancer: Relationship between the size of the primary tumour and the probability of metastatic dissemination, Br J Cancer. 1984 Jun;49(6):709-715.)Axillary Lymph Node Metastases. As the size of the pri-mary breast cancer increases, some cancer cells are shed into cellular spaces and transported via the lymphatic network of the breast to the regional lymph nodes, especially the axillary lymph nodes. Lymph nodes that contain metastatic cancer are at first ill-defined and soft but become firm or hard with con-tinued growth of the metastatic cancer. Eventually the lymph nodes adhere to each other and form a conglomerate mass. Cancer cells may grow through the lymph node capsule and fix to contiguous structures in the axilla, including the chest wall. Typically, axillary lymph nodes are involved sequentially from the low (level I) to the central (level II) to the apical (level III) lymph node groups. Approximately 95% of the women who die of breast cancer have distant metastases, and traditionally the most important prognostic correlate of disease-free and over-all survival was axillary lymph node status (see Fig. 17-14A). Women with node-negative disease had less than a 30% risk of recurrence, compared with as much as a 75% risk for women with node-positive disease.Distant Metastases. At approximately the 20th cell dou-bling, breast cancers acquire their own blood supply (neovas-cularization). Thereafter, cancer cells may be shed directly into the systemic venous blood to seed the pulmonary circulation via the axillary and intercostal veins or the vertebral column via Batson’s plexus of veins, which courses the length of the vertebral column. These cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of metastatic foci from breast cancer predictably occurs after the primary cancer exceeds 0.5 cm in diameter, which corresponds to the 27th cell doubling. For 10 years after initial treatment, distant metastases are the most common cause of death in breast cancer patients. For this reason, conclusive results cannot be derived from breast cancer trials until at least 5 to 10 years have elapsed. Although 60% of the women who develop distant metastases will do so within 60 months of treatment, metastases may become evident as late as 20 to 30 years after treatment of the primary cancer.123 Patients with estrogen receptor nega-tive breast cancers are proportionately more likely to develop recurrence in the first 3 to 5 years, whereas those with estrogen receptor positive tumors have a risk of developing recurrence, which drops off more slowly beyond 5 years than is seen with ER-negative tumors.124 Recently, a report showed that tumor size and nodal status remain powerful predictors of late recur-rences compared to more recently developed tools such as the immunohistochemical score (IHC4) and two gene expression profile tests (Recurrence Score and PAM50).125 Common sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues, and liver. Brain metastases are less frequent over-all, although with the advent of adjuvant systemic therapies it has been reported that CNS disease may be seen earlier.126,127 There are also reports of factors that are associated with the risk of developing brain metastases.128 For example, they are more likely to be seen in patients with triple receptor negative breast cancer (ER-negative, PR-negative, and HER2-negative) or patients with HER2-positive breast cancer who have received chemotherapy and HER2-directed therapies.HISTOPATHOLOGY OF BREAST CANCERCarcinoma In SituCancer cells are in situ or invasive depending on whether or not they invade through the basement membrane.129,130 Broders’s original description of in situ breast cancer stressed the absence of invasion of cells into the surrounding stroma and their confine-ment within natural ductal and alveolar boundaries.129 Because areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates the analysis of multiple microscopic sec-tions to exclude invasion. In 1941, Foote and Stewart published Brunicardi_Ch17_p0541-p0612.indd 56301/03/19 5:04 PM 564SPECIFIC CONSIDERATIONSPART IITable 17-8Salient characteristics of in situ ductal (DCIS) and lobular (LCIS) carcinoma of the breast LCISDCISAge (years)44–4754–58Incidencea2%–5%5%–10%Clinical signsNoneMass, pain, nipple dischargeMammographic signsNoneMicrocalcificationsPremenopausal2/31/3Incidence of synchronous invasive carcinoma5%2%–46%Multicentricity60%–90%40%–80%Bilaterality50%–70%10%–20%Axillary metastasis1%1%–2%Subsequent carcinomas:   Incidence25%–35%25%–70% LateralityBilateralIpsilateral Interval to diagnosis15–20 y5–10 y Histologic typeDuctalDuctalaIn biopsy specimens of mammographically detected breast lesions.Reproduced with permission from Bland KI, Copeland ED: The Breast: Comprehensive Management of Benign and Malignant Diseases, 2nd ed. Philadelphia, PA: Elsesvier/Saunders; 1998.Table 17-9Classification of breast ductal carcinoma in situ (DCIS)HISTOLOGIC SUBTYPE DETERMINING CHARACTERISTICSDCIS GRADE NUCLEAR GRADENECROSISComedoHighExtensiveHighIntermediateaIntermediateFocal or absentIntermediateNoncomedobLowAbsentLowaOften a mixture of noncomedo patterns.bSolid, cribriform, papillary, or focal micropapillary.Adapted with permission from Koo JS, Kim MJ, Kim EK, et al: Comparison of immunohistochemical staining in breast papillary neoplasms of cytokeratin 5/6 and p63 in core needle biopsies and surgical excisions, Appl Immunohistochem Mol Morphol. 2012 Mar;20(2):108-115.a landmark description of LCIS, which distinguished it from DCIS.130 In the late 1960s, Gallagher and Martin published their study of whole-breast sections and described a stepwise progres-sion from benign breast tissue to in situ cancer and subsequently to invasive cancer. Before the widespread use of mammography, diagnosis of breast cancer was by physical examination. At that time, in situ cancers constituted <6% of all breast cancers, and LCIS was more frequently diagnosed than DCIS by a ratio of >2:1. However, when screening mammography became popular, a 14-fold increase in the incidence of in situ cancer (45%) was demonstrated, and DCIS was more frequently diagnosed than LCIS by a ratio of >2:1. Table 17-8 lists the clinical and patho-logic characteristics of DCIS and LCIS. Multicentricity refers to the occurrence of a second breast cancer outside the breast quadrant of the primary cancer (or at least 4 cm away), whereas multifocality refers to the occurrence of a second cancer within the same breast quadrant as the primary cancer (or within 4 cm of it). Multicentricity occurs in 60% to 90% of women with LCIS, whereas the rate of multicentricity for DCIS is reported to be 40% to 80%. LCIS occurs bilaterally in 50% to 70% of cases, whereas DCIS occurs bilaterally in 10% to 20% of cases.Lobular Carcinoma In Situ. LCIS originates from the termi-nal duct lobular units and develops only in the female breast. It is characterized by distention and distortion of the terminal duct lobular units by cells that are large but maintain a normal nuclear to cytoplasmic ratio. Cytoplasmic mucoid globules are a distinctive cellular feature. LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications associated with LCIS typically occur in adjacent tissues. This neighborhood calcification is a feature that is unique to LCIS and contributes to its diagnosis. The frequency of LCIS in the general population cannot be reliably determined because it usu-ally presents as an incidental finding. The average age at diag-nosis is 45 years, which is approximately 15 to 25 years younger than the age at diagnosis for invasive breast cancer. LCIS has a distinct racial predilection, occurring 12 times more frequently in white women than in African-American women. Invasive breast cancer develops in 25% to 35% of women with LCIS. Invasive cancer may develop in either breast, regardless of which breast harbored the initial focus of LCIS, and is detected synchronously with LCIS in 5% of cases. In women with a his-tory of LCIS, up to 65% of subsequent invasive cancers are duc-tal, not lobular, in origin. For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer rather than as an anatomic precursor. Individuals should be counseled regarding their risk of developing breast cancer and appropriate risk reduction strategies, including observation with screening, chemoprevention, and risk-reducing bilateral mastectomy.Ductal Carcinoma In Situ. Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast cancers. Published series suggest a detection frequency of 7% in all biopsy tissue specimens. The term intraductal carcinoma is frequently applied to DCIS, which carries a high risk for progres-sion to an invasive cancer. Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which leads to difficulty in distinguishing early DCIS from benign hyperplasia. The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show hyperchroma-sia and loss of polarity (cribriform growth pattern). Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend the ducts (solid growth pattern). With continued growth, these cells outstrip their blood supply and become necrotic (comedo growth pattern). Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 17-9). Based Brunicardi_Ch17_p0541-p0612.indd 56401/03/19 5:04 PM 565THE BREASTCHAPTER 17on multiple consensus meetings, grading of DCIS has been rec-ommended. Although there is no universal agreement on clas-sification, most systems endorse the use of cytologic grade and presence or absence of necrosis.131The risk for invasive breast cancer is increased nearly fivefold in women with DCIS.132 The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of invasive ductal carcinoma (Fig. 17-15A and B).Invasive Breast CarcinomaInvasive breast cancers have been described as lobular or duc-tal in origin.128-131 Early classifications used the term lobular to describe invasive cancers that were associated with LCIS, whereas all other invasive cancers were referred to as ductal. Current histologic classifications recognize special types of breast cancers (10% of total cases), which are defined by spe-cific histologic features. To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic features. About 80% of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These can-cers generally have a worse prognosis than special-type cancers. Foote and Stewart originally proposed the following classifica-tion for invasive breast cancer130:1. Paget’s disease of the nipple2. Invasive ductal carcinoma—Adenocarcinoma with produc-tive fibrosis (scirrhous, simplex, NST), 80%3. Medullary carcinoma, 4%4. Mucinous (colloid) carcinoma, 2%5. Papillary carcinoma, 2%6. Tubular carcinoma, 2%7. Invasive lobular carcinoma, 10%8. Rare cancers (adenoid cystic, squamous cell, apocrine)Paget’s disease of the nipple was described in 1874. It fre-quently presents as a chronic, eczematous eruption of the nipple, which may be subtle but may progress to an ulcerated, weeping lesion. Paget’s disease usually is associated with extensive DCIS and may be associated with an invasive cancer. A palpable mass may or may not be present. A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium. Paget’s disease may be confused with superficial spreading melanoma. Differ-entiation from pagetoid intraepithelial melanoma is based on the presence of S-100 antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget’s disease. Surgical therapy for Paget’s disease may involve lumpectomy or mastectomy, depending on the extent of involvement of the nipple-areolar complex and the presence of DCIS or invasive cancer in the underlying breast parenchyma.Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 25% of screen-detected cases and up to 60% of symptomatic cases. This cancer occurs most frequently in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. It has poorly defined margins, and its cut surfaces show a central stellate con-figuration with chalky white or yellow streaks extending into surrounding breast tissues. The cancer cells often are arranged in small clusters, and there is a broad spectrum of histologic types with variable cellular and nuclear grades (Fig. 17-16A and B). In a large patient series from the SEER database, 75% of ductal cancers showed estrogen receptor expression.133Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all invasive breast cancers and is a fre-quent phenotype of BRCA1 hereditary breast cancer. Grossly, the cancer is soft and hemorrhagic. A rapid increase in size may occur secondary to necrosis and hemorrhage. On physi-cal examination, it is bulky and often positioned deep within the breast. Bilaterality is reported in 20% of cases. Medullary carcinoma is characterized microscopically by: (a) a dense lym-phoreticular infiltrate composed predominantly of lymphocytes and plasma cells; (b) large pleomorphic nuclei that are poorly ABFigure 17-15. Ductal carcinoma in situ (DCIS). A. Craniocau-dal mammographic view shows a poorly defined mass containing microcalcifications. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.) B. Histopathologic preparation of the sur-gical specimen confirms DCIS with necrosis (100x). (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 56501/03/19 5:04 PM 566SPECIFIC CONSIDERATIONSPART IIABFigure 17-16. Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) A. 100x. B. 200x. (Used with permis-sion from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)Figure 17-17. Lobular carcinoma (100×). Uniform, relatively small lobular carcinoma cells are seen arranged in a single-file orientation (“Indian file”). (Used with permission from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consul-tant Histopathologist and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)differentiated and show active mitosis; and (c) a sheet-like growth pattern with minimal or absent ductal or alveolar dif-ferentiation. Approximately 50% of these cancers are associated with DCIS, which characteristically is present at the periphery of the cancer, and <10% demonstrate hormone receptors. In rare circumstances, mesenchymal metaplasia or anaplasia is noted. Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging. Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma.Mucinous carcinoma (colloid carcinoma), another spe-cial-type breast cancer, accounts for 2% of all invasive breast cancers and typically presents in the older population as a bulky tumor. This cancer is defined by extracellular pools of mucin, which surround aggregates of low-grade cancer cells. The cut surface of this cancer is glistening and gelatinous in quality. Fibrosis is variable, and when abundant it imparts a firm consis-tency to the cancer. Over 90% of mucinous carcinomas display hormone receptors.133 Lymph node metastases occur in 33% of cases, and 5and 10-year survival rates are 73% and 59%, respectively. Because of the mucinous component, cancer cells may not be evident in all microscopic sections, and analysis of multiple sections is essential to confirm the diagnosis of a mucinous carcinoma.Papillary carcinoma is a special-type cancer of the breast that accounts for 2% of all invasive breast cancers. It generally presents in the seventh decade of life and occurs in a dispropor-tionate number of nonwhite women. Typically, papillary car-cinomas are small and rarely attain a size of 3 cm in diameter. These cancers are defined by papillae with fibrovascular stalks and multilayered epithelium. In a large series from the SEER database 87% of papillary cancers have been reported to express estrogen receptor.133 McDivitt and colleagues noted that these tumors showed a low frequency of axillary lymph node metas-tases and had 5and 10-year survival rates similar to those for mucinous and tubular carcinoma.134Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammographic screening and usually is diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. In a large SEER database 94% of tubular cancers were reported to express estrogen receptor.133 Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will develop axillary lymph node metastases. However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%.Invasive lobular carcinoma accounts for 10% of breast cancers. The histopathologic features of this cancer include small cells with rounded nuclei, inconspicuous nucleoli, and scant cytoplasm (Fig. 17-17). Special stains may confirm the Brunicardi_Ch17_p0541-p0612.indd 56601/03/19 5:04 PM 567THE BREASTCHAPTER 17presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). At presentation, invasive lobular carcinoma varies from clinically inapparent carcinomas to those that replace the entire breast with a poorly defined mass. It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic fea-tures, invasive lobular carcinoma may be difficult to detect. Over 90% of lobular cancers express estrogen receptor.133DIAGNOSIS OF BREAST CANCERIn ∼30% of cases, the woman discovers a lump in her breast. Other less frequent presenting signs and symptoms of breast cancer include: (a) breast enlargement or asymmetry; (b) nipple changes, retraction, or discharge; (c) ulceration or erythema of the skin of the breast; (d) an axillary mass; and (e) musculoskel-etal discomfort. However, up to 50% of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease.Misdiagnosed breast cancer accounts for the greatest num-ber of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and mammogram may be misleading. If a young woman (≤45 years) presents with a palpable breast mass and equivocal mammographic findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis.ExaminationInspection. The clinician inspects the woman’s breast with her arms by her side (Fig. 17-18A), with her arms straight up in the air (Fig. 17-18B), and with her hands on her hips (with and without pectoral muscle contraction).135,136 Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d’orange), nipple or skin retraction, or erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.Figure 17-18. Examination of the breast. A. Inspection of the breast with arms at sides. B. Inspection of the breast with arms raised. C. Palpation of the breast with the patient supine. D. Palpa-tion of the axilla.Palpation. As part of the physical examination, the breast is carefully palpated. With the patient in the supine position (see Fig. 17-18C) the clinician gently palpates the breasts, making certain to examine all quadrants of the breast from the sternum laterally to the latissimus dorsi muscle and from the clavicle inferiorly to the upper rectus sheath. The examination is per-formed with the palmar aspects of the fingers, avoiding a grasp-ing or pinching motion. The breast may be cupped or molded in the examiner’s hands to check for retraction. A systematic search for lymphadenopathy then is performed. Figure 17-18D shows the position of the patient for examination of the axilla. By supporting the upper arm and elbow, the examiner stabi-lizes the shoulder girdle. Using gentle palpation, the clinician assesses all three levels of possible axillary lymphadenopathy. Careful palpation of supraclavicular and parasternal sites also is performed. A diagram of the chest and contiguous lymph node sites is useful for recording location, size, consistency, shape, mobility, fixation, and other characteristics of any palpable breast mass or lymphadenopathy (Fig. 17-19).Imaging TechniquesMammography. Mammography has been used in North Amer-ica since the 1960s, and the techniques used continue to be mod-ified and improved to enhance image quality.137-140 Conventional mammography delivers a radiation dose of 0.1 cGy per study. By comparison, chest radiography delivers 25% of this dose. However, there is no increased breast cancer risk associated with the radiation dose delivered with screening mammography. Screening mammography is used to detect unexpected breast cancer in asymptomatic women. In this regard, it supplements history taking and physical examination. With screening mam-mography, two views of the breast are obtained: the craniocau-dal (CC) view (Fig. 17-20A,B) and the mediolateral oblique (MLO) view (Fig. 17-20C,D). The MLO view images the great-est volume of breast tissue, including the upper outer quadrant and the axillary tail of Spence. Compared with the MLO view, the CC view provides better visualization of the medial aspect of the breast and permits greater breast compression. Diagnos-tic mammography is used to evaluate women with abnormal Figure 17-19. A breast examination record. Brunicardi_Ch17_p0541-p0612.indd 56701/03/19 5:04 PM 568SPECIFIC CONSIDERATIONSPART IIABCDFigure 17-20. A-D. Mammogram of a premenopausal breast with a dense fibroglandular pattern. E-H. Mammogram of a postmenopausal breast with a sparse fibroglandular pattern. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 56801/03/19 5:04 PM 569THE BREASTCHAPTER 17EFGHFigure 17-20. (Continued)findings such as a breast mass or nipple discharge. In addition to the MLO and CC views, a diagnostic examination may use views that better define the nature of any abnormalities, such as the 90° lateral and spot compression views. The 90° lateral view is used along with the CC view to triangulate the exact location of an abnormality. Spot compression may be done in any pro-jection by using a small compression device, which is placed directly over a mammographic abnormality that is obscured by overlying tissues (Fig. 17-21C). The compression device mini-mizes motion artifact, improves definition, separates overlying tissues, and decreases the radiation dose needed to penetrate the breast. Magnification techniques (×1.5) often are combined with spot compression to better resolve calcifications and the margins of masses. Mammography also is used to guide inter-ventional procedures, including needle localization and needle biopsy.Brunicardi_Ch17_p0541-p0612.indd 56901/03/19 5:04 PM 570SPECIFIC CONSIDERATIONSPART IIABCFigure 17-21. Mammogram revealing a small, spiculated mass in the right breast A. A small, spiculated mass is seen in the right breast with skin tethering (CC view). B. Mass seen on oblique view of the right breast. C. Spot compression mammography view of the cancer seen in A and B. The spiculated margins of the cancer are accentuated by compression. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Specific mammographic features that suggest a diagnosis of breast cancer include a solid mass with or without stellate features, asymmetric thickening of breast tissues, and clustered microcalcifications. The presence of fine, stippled calcium in and around a suspicious lesion is suggestive of breast cancer and occurs in as many as 50% of nonpalpable cancers. These microcalcifications are an especially important sign of cancer in younger women, in whom it may be the only mammographic abnormality. The clinical impetus for screening mammogra-phy came from the Health Insurance Plan study and the Breast Cancer Detection Demonstration Project, which demonstrated a 33% reduction in mortality for women after72 screening mam-mography. Mammography was more accurate than clinical examination for the detection of early breast cancers, providing a true-positive rate of 90%. Only 20% of women with nonpal-pable cancers had axillary lymph node metastases, compared with 50% of women with palpable cancers.141 Current guide-lines of the National Comprehensive Cancer Network suggest that normal-risk women ≥20 years of age should have a breast examination at least every 3 years. Starting at age 40 years, breast examinations should be performed yearly, and a yearly mammogram should be taken.142 Screening mammography in women ≥50 years of age has been noted to reduce breast cancer mortality by 20% to 25%.72,79 With the increased discussion about the potential harms associated with breast screening, the United Kingdom recently established an independent expert panel to review the published literature and estimate the ben-efits and harms associated with its national screening program for women age >50 years. The panel estimated that in women invited to screening, about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis. Despite this overdiagno-sis, the panel concluded that breast screening programs confer significant benefit and should continue. The use of screening mammography in women <50 years of age is more controversial for previously noted reasons: (a) reduced sensitivity, (b) reduced specificity, and (c) lower incidence of breast cancer. Because of the combination of these three reasons, targeting mammography screening to women <50 years of age, who are at higher risk of breast cancer, improves the balance of risks and benefits and is the approach some health care systems have taken. There are now a number of risk assessment models—as described earlier in this chapter—that can be used to estimate a younger woman’s risk of developing breast cancer and that help assess the risks and benefits of regular screening.Screen film mammography has replaced xeromam-mography because it requires a lower dose of radiation and provides similar image quality. Digital mammography was developed to allow the observer to manipulate the degree of contrast in the image. This is especially useful in women with dense breasts and women <50 years of age. Recently, investigators directly compared digital vs. screen film mam-mography in a prospective (DMIST) trial that enrolled over 42,000 women.143 The investigators found that digital and screen film mammography had similar accuracy; however, digital mammography was more accurate in women <50 years of age, women with mammographically dense breasts, and premenopausal or perimenopausal women. The use of digital breast tomosynthesis with 3D images has been introduced as an alternative to standard 2D mammography imaging that is limited by superimposition of breast parenchyma and breast density.144,145 The STORM trial reported that in 7,292 women screened, 3D mammography had a higher cancer detection rate and fewer false-positive recalls than the standard 2D imaging.146,147 Randomized controlled trials are planned to fur-ther study tomosynthesis and its role in breast cancer screen-ing. Standard two-dimensional mammography has limitations, Brunicardi_Ch17_p0541-p0612.indd 57001/03/19 5:04 PM 571THE BREASTCHAPTER 17such as the parenchymal density or superimposition of breast tissue, which obscures cancers or causes normal structures to appear suspicious reducing the sensitivity of mammography and increasing the false-positive rates. Digital breast tomo-synthesis is a technology developed to assist with overcom-ing these limitations. In digital breast tomosynthesis, multiple projection images are reconstructed to allow visual review of thin breast sections, each reconstructed slice as thin as 0.5 mm, which provides better characterization of noncalcified lesions. These multiple projection exposures are obtained by a digi-tal detector from a mammography X-ray source that moves through a limited arc angle while the breast is compressed. Then these projection image data sets are reconstructed using specific algorithms, which provide the clinical reader a series of images through the entire breast.148In 2011, tomosynthesis was approved by the U.S. Food and Drug Administration (FDA) to be used in combination with standard digital mammography for breast cancer screening. The total radiation dose when tomosynthesis is added is about twice the current dose of digital mammography alone but remains below the limits set by the FDA.149The STORM-2 trial reported that synthetic 2D-3D mammography yields similar breast cancer detection as dual-acquisition 2D-3D mammography with the advantage of reduc-ing radiation exposure.150Contrast-enhanced digital mammography (CEDM) was also approved by the FDA in 2001, which utilizes an iodinated contrast material and modified digital mammography units for imaging.148 CEDM has been shown to be feasible and detects breast cancers at a rate similar to MRI, which has potential to offer an alternative to MRI.151 The advantages of CEDM over MRI are that the use of compression limits motion, there is decrease in cost, decrease in exam time, and there is an option for patients who are unable to tolerate MRI or who due to vari-ous reasons cannot have MRI due to incompatibility, such as the presence of a pacemaker or tissue expanders.148,152Ductography. The primary indication for ductography is nipple discharge, particularly when the fluid contains blood. Radiopaque contrast media is injected into one or more of the major ducts, and mammography is performed. A duct is gen-tly enlarged with a dilator, and then a small, blunt cannula is inserted under sterile conditions into the nipple ampulla. With the patient in a supine position, 0.1 to 0.2 mL of dilute con-trast media is injected, and CC and MLO mammographic views are obtained without compression. Intraductal papillomas are seen as small filling defects surrounded by contrast media (Fig. 17-22). Cancers may appear as irregular masses or as mul-tiple intraluminal filling defects.Ultrasonography. Second only to mammography in fre-quency of use for breast imaging, ultrasonography is an impor-tant method of resolving equivocal mammographic findings, defining cystic masses, and demonstrating the echogenic qual-ities of specific solid abnormalities. On ultrasound examina-tion, breast cysts are well circumscribed, with smooth margins and an echo-free center (Fig. 17-23). Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior mar-gins (Fig. 17-24). Breast cancer characteristically has irregular walls (Fig. 17-25) but may have smooth margins with acous-tic enhancement. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization ABFigure 17-22. Ductogram. Craniocaudal (A) and mediolateral oblique (B) mammographic views demonstrate a mass (arrows) posterior to the nipple and outlined by contrast, which also fills the proximal ductal structures. (Used with permission from B. Steinbach.)of breast lesions. Its findings are highly reproducible, and it has a high patient acceptance rate, but it does not reliably detect lesions that are ≤1 cm in diameter. Ultrasonography can also be utilized to image the regional lymph nodes in patients with breast cancer (Fig. 17-26). The sensitivity of examination for the status of axillary nodes ranges from 35% to 82% and specificity ranges from 73% to 97%. The features of a lymph node involved with cancer include cortical thickening, change in shape of the node to more circular appearance, size larger Brunicardi_Ch17_p0541-p0612.indd 57101/03/19 5:05 PM 572SPECIFIC CONSIDERATIONSPART IIABFigure 17-24. Ultrasonography images of benign breast tumors. A. Fibroadenoma. B. Intraductal papilloma (see arrow). (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)ABCFigure 17-23. Breast cyst. A. Simple cyst. Ultrasound image of the mass shows it to be anechoic with a well-defined back wall, characteristic of a cyst. B. Complex solid and cystic mass. C. Complex solid and cystic mass characteristic of intracystic papillary tumor. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)than 10 mm, absence of a fatty hilum and hypoechoic internal echoes.153Magnetic Resonance Imaging. In the process of evaluating magnetic resonance imaging (MRI) as a means of character-izing mammographic abnormalities, additional breast lesions have been detected. However, in the circumstance of negative findings on both mammography and physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in the use of MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women who have a strong family history of breast cancer or who carry known genetic mutations require screening at an early age because mammographic evaluation is limited due to the increased breast density in younger women. In the second case, an MRI study of the contralateral breast in women with a known breast cancer has shown a contralateral breast cancer in 5.7% of these women (Fig. 17-27). MRI can also detect additional tumors in the index breast (multifocal or multicen-tric disease) that may be missed on routine breast imaging and this may alter surgical decision making (Fig. 17-28). In fact, MRI has been advocated by some for routine use in surgical treatment planning based on the fact that additional disease can be identified with this advanced imaging modality and the Brunicardi_Ch17_p0541-p0612.indd 57201/03/19 5:05 PM 573THE BREASTCHAPTER 17Figure 17-25. Ultrasonography images of malignant breast lesions. A. 25 mm irregular mass. B. Ultrasound 30 mm mass anterior to an implant. C. Ultrasound breast cancer with calcification. D. Ultrasound shows a 9 mm spiculated mass (see arrow) with attenuation. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)extent of disease may be more accurately assessed. A random-ized trial performed in the United Kingdom (COMICE trial) that enrolled 1623 women did not show a decrease in rates of reoperation in those women randomized to undergo MRI in addition to mammography and ultrasonography (19%) com-pared to those undergoing standard breast imaging without MRI (19%).154 Houssami and colleagues performed a meta-analysis including two randomized trials and seven compara-tive cohort studies to examine the effect of preoperative MRI compared to standard preoperative evaluation on surgical out-comes.155 They reported that the use of MRI was associated with increased mastectomy rates. This is problematic because there is no evidence that the additional disease detected by MRI is of clinical or biologic significance, particularly in light of the low local-regional failure rates currently reported in patients undergoing breast conserving surgery who receive whole breast irradiation and systemic therapies. There is an ongoing trial in the Alliance for Clinical Trials in Oncology that is randomizing patients to preoperative MRI vs. standard imaging to assess the impact of MRI on local regional recur-rence rates in patients with triple receptor negative and HER2 positive breast cancers.The use of dedicated breast coils is mandatory in the MRI imaging of the breast. A BIRADS lexicon is assigned to each examination and an abnormality noted on MRI that is not seen on mammography requires a focused ultrasound examination for further assessment. If the abnormality is not seen on corre-sponding mammogram or ultrasound, then MRI-guided biopsy is necessary. Some clinical scenarios where MRI may be use-ful include the evaluation of a patient who presents with nodal metastasis from breast cancer without an identifiable primary tumor; to assess response to therapy in the setting of neoadjuvant ABCDBrunicardi_Ch17_p0541-p0612.indd 57301/03/19 5:05 PM 574SPECIFIC CONSIDERATIONSPART IIFigure 17-26. Ultrasonography images of lymph nodes. A. Nor-mal axillary lymph node (see arrows). B. Indeterminate axillary lymph node. C. Malignant appearing axillary lymph node. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)ABCsystemic treatment; to select patients for partial breast irradia-tion techniques; and evaluation of the treated breast for tumor recurrence.Breast BiopsyNonpalpable Lesions. Image-guided breast biopsy specimens are frequently required to diagnose nonpalpable lesions.156 Ultrasound localization techniques are used when a mass is present, whereas stereotactic techniques are used when no mass is present (microcalcifications or architectural distortion only). The combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-needle aspiration (FNA) biopsy achieves almost 100% accuracy in the preoperative diag-nosis of breast cancer. However, although FNA biopsy permits cytologic evaluation, core-needle permits the analysis of breast tissue architecture and allows the pathologist to determine whether invasive cancer is present. This permits the surgeon and patient to discuss the specific management of a breast cancer before therapy begins. Core-needle biopsy is preferred over open biopsy for nonpalpable breast lesions because a single sur-gical procedure can be planned based on the results of the core biopsy. The advantages of core-needle biopsy include a low complication rate, minimal scarring, and a lower cost compared with excisional breast biopsy.Palpable Lesions. FNA or core biopsy of a palpable breast mass can usually be performed in an outpatient setting.157 A 1.5-in, 22-gauge needle attached to a 10-mL syringe or a 14-gauge core biopsy needle is used. For FNA, use of a syringe holder 7Figure 17-27. MRI examination revealing contralateral breast cancer (see arrows) in a patient diag-nosed with unilateral breast cancer on mammography (two arrows). (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 57401/03/19 5:05 PM 575THE BREASTCHAPTER 17enables the surgeon performing the FNA biopsy to control the syringe and needle with one hand while positioning the breast mass with the opposite hand. After the needle is placed in the mass, suction is applied while the needle is moved back and forth within the mass. Once cellular material is seen at the hub of the needle, the suction is released and the needle is with-drawn. The cellular material is then expressed onto microscope slides. Both air-dried and 95% ethanol–fixed microscopic sec-tions are prepared for analysis. When a breast mass is clinically and mammographically suspicious, the sensitivity and specific-ity of FNA biopsy approaches 100%. Core-needle biopsy of palpable breast masses is performed using a 14-gauge needle, such as the Tru-Cut needle. Automated devices also are avail-able. Vacuum-assisted core biopsy devices (with 8–10 gauge needles) are commonly utilized with image guidance where between 4 and 12 samples can be acquired at different posi-tions within a mass, area of architectural distortion or micro-calcifications. If the target lesion was microcalcifications, the specimen should be radiographed to confirm appropriate sam-pling. A radiopaque marker should be placed at the site of the biopsy to mark the area for future intervention. In some cases the entire lesion is removed with the biopsy technique and clip placement allows for accurate targeting of the site for surgi-cal resection. Tissue specimens are placed in formalin and then processed to paraffin blocks. Although the false-negative rate for core-needle biopsy specimens is very low, a tissue speci-men that does not show breast cancer cannot conclusively rule out that diagnosis because a sampling error may have occurred. The clinical, radiographic, and pathologic findings should be in concordance. If the biopsy findings do not concur with the clinical and radiographic findings, the multidisciplinary team (including clinician, radiologist, and pathologist) should review the findings and decide whether or not to recommend an image-guided or open biopsy to be certain that the target lesion has been adequately sampled for diagnosis.BREAST CANCER STAGING AND BIOMARKERSBreast Cancer StagingThe clinical stage of breast cancer is determined primarily through physical examination of the skin, breast tissue, and regional lymph nodes (axillary, supraclavicular, and internal mammary).158 However, clinical determination of axillary lymph node metastases has an accuracy of only 33%. Ultrasound (US) is more sensitive than physical examination alone in determining axillary lymph node involvement during preliminary staging of breast carcinoma. FNA or core biopsy of sonographically inde-terminate or suspicious lymph nodes can provide a more defini-tive diagnosis than US alone.153,159 Pathologic stage combines the findings from pathologic examination of the resected pri-mary breast cancer and axillary or other regional lymph nodes. Fisher and colleagues found that accurate predictions regarding the occurrence of distant metastases were possible after resec-tion and pathologic analysis of 10 or more levels I and II axillary lymph nodes.160 A frequently used staging system is the TNM (tumor, nodes, and metastasis) system. The American Joint Committee on Cancer (AJCC) has recently modified the TNM system for breast cancer to include both anatomic and biologic factors161 (Tables 17-10 and 17-11). Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary lymph node metastases (see Fig. 17-14B). Others have shown an association between tumor size, axillary lymph node metastases, and disease-free survival. One of the most important predictors of 10and 20-year survival rates in breast cancer is the number of axillary lymph nodes involved with metastatic disease. Routine biopsy of internal mammary lymph nodes is not generally performed; however, it has been reported that in the context of a “triple node” biopsy approach either the internal mammary node or a low axillary node when positive alone carried the same prognostic weight. When both nodes were positive, the prognosis declined to the level associated with apical node positivity. A double node biopsy of the low axil-lary node and either the apical or the internal mammary node gave the same maximum prognostic information as a triple node biopsy.162 With the advent of sentinel lymph node dissection and the use of preoperative lymphoscintigraphy for localization of the sentinel nodes, surgeons have again begun to biopsy the internal mammary nodes but in a more targeted manner. The 8th edition of the AJCC staging system does allow for staging based on findings from the internal mammary sentinel nodes.163 Drainage to the internal mammary nodes is more frequent with central and medial quadrant cancers. Clinical or pathologic evi-dence of metastatic spread to supraclavicular lymph nodes is no longer considered stage IV disease, but routine scalene or supraclavicular lymph node biopsy is not indicated.BiomarkersBreast cancer biomarkers are of several types. Risk factor biomarkers are those associated with increased cancer risk.164-168 These include familial clustering and inherited germline abnormalities, proliferative breast disease with atypia, and mammographic density. Exposure biomarkers are a subset of risk factors that include measures of carcinogen exposure such as DNA adducts. Surrogate endpoint biomarkers are biologic alterations in tissue that occur between cancer initiation and development. These biomarkers are used as endpoints in short-term chemoprevention trials and include histologic changes, indices of proliferation, and genetic alterations leading to cancer. Prognostic biomarkers provide information regarding Figure 17-28. MRI imaging of the breast reveal-ing multifocal tumors not detected with standard breast imaging. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Brunicardi_Ch17_p0541-p0612.indd 57501/03/19 5:05 PM 576SPECIFIC CONSIDERATIONSPART IITable 17-10TNM staging system for breast cancerPrimary tumor (T)The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p” modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size.TXT0Tis (DCIS)*Tis (Paget)T1 T1mi T1a T1b T1cT2T3T4 T4a T4b T4c T4dPrimary tumor cannot be assessedNo evidence of primary tumorDuctal carcinoma in situPaget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.Tumor ≤20 mm in greatest dimensionTumor ≤1 mm in greatest dimensionTumor >1 mm but ≤5 mm in greatest dimension (round any measurement >l.0–1.9 mm to 2 mm).Tumor >5 mim but ≤10 mm in greatest dimensionTumor >10 mm but ≤20 mm in greatest dimensionTumor >20 mm but ≤50 mm in greatest dimensionTumor >50 mm in greatest dimensionTumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinomaBoth T4a and T4b are presentInflammatory carcinoma (see section “Rules for Classification”)*Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th edition.Regional lymph nodes—Clinical (N)cNX*cN0cN1 cN1mi**cN2 cN2a cN2bcN3 cN3a cN3b cN3cRegional lymph nodes cannot be assessed (e.g., previously removed)No regional lymph node metastases (by imaging or clinical examination)Metastases to movable ipsilateral Level I, II axillary lymph node(s)Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastasesMetastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structuresMetastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastasesMetastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement;or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases;or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvementMetastases in ipsilateral infraclavicular lymph node(s)Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)Metastases in ipsilateral supraclavicular lymph node(s)Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy respectively.*the cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.**cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.(Continued)Brunicardi_Ch17_p0541-p0612.indd 57601/03/19 5:05 PM 577THE BREASTCHAPTER 17Table 17-10TNM staging system for breast cancerRegional lymph nodes—Pathologic (pN)pNXpN0 pN0(i+) pN0(mol+)pN1 pN1mi pN1a pN1b pN1cRegional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)No regional lymph node metastasis identified or ITCs onlyITCs only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s)Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detectedMicrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsyMicrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)Metastases in 1–3 axillary lymph nodes, at least one metastasis larger than 2.0 mmMetastases in ipsilateral internal mammary sentinel nodes, excluding ITCspN1a and pNlb combinedpN2 pN2a pN2bpN3 pN3a pN3b pN3cMetastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastasesMetastases in 4–9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodesMetastases in 10 or more axillary lymph nodes;or in infraclavicular (Level III axillary) lymph nodes;or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level I, II axillary lymph nodes; or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodesMetastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (Level III axillary lymph) nodespNla or pN2a in the presence of cN2b (positive internal mammary nodes by imaging); or pN2a in the presence of pNlbMetastases in ipsilateral supraclavicular lymph nodesNote: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy respectively, with NO further resection of nodes.Distant metastasis (M)M0 cM0(i+)cM1pM1No clinical or radiographic evidence of distant metastases*No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastasesDistant metastases detected by clinical and radiographic meansAny histologically proven metastases in distant organs; or if in non-regional nodes, metastases greater than 0.2 mmUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.(Continued)cancer outcome irrespective of therapy, whereas predictive bio-markers provide information regarding response to therapy.169 Candidate prognostic and predictive biomarkers and biologic targets for breast cancer include (a) the steroid hormone recep-tor pathway; (b) growth factors and growth factor receptors such as human epidermal growth factor receptor 2 (HER2)/neu, epidermal growth factor receptor (EGFR), transforming growth factor, platelet-derived growth factor, and the insulin-like growth factor family; (c) indices of proliferation such as proliferating cell nuclear antigen (PCNA) and Ki-67; (d) indi-ces of angiogenesis such as vascular endothelial growth factor (VEGF) and the angiogenesis index; (e) the mammalian target of rapamycin (mTOR) signaling pathway; (f) tumor-suppressor genes such as p53; (g) the cell cycle, cyclins, and cyclin-depen-dent kinases; (h) the proteasome; (i) the COX-2 enzyme; (j) the peroxisome proliferator-activated receptors (PPARs); and (k) indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio.Steroid Hormone Receptor Pathway. Hormones play an important role in the development and progression of breast cancer. Estrogens, estrogen metabolites, and other steroid hor-mones such as progesterone all have been shown to have an effect. Breast cancer risk is related to estrogen exposure over time. In postmenopausal women, hormone replacement therapy consisting of estrogen plus progesterone increases the risk of breast cancer by 26% compared to placebo.70 Patients with hor-mone receptor-positive tumors survive two to three times longer after a diagnosis of metastatic disease than do patients with hor-mone receptor-negative tumors. Patients with tumors negative for both estrogen receptors and progesterone receptors are not considered candidates for hormonal therapy. Tumors positive Brunicardi_Ch17_p0541-p0612.indd 57701/03/19 5:05 PM 578SPECIFIC CONSIDERATIONSPART IITable 17-11TNM stage groupingsWhen T is...And N is...And M is...Then the stage group is...TisN0M00T1N0M0IAT0N1miM0IBT1N1miM0IBT0N1M0IIAT1N1M0IIAT2N0M0IIAT2N1M0IIBT3N0M0IIBT0N2M0IIIAT1N2M0IIIAT2N2M0IIIAT3N1M0IIIAT3N2M0IIIAT4N0M0IIIBT4N1M0IIIBT4N2M0IIIBAny TN3M0IIICAny TAny NM1IVNotes:1. T1 includes Tl mi.2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.4. M0 includes M0(i+).5. The designation pM0 is not valid; any M0 is clinical.6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are per-formed within 4 months of diagnosis in the absence of disease progres-sion, and provided the patient has not received neoadjuvant therapy.8. Staging following neoadjuvant therapy is denoted with a “yc” or “yp” prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoad-juvant therapy, for example, ypT0ypN0cM0.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.for estrogen or progesterone receptors have a higher response rate to endocrine therapy than tumors that do not express estro-gen or progesterone receptors. The determination of estrogen and progesterone receptor status used to require biochemical evaluation of fresh tumor tissue. Today, however, estrogen and progesterone receptor status can be measured in archived tis-sue using immunohistochemical techniques. Hormone receptor status also can be measured in specimens obtained with fine-needle aspiration biopsy or core-needle biopsy, and this can help guide treatment planning. Testing for estrogen and progesterone receptors should be performed on all primary invasive breast cancer specimens. The tumor hormone receptor status should be ascertained for both premenopausal and postmenopausal patients to identify patients who are most likely to benefit from endocrine therapy.Growth Factor Receptors and Growth Factors. Overexpres-sion of EGFR in breast cancer correlates with estrogen recep-tor–negative status and with p53 overexpression.170-172 Similarly, increased immunohistochemical membrane staining for the HER2 growth factor receptor in breast cancer is associated with mutated TP53, Ki67 overexpression, and estrogen receptor–negative status. HER2 is a member of the ErbB family of growth factor receptors in which ligand binding results in recep-tor homodimerization and tyrosine phosphorylation by tyrosine kinase domains within the receptor. Tyrosine phosphorylation is followed by signal transduction, which results in changes in cell behavior. An important property of this family of receptors is that ligand binding to one receptor type also may result in heterodimerization between two different receptor types that are coexpressed; this leads to transphosphorylation and transactiva-tion of both receptors in the complex (transmodulation). In this context, the lack of a specific ligand for the HER2/neu receptor suggests that HER2/neu may function solely as a co-receptor, modulating signaling by other EGFR family members. HER2/neu is both an important prognostic factor and a predictive fac-tor in breast cancer.173 When overexpressed in breast cancer, HER2/neu promotes enhanced growth and proliferation, and increases invasive and metastatic capabilities. Clinical studies have shown that patients with HER2/neu–overexpressing breast cancer have poorly differentiated tumors with high prolifera-tion rates, positive lymph nodes, decreased hormone receptor expression, and an increased risk of recurrence and death due to breast cancer.173-177 Routine testing of the primary tumor specimen for HER2/neu expression should be performed on all invasive breast cancers. This can be done with immunohis-tochemical analysis to evaluate for overexpression of the cell-surface receptor at the protein level or by using fluorescence in situ hybridization to evaluate for gene amplification. While HER2/ERBB2 activation can also be assessed based on mRNA expression and reverse transcription polymerase chain reaction (RT-PCR) (Oncotype Dx, Genomic Health), this approach is not recommended for clinical decision-making because of the high false negative rate.178 Patients whose tumors show HER2 ampli-fication or HER2/neu protein overexpression are candidates for anti-HER2/neu therapy. Trastuzumab (Herceptin) is a recombi-nant humanized monoclonal antibody directed against HER2. Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is well tolerated and active in the treatment of women with HER2/neu–overexpressing metastatic breast cancer.179 Subsequent adjuvant trials demonstrated that trastu-zumab also was highly effective in the treatment of women with early-stage breast cancer when used in combination with che-motherapy.180-182 Patients who received trastuzumab in combina-tion with chemotherapy had between a 40% and 50% reduction in the risk of breast cancer recurrence and approximately a one-third reduction in breast cancer mortality compared with those who received chemotherapy alone.181,183-185Indices of Proliferation. PCNA is a nuclear protein asso-ciated with a DNA polymerase whose expression increases in phase G1 of the cell cycle, reaches its maximum at the G1/S inter-face, and then decreases through G2.186-189 Immunohistochemical staining for PCNA outlines the proliferating compartments in Brunicardi_Ch17_p0541-p0612.indd 57801/03/19 5:05 PM 579THE BREASTCHAPTER 17breast tissue. Good correlation is noted between PCNA expres-sion and (a) cell-cycle distributions seen on flow cytometry based on DNA content, and (b) uptake of bromodeoxyuridine and the proliferation-associated Ki67 antigen. Individual prolif-eration markers are associated with slightly different phases of the cell cycle and are not equivalent. PCNA and Ki67 expression are positively correlated with p53 overexpression, high S-phase fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer specimens, and are negatively cor-related with estrogen receptor content. Ki67 was included with three other widely measured breast cancer markers (ER, PR, and HER2) into a panel of four immunohistochemical makers (IHC4), which together provided similar prognostic informa-tion to that in the 21 Gene Recurrence Score (Oncotype DX, Genomic Health).190 While there has been significant interest in using Ki67 as a biomarker, and while the IHC4 panel would be much less expensive than the 21 Gene Recurrence Score, there remain issues regarding reproducibility across laboratories.Indices of Angiogenesis. Angiogenesis is necessary for the growth and invasiveness of breast cancer and promotes cancer progression through several different mechanisms, including delivery of oxygen and nutrients and the secretion of growth-promoting cytokines by endothelial cells.191,192 VEGF induces its effect by binding to transmembrane tyrosine kinase recep-tors. Overexpression of VEGF in invasive breast cancer is cor-related with increased microvessel density and recurrence in node-negative breast cancer. An angiogenesis index has been developed in which microvessel density (CD31 expression) is combined with expression of thrombospondin (a negative modulator of angiogenesis) and p53 expression. Both VEGF expression and the angiogenesis index may have prognostic and predictive significance in breast cancer.193 Bevacizumab (a monoclonal antibody to VEGF) was approved by the FDA for use in metastatic breast cancer in combination with pacli-taxel chemotherapy. This approval was based on results from a phase 3 trial by the Eastern Cooperative Oncology Group. The group’s E2100 trial showed that when bevacizumab was added to paclitaxel chemotherapy, median progression-free survival increased to 11.3 months from the 5.8 months seen in patients who received paclitaxel alone.194 The results were not repro-duced in other trials, and the indication for the drug was revoked by the FDA in 2011.Indices of Apoptosis. Alterations in programmed cell death (apoptosis), which may be triggered by p53-dependent or p53-independent factors, may be important prognostic and pre-dictive biomarkers in breast cancer.195-197 Bcl-2 family proteins appear to regulate a step in the evolutionarily conserved pathway for apoptosis, with some members functioning as inhibitors of apoptosis and others as promoters of apoptosis. Bcl-2 is the only oncogene that acts by inhibiting apoptosis rather than by directly increasing cellular proliferation. The death-signal protein bax is induced by genotoxic stress and growth factor deprivation in the presence of wild-type (normal) p53 and/or AP-1/fos. The bax to bcl-2 ratio and the resulting formation of either bax-baxhomodimers, which stimulate apoptosis, or bax–bcl-2 het-erodimers, which inhibit apoptosis, represent an intracellular regulatory mechanism with prognostic and predictive implica-tions. In breast cancer, overexpression of bcl-2 and a decrease in the bax to bcl-2 ratio correlate with high histologic grade, the presence of axillary lymph node metastases, and reduced disease-free and overall survival rates. Similarly, decreased bax expression correlates with axillary lymph node metastases, a poor response to chemotherapy, and decreased overall survival.The remaining biomarkers and biologic targets listed ear-lier are still in preclinical testing, and clinical trials are evaluat-ing their importance in breast cancer for both prognostic and predictive purposes.Coexpression of Biomarkers. Selection of optimal therapy for breast cancer requires both an accurate assessment of prog-nosis and an accurate prediction of response to therapy. The breast cancer markers that are most important in determining therapy are estrogen receptor, progesterone receptor, and HER2/neu. Clinicians evaluate clinical and pathologic staging and the expression of estrogen receptor, progesterone receptor, and HER2/neu in the primary tumor to assess prognosis and assign therapy. Adjuvant! Online (http://www.adjuvantonline.com) is one of a number of programs available to clinicians that incor-porates clinical and pathologic factors for an individual patient and calculates risk of recurrence and death due to breast cancer and then provides an assessment of the reduction in risk of recurrence that would be expected with the use of combination chemotherapy, endocrine therapy, or both of these. Adjuvant! Online was developed using information from the SEER data-base, the EBCTCG overview analyses, and results from other individual published trials.198 The website is updated and modi-fied as new information becomes available. Clinicopathologic factors are used to separate breast cancer patients into broad prognostic groups, and treatment decisions are made on this basis (Table 17-12). Other indices and programs that are vali-dated and used include the Nottingham Prognostic Index, and PREDICT.199-201 When an approach, which combines prognostic factors is used, up to 70% of early breast cancer patients receive adjuvant chemotherapy that is either unnecessary or ineffective. As described earlier, a wide variety of biomarkers have been shown to individually predict prognosis and response to therapy, but they do not improve the accuracy of either the assessment of prognosis or the prediction of response to therapy.As knowledge regarding cellular, biochemical, and molec-ular biomarkers for breast cancer have improved, prognostic indices have been developed that combine the predictive power Table 17-12Traditional prognostic and predictive factors for invasive breast cancerTUMOR FACTORSHOST FACTORSNodal statusAgeTumor sizeMenopausal statusHistologic/nuclear gradeFamily historyLymphatic/vascular invasionPrevious breast cancerPathologic stageImmunosuppressionHormone receptor statusNutritionDNA content (ploidy, S-phase fraction)Prior chemotherapyExtent of intraductal componentPrior radiation therapyHER2/neu expression Modified with permission from Ellis N: Inherited Cancer Syndromes. New York, NY: Springer-Verlag; 2004.Brunicardi_Ch17_p0541-p0612.indd 57901/03/19 5:05 PM 580SPECIFIC CONSIDERATIONSPART IITable 17-13Diagnostic studies for breast cancer patients CANCER STAGE 0IIIIIIIVHistory & physicalXXXXXComplete blood count, platelet count  XXXLiver function tests and alkaline phosphatase level  XXXChest radiograph  XXXBilateral diagnostic mammograms, ultrasound as indicatedXXXXXHormone receptor statusXXXXXHER2/neu expression XXXXBone scan   XXAbdominal (without or without pelvis) computed tomographic scan or ultrasound or magnetic resonance imaging   XXAbdominal imaging and bone scanning are indicated for evaluation of symptoms or abnormal laboratory test results at any presenting stage.Data from NCCN Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network, 2006.of several individual biomarkers with the relevant clinicopatho-logic factors.Recent technological advances have enabled implemen-tation of high throughput gene expression assays in clinical practice.202 These assays enable detailed stratification of breast cancer patients for assessment of prognosis and for predic-tion of response to therapy. The Oncotype DX is a 21-gene RT-PCR–based assay that has been approved for use in newly diagnosed patients with node-negative, ER-positive breast cancer.203 A recurrence score is generated, and those patients with high recurrence scores are likely to benefit from che-motherapy, whereas those with low recurrence scores benefit most from endocrine therapy and may not require chemother-apy. Results from the Trial Assessing Individualized Options for Treatment for breast cancer (TAILORx), designed to pro-spectively validate the use of 21-gene expression assay, have shown that patients with low recurrence score (0 to 10) have a low rate of local-regional and distant recurrence (98.7%) and very good overall survival at 5 years (98%) with endocrine therapy alone without chemotherapy.204 This study has ran-domly assigned patients with an intermediate recurrence score (11 to 25) to endocrine therapy alone or to chemotherapy fol-lowed by endocrine therapy.Additionally, retrospective analysis has shown that the 21-gene recurrence score can be used in postmenopausal patients with ER-positive tumors and 1 to 3 involved axillary lymph nodes to predict the benefit of chemotherapy in addition to endocrine therapy.205 Knowledge of the recurrence score has been shown to alter treatment recommendations by oncologists, and patients likewise change their decision to undergo treatment based on the risk of recurrence.206 The MammaPrint assay uses a 70-gene expression profile to assess the risk of distant metas-tasis. Mammaprint is FDA approved for use in stage-1 or stage-2, node negative, ER-positive or ER-negative breast cancers to identify patients with high or low risk of recurrence. Although fresh tissue was initially required to perform the assay, it has since been adapted for use in paraffin-embedded tissue sam-ples. The prospective RASTER study reported that patients classified as low risk based on MammaPrint had a 97% distant recurrence-free interval at five years.207 Results of the prospec-tive MINDACT (MicroarrayInNode negative and 1–3 positive lymph node Disease may Avoid ChemoTherapy) trial were recently reported.208 The study was designed to assess whether the 70-gene expression assay would help avoid chemotherapy in patients who are considered clinically high risk but categorized as low genomic risk based on the assay. A 5-year rate of distant metastasis-free survival of more than 92% was identified as the cutoff for the benefit of chemotherapy. At 5 years, the rate of survival without distant metastasis in patients with high clinical risk and low genomic risk was 94.7%, meeting the criteria for noninferiority. However, the rate of disease-free survival and overall survival was higher with chemotherapy in the intention to treat population.OVERVIEW OF BREAST CANCER THERAPYBefore diagnostic biopsy, the surgeon must consider the possi-bility that a suspicious mass or mammographic finding may be a breast cancer. Once a diagnosis of breast cancer is made, the type of therapy offered to a breast cancer patient is determined by the stage of the disease, the biologic subtype, and the general health status of the individual. Laboratory tests and imaging studies are performed based on the initial stage as presented in Table 17-13. Before therapy is initiated, the patient and the sur-geon must share a clear perspective on the planned course of treatment. Before initiating local therapy, the surgeon should determine the clinical stage, histologic characteristics, and appropriate biomarker levels.In Situ Breast Cancer (Stage 0)Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from cancers with early invasion.60,209-214 Expert pathologic review is required in all cases. Bilateral mammography is performed to determine the extent of the in situ cancer and to exclude a second cancer. Because LCIS is considered a marker for increased risk rather than an inevitable precursor of invasive disease, the current treatment options for LCIS include observation, chemoprevention, and bilateral total mastectomy. The goal of treatment is to prevent or detect at an early stage the invasive cancer that subsequently develops in 25% to 35% of these women. There is no benefit to excis-ing LCIS because the disease diffusely involves both breasts in many cases and the risk of developing invasive cancer is equal for both breasts. The use of tamoxifen as a risk-reduction strat-egy should be considered in women with a diagnosis of LCIS.Women with DCIS and evidence of extensive disease (>4 cm of disease or disease in more than one quadrant) usu-ally require mastectomy (Fig. 17-29). For women with lim-ited disease, lumpectomy and radiation therapy are generally recommended. For nonpalpable DCIS, needle localization or other image-guided techniques are used to guide the surgical resection. Specimen mammography is performed to ensure that all visible evidence of cancer is excised. Adjuvant tamoxi-fen therapy is considered for DCIS patients with ER-positive 8Brunicardi_Ch17_p0541-p0612.indd 58001/03/19 5:05 PM 581THE BREASTCHAPTER 17ABFigure 17-29. Extensive DCIS seen on mammography. A. Exten-sive calcifications are seen throughout the breast on this cranial caudal view. B. Magnification view of calcifications. Due to the extent of the disease the patient is not a good candidate for breast conserving surgery. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)disease. The gold standard against which breast conservation therapy for DCIS is evaluated is mastectomy. Women treated with mastectomy have local recurrence and mortality rates of <2%. There is no randomized trial comparing mastectomy vs. breast conserving surgery, and none of the randomized trials of breast-conserving surgery with or without radiotherapy for DCIS were powered to show a difference in mortality. Women treated with lumpectomy and adjuvant radiation therapy in the initial clinical trials were noted to have a local recurrence rate that is increased compared to mastectomy. About 45% of these recurrences will be invasive cancer when radiation therapy is not used. The B-17 trial was conducted by the NSABP to assess the need for radiation in patients treated with breast conserv-ing surgery for DCIS.215 Patients were randomly assigned to lumpectomy with radiation or lumpectomy alone, and after a mean follow-up time of 90 months rates of both ipsilateral noninvasive and invasive recurrences were significantly lower in patients who received radiation. However, in the B-17 trial the margins were not prospectively assessed, and it is estimated that up to half of the patients may have had tumor at the mar-gin of resection. The benefit of the addition of radiation over breast-conserving surgery alone for DCIS has also been dem-onstrated in several other randomized trials where margins were prospectively assessed including the European Organization for Research and Treatment of Cancer (EORTC) protocol 10853; the United Kingdom, Australia, New Zealand DCIS Trial; and the Swedish Trial.209,216-218 In 2016, the Society of Surgi-cal Oncology (SSO), American Society for Radiation Oncol-ogy (ASTRO), and the American Society of Clinical Oncology (ASCO) established consensus guidelines on margins for patients with DCIS undergoing breast-conserving surgery.219 Based on a multidisciplinary consensus panel using a meta-analysis of margin width and ipsilateral breast tumor recur-rence, a 2-mm margin was determined as adequate width for DCIS for patients undergoing breast-conserving surgery with whole-breast radiation therapy.219Despite the data from randomized trials showing a benefit in all patient subgroups with the addition of radiation in DCIS, there has been an interest in trying to define a subset where radiation could be avoided in order to minimize the cost and inconvenience associated with radiation. In addition, there have been several studies published where patients were treated with excision alone and never developed invasive breast cancer even at 25 years of follow-up. Silverstein and colleagues were pro-ponents of avoiding radiation therapy in selected patients with DCIS who have widely negative margins after surgery.213 They reported that when greater than 10-mm margins were achieved, there was no additional benefit from radiation therapy. When margins were between 1 and 10 mm, there was a relative risk of local recurrence of 1.49, compared to 2.54 for those with margins less than 1 mm. These data suggested that appropri-ately selected patients with DCIS might not require postopera-tive radiation therapy.The Eastern Cooperative Oncology Group (ECOG) initi-ated a prospective registry trial (ECOG 5194) to identify those patients who could safely undergo breast-conserving surgery without radiation.222 Eligible patients were those with low or intermediate grade DCIS measuring 2.5 cm or less who had negative margins of at least 3 mm and those with high-grade DCIS who had tumors measuring 1 cm or less with a negative margin of at least 3 mm. At a median follow-up of 6.2 years, patients with low or intermediate grade DCIS had an in-breast Brunicardi_Ch17_p0541-p0612.indd 58101/03/19 5:05 PM 582SPECIFIC CONSIDERATIONSPART IIrecurrence rate of 6.1% while those with high-grade DCIS had a recurrence rate of 15.3%. Approximately 4% of patients developed a contralateral breast cancer during follow-up in both the low/intermediate and high-grade groups. This study identi-fied an acceptable recurrence rate for those patients with low or intermediate grade DCIS treated with excision alone with a margin of at least 3 mm. In contrast, patients with high-grade DCIS had an unacceptably high local recurrence rate.The Radiation Therapy Oncology Group (RTOG) initi-ated the 9804 trial for patients with “good risk” DCIS and randomized them to lumpectomy vs. lumpectomy with whole breast irradiation. Eligible patients were those with unicentric, low or intermediate grade DCIS measuring 2.5 cm or less with a margin of 3 mm or greater. The trial was closed early due to slow accrual; however, the results for 585 patients were recently reported with a median follow-up of 6.46 years.223,224 The local recurrence rate at 5 years was 0.4% for patients ran-domized to receive radiation and 3.2% for those who did not receive radiation.Solin et al utilized samples from the ECOG 5194 trial to develop a quantitative multigene RT-PCR assay for predict-ing recurrence risk in patients with DCIS treated with surgery alone.201 They were able to define low, intermediate, and high risk groups using a DCIS Score. The DCIS Score was able to quantify the risk of recurrence in the breast for both DCIS and invasive events. This tool has recently been evaluated in another dataset and appears to be a promising tool for clinical use.225 When selecting therapy for patients with DCIS, one must con-sider clinical and pathologic factors, including tumor size, grade, mammographic appearance, and patient preference. There is no single correct surgical treatment, and many patients will require extensive counseling in order to make a decision regarding sur-gical therapy. The role of axillary staging in patients with DCIS is limited. One consideration is for patients undergoing mastec-tomy. Since most lesions are currently diagnosed with needle core biopsy, there is about a 20% incidence of invasive breast cancer on final pathologic assessment of the primary tumor. Since it is not feasible to perform sentinel node dissection after mastectomy, most surgeons will recommend the use of sentinel node dissection at the time of mastectomy for DCIS.Results from the NSABP B-24 trial reported a signifi-cant reduction in local recurrence after 5 years of tamoxifen in women with ER-positive DCIS. Based on this finding, some guidelines have advocated that all patients (women with ER-positive DCIS without contraindications to tamoxifen therapy) should be offered tamoxifen following surgery and radiation therapy for a duration of 5 years. The B-24 trial revealed a sig-nificant reduction in recurrence with adjuvant tamoxifen therapy for patients with DCIS; however, the results were not initially assessed based on ER status.226 There were 1804 women with DCIS randomized to lumpectomy and radiation with or without tamoxifen. The rate of breast cancer events was significantly lower in those who received tamoxifen at a median follow-up of 74 months (8.2% vs. 13.4%, P = 0.0009). Subsequently, Allred and colleagues evaluated 41% of patients with DCIS in the NSABP B-24 trial to determine the effect of tamoxifen based on ER status measured in the primary tumor.203 They found that 76% of women had DCIS that was ER-positive and these women had a greater reduction in ipsilateral breast tumor recur-rence with tamoxifen than did patients with ER-negative DCIS (11% vs. 5.2%, P <0.001). However, it should be noted that 15% of patients in B-24 had tumor at the resection margins. For these patients, tamoxifen could be viewed as treating what, by the current standard, would be viewed as inadequate local exci-sion of the primary tumor.Early Invasive Breast Cancer (Stage I, IIA, or IIB)There have been six prospective randomized trials comparing breast-conserving surgery to mastectomy in early stage breast cancer, and all have shown equivalent survival rates regardless of the surgical treatment type. One caveat, however, is that the majority of studies had a restriction of tumor size; most were either 2 cm or 2.5 cm, while the NSABP B-06 trial was 4 cm, and the NCI trial was up to 5 cm. NSABP B-06, which is the largest of all the breast conservation trials, compared total mastectomy to lumpectomy with or without radiation therapy in the treatment of women with stages I and II breast cancer.227-233 After 5and 8-year follow-up periods, the disease-free (DFS), distant dis-ease-free, and overall survival (OS) rates for lumpectomy with or without radiation therapy were similar to those observed after total mastectomy. However, the incidence of ipsilateral breast cancer recurrence was higher in the group not receiving radia-tion therapy. These findings supported the use of lumpectomy and radiation therapy in the treatment of stages I and II breast cancer and this has since become the preferred method of treat-ment for women with early stage breast cancer who have uni-focal disease and who are not known BRCA mutation carriers. Reanalysis of the B-06 study results was undertaken after 20 years of follow-up and confirmed that there was no differ-ence in disease-free survival rates after total mastectomy or after lumpectomy with or without adjuvant radiation therapy. The in-breast recurrence rate was substantially higher in the lumpec-tomy alone group (39.2%) compared with the lumpectomy plus adjuvant radiation therapy group (14.3%), confirming the importance of radiation therapy in the management of patients with invasive disease. However, it should be noted that there were several criteria in the B-06 study. There was a specific lymphadenopathy exclusion criteria. Secondly, all patients ran-domized to breast-conserving surgery had a frozen section, and if the margins were involved, they were converted to mastec-tomy but were included in the analysis as having had a breast-conserving operation (on the basis of intention to treat). Finally, in the breast-conserving group recurrences in the treated breast were considered as a “nonevent.”Data from all of the randomized trials where breast con-servation was performed with or without radiation therapy have been examined by the EBCTCG.12 At 15 years of follow-up, the absolute reduction in mortality with the use of radiation therapy after lumpectomy was 5.1% in node-negative patients and 7.1% in node-positive patients. These data support the concept that the addition of radiation not only improves local control but also has an impact on survival. Similar to DCIS, clinicians have sought to identify subgroups of patients who may not benefit from the addition of radiation therapy, particularly older patients who may have a shorter life expectancy due to medical comor-bidities. Randomized trials have shown that in selected patients with small, ER-positive, low-grade tumors, lumpectomy alone without radiation therapy may be appropriate.211,212 The Cancer and Leukemia Group B (CALGB) C9343 trial enrolled women over the age of 70 with T1N0 breast cancer and randomized them to lumpectomy with or without radiation therapy. All patients received adjuvant tamoxifen.233a At 5 years, although Brunicardi_Ch17_p0541-p0612.indd 58201/03/19 5:05 PM 583THE BREASTCHAPTER 17there were fewer local recurrences with radiation (1% vs. 4%, P <0.001), there were no differences in DFS and OS. While long-term follow-up at 10 years showed fewer local recurrences with radiation (2% vs. 10%), there were no significant differ-ences in time to distant metastasis, breast cancer–specific sur-vival, or OS between the two groups. A trial similar to CALGB C9343 was conducted in Canada where they enrolled women age 50 years and older and randomized them to lumpectomy with or without radiation. Mean age was 68 years, and 80% of women had ER-positive tumors. Again, local recurrence rates were lower in women who received radiation (0.6% vs. 7.7%, P <0.001); however, at a median follow-up of 5.6 years, there were no differences in DFS or OS. The PRIME-2 study enrolled women age 65 years or older with ER-positive, node-negative, up to 3 cm breast cancers, who had undergone breast-conserving surgery and were candidates for adjuvant endocrine treatment. They were assigned to receive whole-breast irradiation or no treatment. After a median follow-up of 5 years, ipsilateral breast tumor recurrence was 1.3% with radiation vs. 41% in those assigned to no radiotherapy. However, no differences in distant metastases, contralateral breast cancers, or overall survival were noted between the groups.234 These studies suggest that radia-tion can be avoided in select older patients with ER-positive, early-stage breast cancer.Accelerated partial breast irradiation (APBI) is also an option for carefully selected patients with DCIS and early-stage breast cancer. Since the majority of recurrences after breast conservation occur in or adjacent to the tumor bed, there has been interest in limiting the radiation to the area of the primary tumor bed with a margin of normal tissue. APBI is delivered in an abbreviated fashion (twice daily for 5 days) and at a lower total dose compared with the standard course of 5 to 6 weeks of radiation (50 Gy with or without a boost) in the case of whole breast irradiation. Proponents have suggested that this shortened course of treatment may increase the feasibility of breast con-servation for some women and may improve radiation therapy compliance. The RTOG 04-13/NSABP B-39 trial is a random-ized comparison of whole breast irradiation to APBI in women with early stage breast cancer. The trial has completed accrual, and it will likely be several years before data are mature to report outcomes between the two radiation treatment strategies. TARGIT is another study that randomized 3451 patients in 33 centers in over 10 countries to intraoperative breast irradiation (IORT) or external beam radiotherapy (EBRT). The prelimi-nary results were reported in 2012: with a median follow-up of 2.4 years, use of IORT had a recurrence rate of 3.3% vs. 1.3% with EBRT, a 2% increased recurrence risk.235,236 ASTRO developed guidelines for the use of APBI outside of clinical trials based on data reported from published studies.237,238 The ASTRO guidelines describe patients “suitable” for APBI to include women age 60 years or older with a unifocal, T1, ER-positive tumor with no lymphovascular invasion and margins of at least 2 mm. They describe a group where there is uncer-tainty about the appropriateness of APBI (“cautionary” group) to include patients with invasive lobular histology, a tumor size of 2.1 cm to 3 cm, ER-negative disease, focal lymphovascular invasion, or margins less than 2 mm. Finally, a group felt to be “unsuitable” for APBI includes those with T3 or T4 disease, ER-negative disease, multifocality, multicentricity, extensive LVI, or positive margins.Currently, mastectomy with axillary staging and breast conserving surgery with axillary staging and radiation therapy are considered equivalent treatments for patients with stages I and II breast cancer. Breast conservation is considered for all patients because of the important cosmetic advantages and equivalent survival outcomes; however, this approach is not advised in women who are known BRCA mutation carriers due to the high lifetime risk for development of additional breast cancers. Relative contraindications to breast conserva-tion therapy include (a) prior radiation therapy to the breast or chest wall, (b) persistently positive surgical margins after reex-cision, (c) multicentric disease, and (d) scleroderma or lupus erythematosus.For most patients with early-stage disease, reconstruc-tion can be performed immediately at the time of mastectomy. Immediate reconstruction allows for skin-sparing, thus optimiz-ing cosmetic outcomes. Skin-sparing mastectomy with immedi-ate reconstruction has been popularized over the past decade as reports of low local-regional failure rates have been reported and reconstructive techniques have advanced. There is a grow-ing interest in the use of nipple-areolar sparing mastectomy with reports suggesting the oncologic safety of this approach in early stage breast cancer. Patients who are planned for postmastec-tomy radiation therapy may not be ideal candidates for nipple-sparing mastectomy because of the effects of radiation on the preserved nipple. In addition to providing optimal cosmesis from preservation of the skin and/or the nipple-areolar complex, immediate reconstruction allows patients to wake up with a breast mound, which provides some psychological benefit for the patient. Immediate reconstruction is also more economical as both the extirpative and reconstructive surgery are combined in one operation.Immediate reconstruction can be performed using implants or autologous tissue; tissue flaps commonly used include the transverse rectus abdominis myocutaneous flap, deep inferior epigastric perforator flap, and latissimus dorsi flap (with or without an implant). If postmastectomy radiation therapy is needed, a tissue expander can be placed at the time of mastec-tomy to save the shape of the breast and reduce the amount of skin replacement needed at the time of definitive reconstruc-tion. The expander can be deflated at the initiation of radiation therapy to allow for irradiation of the chest wall and regional nodal basins. Removal of the tissue expander and definitive reconstruction, usually with autologous tissue, can proceed 6 months to 1 year after completion of radiation therapy.Axillary lymph node status has traditionally been an important determinant in staging and prognosis for women with early stage breast cancer. Historically, axillary lymph node dis-section (ALND) was utilized for axillary staging and regional control by removing involved lymph nodes. Randomized tri-als evaluating immediate ALND over ALND performed in a delayed fashion once clinically palpable axillary disease became evident have not shown any detriment in survival.9,239 With increased mammographic screening and detection of smaller, node-negative breast cancers, it became clear that routine use of ALND for axillary staging was not necessary in up to 75% percent of women with operable breast cancer presenting with a negative axilla at the time of screening. Lymphatic mapping and sentinel lymph node (SLN) dissection were initially devel-oped for assessment of patients with clinically node-negative melanoma. Given the changing landscape of newly diagnosed breast cancer patients with a clinically node-negative axilla, sur-geons quickly began to explore the utility of SLN dissection as a replacement for ALND in axillary staging.Brunicardi_Ch17_p0541-p0612.indd 58301/03/19 5:05 PM 584SPECIFIC CONSIDERATIONSPART IIIn the early 1990s, David Krag at the University of Vermont began performing SLN dissection with injection of a radioisotope in the primary tumor site and localizing the SLN node with a handheld gamma probe.240 He was able to identify a SLN in 18 of 22 patients examined, and the SLN was posi-tive in all 7 patients with positive lymph nodes. Giuliano and colleagues initiated a pilot study in 1991 to examine the use of SLN dissection using blue dye in patients with clinically nega-tive nodes. They reported successful identification of a SLN in 114 (65.5%) of 174 patients, and in 109 (95.6%), the SLN accurately predicted the status of the axillary nodes.241,242 These studies along with initial work by Doug Reintgen and Charles Cox at the Moffitt Cancer Center and Umberto Veronesi and his colleagues at the European Institute of Oncology in Milan led the way toward validation of the technique in large single institution and multicenter studies.Following validation of the technique of SLN dissection for staging of the axilla by multiple centers, randomized tri-als were initiated in order to determine if SLN dissection could replace ALND in the contemporary management of breast cancer patients. The ALMANAC trial randomized 1031 patients with primary operable breast cancer to SLN dissection vs. standard axillary surgery. The incidence of lymphedema and sensory loss for the SLN group was significantly lower than with the standard axillary treatment. At 12 months, drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were also statistically significantly lower in the SLN group.221The NSABP B-32 trial compared clinically node-negative patients undergoing SLN dissection followed by ALND with patients undergoing SLN dissection with ALND only if a SLN was positive for metastatic disease.243 A total of 5611 patients were randomized with a SLN identification rate of 97% and a false-negative rate of 9.7%. A total of 26% of these clini-cally node-negative patients had a positive SLN. Over 60% of patients with positive SLNs had no additional positive lymph nodes within the ALND specimen. The B-32 trial and other randomized trials demonstrated no difference in DFS, OS, and local-regional recurrence rates between patients with negative SLNs who had SLN dissection alone compared with those who underwent ALND.244,245 Most important, patients who had SLN dissection alone were found to have decreased morbidity (arm swelling and range of motion) and improved quality of life vs. patients who underwent ALND.245,246The American College of Surgeons Oncology Group (ACOSOG) initiated the Z0010 and Z0011 trials in order to evaluate the incidence and prognostic significance of occult metastases identified in the bone marrow and SLNs (Z0010) of early-stage clinically node-negative patients and to evaluate the utility of ALND in patients with clinical T1-2, N0 breast cancer with 1 or 2 positive SLNs for patients treated with breast-conserving surgery and whole breast irradiation (WBI) (Z0011).247,248The Z0010 study enrolled 5539 patients with clinical T1-2 breast cancer planned for breast conserving surgery and WBI.247 Of these patients, 24% proved to have positive SLNs based on standard pathologic assessment, and of the negative SLNs sub-jected to immunohistochemical staining for cytokeratin, 10.5% proved to have occult metastasis. Of the patients who had bone marrow aspiration, 3.0% had immunohistochemically detected tumor cells in the bone marrow. Although the presence of dis-ease in the bone marrow identified a population at high risk for recurrence, neither immunohistochemical detection of disease in the SLNs or the bone marrow was statistically significant on multivariable analysis with clinicopathologic and treatment factors included. The investigators concluded that routine use of immunohistochemistry to detect occult disease in SLNs is not warranted.The Z0011 trial was a companion study to Z0010 and was designed to study the role of completion ALND on survival in women with positive SLNs. Patients were not eligible if they received neoadjuvant chemotherapy or neoadjuvant hormonal therapy or if their treatment plan included mastectomy, lumpec-tomy without radiation, or lumpectomy with APBI. WBI was to be administered using standard tangential fields without specific treatment of the axilla or additional fields targeting other nodal basins. Patients with 1 or 2 positive SLNs were randomized to completion ALND or no further surgery. Adjuvant systemic therapy recommendations were left to the treating clinicians. After median follow-up of 6.3 years, there was no difference between patients randomized to ALND and those randomized to no further surgery (SLN only) in terms of OS (91.9% and 92.5%, respectively; P = 0.25) or DFS (82.2% and 83.8%, respectively; P = 0.14). The low local regional failure rates and similar survival outcomes were recently reported with 10-year follow-up.249,250The morbidity of SLN dissection alone vs. SLN dissec-tion with completion ALND has been reported by the ACOSOG investigators.251,252 Immediate effects of SLN dissection in the Z0010 trial included wound infection in 1%, axillary seroma in 7.1%, and axillary hematoma in 1.4%.251 At 6 months following surgery, axillary paresthesias were noted in 8.6% of patients, decreased range of motion in the upper extremity was reported in 3.8%, and 6.9% of patients had a change in the arm circum-ference of >2 cm on the ipsilateral side, which was reported as lymphedema. Younger patients were more likely to report paresthesias, whereas increasing age and body mass index were more predictive of lymphedema. When adverse surgical effects were examined in the Z0011 trial, patients undergoing SLN dissection with ALND had more wound infections, seromas, and paresthesias than those women undergoing SLN dissec-tion alone. Lymphedema at 1 year after surgery was reported by 13% in the SLN plus ALND group but only 2% in the SLN dissection alone group. Arm circumference measurements were greater at 1 year in patients undergoing SLN dissection plus ALND, but the difference between study groups was not statisti-cally significant.252 This supports the results published from the ALMANAC trial.Prior to the publication of ACOSOG Z0011, completion ALND was standard of care for patients with positive SLNs. Since the reporting of ACOSOG Z0011, the National Com-prehensive Cancer Network (NCCN) guidelines now state that there was no OS difference for patients with 1 or 2 positive SLNs treated with breast-conserving surgery who underwent completion ALND vs. those who had no further axillary sur-gery. In addition, the American Society of Breast Surgeons issued a consensus statement supporting omission of ALND for patients who meet Z0011 criteria.253 The results of ACOSOG Z0011 have revolutionized management of the axilla and changed practice such that selected patients with axillary metas-tasis can now avoid ALND if they have clinical and pathologic features similar to those patients enrolled on Z0011. However, there have been some concerns raised about the Z0011 study that include the fact that the study only recruited about half of Brunicardi_Ch17_p0541-p0612.indd 58401/03/19 5:05 PM 585THE BREASTCHAPTER 17the intended patients and that there was no standardization of whether or not patients received irradiation to the low axilla when the radiation oncologist irradiated the breast. These issues have thus far limited the uptake of the results of Z0011 by some centers.The International Breast Cancer Study Group (IBCSG) 23-01 trial was similar in design to Z0011 but enrolled only patients with micrometastases in the SLNs. Patients with SLN micrometastases were randomized to ALND vs. no further sur-gery. Unlike Z0011, the 23-01 trial did not exclude patients treated with mastectomy. Approximately 9% of patients ran-domized to each study arm underwent mastectomy. The inves-tigators published the primary and secondary endpoints of the trial showing no differences in OS or local-regional recurrence between the study arms.254 However, as with the Z0011 trial, some concerns have been raised regarding the 23-01 study. For example, in the statistics on the primary endpoint, local recur-rence included contralateral breast cancer and other tumor types as events. No hypothesis was presented as to why the differ-ence in axillary surgery should impact on either of these events. Including these events therefore reduced the power of the study to show a statistical difference between treatment arms. There is also concern that the study appears underpowered to show a meaningful difference in overall survival.Most pathology laboratories perform a more detailed anal-ysis of the SLN than is routinely done for axillary nodes recov-ered from a levels I and II dissection. This can include examining thin sections of the node with step sectioning at multiple levels through the paraffin blocks or performing immunohistochemi-cal staining of the SLN for cytokeratin or a combination of these techniques. The results of ACOSOG Z0010 and NSABP B-32 showed no clinically meaningful difference in survival based on detection of occult metastases in the SLNs using immu-nohistochemical staining and do not support the routine use in SLN processing. The type of intraoperative assessment of SLNs also varies for different clinicians and pathology labo-ratories. Some centers prefer to use touch preparation cyto-logic analysis of the SLNs, whereas others use frozen-section analysis, and the sensitivity and specificity of these assays vary considerably. The GeneSearch Breast Lymph Node Assay is a real-time reverse-transcriptase polymerase chain reaction assay that detects breast tumor cell metastasis in lymph nodes through the identification of the gene expression markers mammaglobin and cytokeratin 19. These markers are present in higher lev-els in breast tissue and not in nodal tissue (cell type-specific messenger RNA). The GeneSearch breast lymph node assay generates expression data for genes of interest, which are then evaluated against predetermined criteria to provide a qualitative (positive/negative) result. The assay is designed to detect foci that correspond to metastases that are seen with examination by standard hematoxylin and eosin staining and measure >0.2 mm. The GeneSearch assay results have been compared with per-manent-section histologic analysis and frozen-section analy-sis of sentinel nodes in a prospective trial, and the assay was approved by the FDA for the intraoperative assessment of senti-nel nodes.255 When a positive node is identified intraoperatively by touch preparation, frozen-section analysis, or GeneSearch assay, the surgeon can proceed with immediate ALND. With the findings of ACOSOG Z0011 that there is not a survival ben-efit to the use of ALND in selected patients, many surgeons have abandoned the intraoperative evaluation of SLNs. There are a number of nomograms and predictive models designed to determine which patients with a positive SLN are at risk for har-boring additional positive non-SLNs in the axilla. These tools can be helpful in determining the likelihood of additional disease in the axilla and may be used clinically to counsel patients.256In patients who present with axillary lymphadenopa-thy that is confirmed to be metastatic disease on FNA or core biopsy, SLN dissection is not necessary, and patients can pro-ceed directly to ALND or be considered for preoperative sys-temic therapy (see “Neoadjuvant [Preoperative] Chemotherapy” under “Nonsurgical Breast Cancer Therapies”). Initially there was controversy about the suitability of SLN dissection in women with larger primary tumors (T3) and those treated with neoadjuvant chemotherapy. The American Society of Clini-cal Oncology has included SLN dissection is its guidelines as appropriate for axillary staging in these patients.257,258 If an SLN cannot be identified, then ALND is generally performed for appropriate staging. However, this is not universally accepted, and there are as yet no randomized studies that have assessed how a patient with a locally advanced cancer at presentation should be treated if SLN dissection reveals no metastases or micrometastases after neoadjuvant therapy.The ASCO guidelines suggest that adjuvant chemo-therapy should be considered for patients with positive lymph nodes, ER-negative disease, HER2-positive disease, Adju-vant! Online mortality greater than 10%, grade 3 node-neg-ative tumors >5 mm, triple-negative tumors, lymphovascular invasion, or estimated distant relapse risk of greater than 15% at 10 years based on the 21 gene recurrence score assay.259 Adjuvant endocrine therapy is considered for women with hormone receptor-positive cancers, and an aromatase inhibi-tor is recommended if the patient is postmenopausal. HER2/neu status is determined for all patients with newly diagnosed invasive breast cancer and when positive, should be used to guide systemic therapy recommendations. The FDA approved trastuzumab in November 2006 for use as part of a treatment regimen containing doxorubicin, cyclophosphamide, and pacli-taxel for treatment of HER2/neu-positive, node-positive breast cancer.181,183 Subsequently, the BCIRG 006 study reported that giving trastuzumab concurrently with docetaxel and carbopla-tin appeared as effective as giving trastuzumab following an anthracycline containing regimen.182,185 In addition to trastu-zumab, pertuzumab has also recently been FDA approved for adjuvant use in patients with HER2 amplified breast cancers with high risk of recurrence.Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB)Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but have no clinically detected distant metastases (Fig. 17-30).260 In an effort to provide opti-mal local-regional disease-free survival as well as distant dis-ease-free survival for these women, surgery is integrated with radiation therapy and chemotherapy (Fig. 17-31). However, it should be noted that these patients have an increased risk of distant metastasis that is often highlighted by radiological evidence when staging PET or CT and bone scans are per-formed. Thus, the paradigm for small screen detected cancers where cure can be expected in >90% of patients, often by local treatment alone, is not appropriate for patients with locally advanced disease.Preoperative (also known as neoadjuvant) chemotherapy should be considered in the initial management of patients with Brunicardi_Ch17_p0541-p0612.indd 58501/03/19 5:05 PM 586SPECIFIC CONSIDERATIONSPART IIFigure 17-30. Locally advanced breast cancer. A. Mammography of the right breast reveals a large tumor with enlarged axillary lymph nodes. B. Imaging of the left breast is normal. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Figure 17-31. Treatment pathways for stage IIIA and stage IIIB breast cancer.locally advanced stage III breast cancer, especially those with estrogen receptor negative tumors. Chemotherapy is used to maximize distant disease-free survival, whereas radiation ther-apy is used to maximize local-regional control and disease-free survival.In selected patients with stage IIIA cancer, preoperative chemotherapy can reduce the size of the primary cancer and permit breast-conserving surgery. Investigators from the MD Anderson Cancer Center reported that low local-regional fail-ure rates could be achieved in selected patients with stage III disease treated with preoperative chemotherapy followed by breast-conserving surgery and radiation.261 The 5-year actuarial ipsilateral breast tumor recurrence-free survival rates in this study were 95%. They noted that the ipsilateral breast tumor recurrence rates increased when patients had clinical N2 or N3 disease, >2 cm of residual disease in the breast at surgery, a pattern of multifocal residual disease in the breast at surgery, and lymphovascular space invasion in the primary tumor. This study demonstrated that breast-conserving surgery can be used for appropriately selected patients with locally advanced breast cancer who achieve a good response with preoperative che-motherapy. However, the Oxford overview of all randomized studies of neoadjuvant therapy (vs. adjuvant therapy) reported a hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates. ABBrunicardi_Ch17_p0541-p0612.indd 58601/03/19 5:05 PM 587THE BREASTCHAPTER 17A meta-analysis reported a hazard ratio of 1.3.262 These stud-ies included some patients treated with radiation therapy alone without resection of the primary tumor bed, which results in higher local failure rates. These findings are important in view of the previous findings that the avoidance of recurrence in a conserved breast avoids about one breast cancer death over the next 15 years for every four such recurrences avoided.12 The German Breast Cancer Group recently reported their local recurrence rate in 5535 patients in seven studies. With a median of 46 months (range 1–127) follow-up the local recurrence rates ranged from 7.6% to 19.5% for T1-T4 tumors and from 6.4% to 17.9% for N0-N3 tumors treated with neoadjuvant therapy.238 For patients with stage IIIA disease who experience minimal response to chemotherapy and for patients with stage IIIB breast cancer, preoperative chemotherapy can decrease the local-regional cancer burden enough to permit subsequent modified radical mastectomy to establish local-regional con-trol. In both stages IIIA and IIIB disease, surgery is followed by adjuvant radiation therapy. However there is a small percent-age of patients who experience progression of disease during neoadjuvant therapy, and therefore the surgeon should review patients with the oncologist at regular points during the neoad-juvant regimen.For selected clinically indolent, ER-positive, locally advanced tumors, primary endocrine therapy may be considered, especially if the patient has other comorbid conditions. A series of 195 patients with ER-positive, locally advanced breast cancer treated by endocrine therapy—median age 69 years, median tumor size 6 cm, median follow-up 61 months—reported a 5-year overall survival of 76%, a breast cancer–specific sur-vival of 86%, and a metastasis-free survival of 77%. The median time to an alternative treatment was 48 months.263 Given that this was a 20-year series, the number of such patients is small but should be considered when the clinician is discussing treat-ment options. Results from the ACOSOG Z1031 trial suggest that neoadjuvant endocrine therapy is a good option for tumor downstaging in patients with strongly ER-positive tumors. The preoperative endocrine prognostic index (PEPI score) can be calculated based on pathologic findings from surgery following neoadjuvant endocrine therapy. This can help guide decision-making regarding the need for systemic chemotherapy in this patient population.264,265Internal Mammary Lymph NodesMetastatic disease to internal mammary lymph nodes may be occult, may be evident on chest radiograph or CT scan, or may present as a painless parasternal mass with or without skin involvement. There is no consensus regarding the need for internal mammary lymph node radiation therapy in women who are at increased risk for occult involvement (cancers involving the medial aspect of the breast, axillary lymph node involve-ment) but who show no signs of internal mammary lymph node involvement. Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly involved internal mammary lymph nodes.Distant Metastases (Stage IV)Treatment for stage IV breast cancer is not curative but may prolong survival and enhance a woman’s quality of life.266 Endocrine therapies that are associated with minimal toxicity are preferred to cytotoxic chemotherapy in ER-positive disease. Appropriate candidates for initial endocrine therapy include women with hormone receptor-positive cancers who do not have immediately life threatening disease (or “visceral crisis”). This includes not only women with bone or soft tissue metastases but also women with limited visceral metastases. Symptoms per se (e.g., breathlessness) are not in themselves an indication for chemotherapy. For example, breathlessness due to a pleural effusion can be treated with percutaneous drainage, and if the breathlessness is relieved, the patient should be commenced on endocrine therapy; if the breathlessness is due to lymphangitic spread, then chemotherapy would be the treatment of choice. The same approach should be taken to other symptoms such as pain. Systemic chemotherapy is indicated for women with hormone receptor-negative cancers, “visceral crisis,” and hormone-refractory metastases. Women with stage IV breast cancer may develop anatomically localized problems that will benefit from individualized surgical or radiation treatment, such as brain metastases, pleural effusion, pericardial effusion, biliary obstruction, ureteral obstruction, impending or existing pathologic fracture of a long bone, spinal cord compression, and painful bone or soft tissue metastases. Bisphosphonates or anti-RANKL (receptor activator of nuclear factor kappa-B ligand) agent, denosumab, which may be given in addition to chemo-therapy or endocrine therapy, should be considered in women with bone metastases. Whether to perform surgical resection of the local-regional disease in women with stage IV breast cancer has been debated after several reports have suggested that women who undergo resection of the primary tumor have improved survival over those who do not. Khan and associates used the National Cancer Data Base to identify patterns of treat-ment in women with metastatic breast cancer and found that those who had surgical resection with negative margins had a better prognosis than those women who did not have surgical therapy.267 Gnerlich et al reported similar findings using the SEER database, and there have been several reports subsequent to this study from single institutions that have confirmed these findings.268 Some have suggested that the finding of improved survival is due to selection bias and that local therapy should be reserved for palliation of symptoms. A randomized trial through ECOG (E2108) was designed to address this question.269 The surgical management of patients with stage IV disease should be addressed by obtaining multidisciplinary input and by con-sidering the treatment goals of each individual patient and the patient’s treating physicians.Local-Regional RecurrenceWomen with local-regional recurrence of breast cancer may be separated into two groups: those who have had mastec-tomy and those who have had lumpectomy. Women treated previously with mastectomy undergo surgical resection of the local-regional recurrence and appropriate reconstruction. Chemotherapy and antiestrogen therapy are considered, and adjuvant radiation therapy is given if the chest wall has not pre-viously received radiation therapy or if the radiation oncologist feels that given the time from previous treatment there is scope for further radiation therapy, particularly if this is palliative. Women treated previously with a breast-conservation procedure undergo a mastectomy and appropriate reconstruction. Chemo-therapy and antiestrogen therapy are considered depending of the hormone receptor status and HER2 status of the tumor.Breast Cancer PrognosisSurvival rates for women diagnosed with breast cancer in the United States can be obtained from the SEER Program of the Brunicardi_Ch17_p0541-p0612.indd 58701/03/19 5:05 PM 588SPECIFIC CONSIDERATIONSPART IIABFigure 17-32. Lesion to be targeted for excisional biopsy. A. Craniocaudal view of the left breast demonstrating 2 lesions (arrows) to be targeted for needle localization and excision. B. Oblique view demonstrating target lesions. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)National Cancer Institute. Data have been collected since 1973 and are updated at regular intervals. The overall 5-year rela-tive survival for breast cancer patients from the time period of 2003 to 2009 from 18 SEER geographic areas was 89.2%.270 The 5-year relative survival by race was reported to be 90.4% for white women and 78.7% for black women. The 5-year sur-vival rate for patients with localized disease (61% of patients) is 98.6%; for patients with regional disease (32% of patients), 84.4%; and for patients with distant metastatic disease (5% of patients), 24.3%. Breast cancer survival has significantly increased over the past two decades due to improvements in screening and local and systemic therapies. Data from the American College of Surgeons National Cancer Data Base can also be accessed; this data reports survival based on stage of disease at presentation using the AJCC staging system.SURGICAL TECHNIQUES IN BREAST CANCER THERAPYExcisional Biopsy With Needle LocalizationExcisional biopsy implies complete removal of a breast lesion with a margin of normal-appearing breast tissue. In the past, surgeons would obtain prior consent from the patient, allow-ing mastectomy if the initial biopsy results confirmed cancer. Today it is important to consider the options for local therapy (lumpectomy vs. mastectomy with or without reconstruction) and the need for nodal assessment with SLN dissection. Needle-core biopsy is the preferred diagnostic method, and excisional biopsy should be reserved for those cases in which the needle biopsy results are discordant with the imaging findings or clini-cal examination (Fig. 17-32). In general, circumareolar incisions can be used to access lesions that are subareolar or within a short distance of the nipple-areolar complex. Elsewhere in the breast, incisions can be placed along the lines of tension in the skin that are generally concentric with the nipple-areola complex. In the lower half of the breast, the use of radial incisions typically provides the best outcome. When the tumor is quite distant from the central breast, the biopsy incision can be excised separately from the primary mastectomy incision, should a mastectomy be required. Radial incisions in the upper half of the breast are not recommended because of possible scar contracture resulting in displacement of the ipsilateral nipple-areola complex. Similarly, curvilinear incisions in the lower half of the breast may displace the nipple-areolar complex downward.After excision of a suspicious breast lesion, the specimen should be X-rayed to confirm that the lesion has been excised with appropriate margins. The biopsy tissue specimen is ori-entated for the pathologist using sutures, clips, or dyes. Addi-tional margins (superior, inferior, medial, lateral, superficial, and deep) may be taken from the surgical bed if the specimen X-ray shows the lesion is close to one or more margins. Some surgeons also take additional shavings from the margins as one approach to confirm complete excision of the suspicious lesion. Electrocautery or absorbable ligatures are used to achieve wound hemostasis. Cosmesis may be facilitated by approxima-tion of the surgical defect using 3-0 absorbable sutures. A run-ning subcuticular closure of the skin using 4-0 or 5-0 absorbable monofilament sutures is performed. Wound drainage is usually not required.Excisional biopsy with needle or seed localization requires a preoperative visit to the mammography suite for placement of a localization wire or a radioactive or magnetic seed that can be detected intraoperatively with a handheld probe. The lesion can also be targeted by sonography in the imaging suite or in the operating room. The lesion to be excised is accurately localized by mammography, and the tip of a thin wire hook or a seed is positioned close to the lesion (Fig. 17-33). Using the wire hook as a guide, or detection of the seed with a handheld probe, the surgeon subsequently excises the suspicious breast lesion while removing a margin of normal-appearing breast tissue. Before the patient leaves the operating room, specimen radiography is performed to confirm complete excision of the suspicious lesion (Fig. 17-34).Brunicardi_Ch17_p0541-p0612.indd 58801/03/19 5:05 PM 589THE BREASTCHAPTER 17Figure 17-33. Wire localization procedure. Mammographic images of hookwire in place targeting lesions for excision in the left breast (A) and the right breast (B). (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screen-ing, Royal Derby Hospital, Derby, UK.)Figure 17-34. Specimen mammography. Specimen mam-mograms demonstrating excision of targeted (A) density, (B) calcifications, and (C) spiculated mass seen on preoperative imaging. (Used with permission from Dr. Anne Turnbull, Con-sultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)ABCABBrunicardi_Ch17_p0541-p0612.indd 58901/03/19 5:05 PM 590SPECIFIC CONSIDERATIONSPART IISentinel Lymph Node DissectionSentinel lymph node (SLN) dissection is primarily used to assess the regional lymph nodes in women with early breast cancers who are clinically node-negative by physical examina-tion and imaging studies.271-279 This method also is accurate in women with larger tumors (T3 N0), but nearly 75% of these women will prove to have axillary lymph node metastases on histologic examination, and wherever possible it is better to identify them preoperatively as this will allow a definitive procedure for known axillary disease. SLN dissection has also been reported to be accurate for staging of the axilla after chemotherapy in women with clinically node-negative dis-ease at initial presentation.280,281 Tan et al in a review and meta-analysis of 449 cases of SLN biopsy in clinically lymph node-negative disease reported a sensitivity of 93%, giving a false negative rate of 7% with a negative predictive value of 94% and an overall accuracy of 95%.282 Clinical situations where SLN dissection is not recommended include patients with inflammatory breast cancers, those with biopsy proven metasta-sis, DCIS without mastectomy, or prior axillary surgery. Although limited data are available, SLN dissection appears to be safe in pregnancy when performed with radioisotope alone.Evidence from large prospective studies suggests that the combination of intraoperative gamma probe detection of radioactive colloid and intraoperative visualization of blue dye (isosulfan blue dye or methylene blue) is more accurate for identification of SLNs than the use of either agent alone. Some surgeons use preoperative lymphoscintigraphy, although it is not required for identification of the SLNs. On the day before surgery, or the day of surgery, the radioactive colloid is injected either in the breast parenchyma around the primary tumor or prior biopsy site, into the subareolar region, or subdermally in proximity to the primary tumor site. With a 25-gauge needle, 0.5 mCi of 0.2-μm technetium 99m–labeled sulfur colloid is injected for same-day surgery, or a higher dose of 2.5 mCi of technetium-labeled sulfur colloid is administered when the isotope is to be injected on the day before surgery. Subdermal injections are given in proximity to the cancer site or in the subareolar location. Later, in the operating room, 3 to 5 mL of blue dye is injected either in the breast parenchyma or in the subareolar location. It is not recommended that the blue dye be used in a subdermal injection because this can result in tattoo-ing of the skin (isosulfan blue dye) or skin necrosis (methylene blue). For nonpalpable cancers, the injection of the technetium-labeled sulfur colloid solution can be guided by ultrasound or by mammographic guidance. In women who have undergone previous excisional biopsy, the injections are made in the breast parenchyma around the biopsy cavity but not into the cavity itself. Women are told preoperatively that the isosulfan blue dye injection will cause a change in the color of their urine and that there is a very small risk of allergic reaction to the dye (1 in 10,000). Anaphylactic reactions have been documented, and some groups administer a regimen of antihistamine, steroids, and a histamine H-2 receptor antagonist preoperatively as a prophylactic regimen to prevent allergic reactions. The use of radioactive colloid is safe, and radiation exposure is very low. Sentinel node dissection can be performed in pregnancy with the radioactive colloid without the use of blue dye.A hand-held gamma counter is used to transcutaneously identify the location of the SLN. This can help to guide place-ment of the incision. A 3to 4-cm incision is made in line with that used for an axillary dissection, which is a curved transverse 9incision in the lower axilla just below the hairline. After dis-secting through the subcutaneous tissue, the surgeon dissects through the axillary fascia, being mindful to identify blue lym-phatic channels. Following these channels can lead directly to the SLN and limit the amount of dissection through the axillary tissues. The gamma probe is used to facilitate the dissection and to pinpoint the location of the SLN. As the dissection continues, the signal from the probe increases in intensity as the SLN is approached. The SLN also is identified by visualization of blue dye in the afferent lymph vessel and in the lymph node itself. Before the SLN is removed, a 10-second in vivo radioactivity count is obtained. After removal of the SLN, a 10-second ex vivo radioactive count is obtained, and the node is then sent to the pathology laboratory for either permanentor frozen-section analysis. The lowest false-negative rates for SLN dissection have been obtained when all blue lymph nodes and all lymph nodes with counts >10% of the 10-second ex vivo count of the SLN are harvested (“10% rule”). Based on this, the gamma counter is used before closing the axillary wound to measure residual radioactivity in the surgical bed. A search is made for additional SLNs if the counts remain high. This procedure is repeated until residual radioactivity in the surgical bed is less than 10% of the 10-second ex vivo count of the most radioac-tive SLN and all blue nodes have been removed. Studies have demonstrated that 98% of all positive SLNs will be recovered with the removal of four SLNs; therefore, it is not necessary to remove greater than four SLNs for accurate staging of the axilla.Results from the NSABP B-32 trial showed that the false-negative rate for SLN dissection is influenced by tumor loca-tion, type of diagnostic biopsy, and number of SLNs removed at surgery.243 The authors reported that tumors located in the lateral breast were more likely to have a false-negative SLN. This may be explained by difficulty in discriminating the hot spot in the axilla when the radioisotope has been injected at the primary tumor site in the lateral breast. Those patients who had undergone an excisional biopsy before the SLN procedure were significantly more likely to have a false-negative SLN. This report further confirms that surgeons should use needle biopsy for diagnosis whenever possible and reserve excisional biopsy for the rare situations in which needle biopsy findings are non-diagnostic or discordant. Finally, removal of a larger number of SLNs at surgery appears to reduce the false-negative rate. In B-32, the false-negative rate was reduced from 17.7% to 10% when two SLNs were recovered and to 6.9% when three SLNs were removed. Yi and associates reported that the number of SLNs that need to be removed for accurate staging is influenced by individual patient and primary tumor factors.283In the B-32 trial, SLNs were identified outside the levels I and II axillary nodes in 1.4% of cases. This was significantly influenced by the site of radioisotope injection. When a subareo-lar or periareolar injection site was used, there were no instances of SLNs identified outside the level I or II axilla, compared with a rate of 20% when a peritumoral injection was used. This sup-ports the overall concept that the SLN is the first site of drain-age from the lymphatic vessels of the primary tumor. Although many patients will have similar drainage patterns from injec-tions given at the primary tumor site and at the subareolar plexus, some patients will have extra-axillary drainage, either alone or in combination with axillary node drainage, and this is best assessed with a peritumoral injection of the radioiso-tope. Kong et al reported that internal mammary node drain-age on preoperative lymphoscintigraphy was associated with Brunicardi_Ch17_p0541-p0612.indd 59001/03/19 5:05 PM 591THE BREASTCHAPTER 17worse distant disease-free survival in early-stage breast cancer patients.284Breast ConservationBreast conservation involves resection of the primary breast cancer with a margin of normal-appearing breast tissue, adju-vant radiation therapy, and assessment of regional lymph node status.285,286 Resection of the primary breast cancer is alterna-tively called segmental mastectomy, lumpectomy, partial mas-tectomy, wide local excision, and tylectomy. For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is preferable to total mastectomy because BCT produces survival rates equivalent to those after total mastectomy while preserv-ing the breast.287 Six prospective randomized trials have shown that overall and disease-free survival rates are similar with BCT and mastectomy; however, three of the studies showed higher local-regional failure rates in patients undergoing BCT. In two of these studies, there were no clear criteria for histologically negative margins.285-287 Data from the EBCTCG meta-analysis revealed that the addition of radiation reduces recurrence by half and improves survival at year 15 by about a sixth.288 When all of this information is taken together, BCT is considered to be oncologically equivalent to mastectomy.In addition to being equivalent to mastectomy in terms of oncologic safety, BCT appears to offer advantages over mas-tectomy with regard to quality of life and aesthetic outcomes. BCT allows for preservation of breast shape and skin as well as preservation of sensation, and it provides an overall psychologic advantage associated with breast preservation.Breast conservation surgery is currently the standard treat-ment for women with stage 0, I, or II invasive breast cancer. Women with DCIS require only resection of the primary cancer and adjuvant radiation therapy without assessment of regional lymph nodes. When a lumpectomy is performed, a curvilinear incision lying concentric to the nipple-areola complex is made in the skin overlying the breast cancer when the tumor is in the upper aspect of the breast. Radial incisions are preferred when the tumor is in the lower aspect of the breast. Skin excision is not necessary unless there is direct involvement of the overlying skin by the primary tumor. The breast cancer is removed with an envelope of normal-appearing breast tissue that is adequate to achieve a cancer-free margin. Significant controversy has existed on the appropriate margin width for BCT.260 However, recently the SSO and ASTRO developed a consensus statement, supported by data from a systematic review data, encouraging “no tumor on ink” to be the standard definition of a negative margin for invasive stages I and II breast cancer in patients who undergo breast conserving surgery with whole-breast irradiation. The meta-analysis found that increasing the margin width does not affect local recurrence rates as long as the inked or transected margin is microscopically negative.289-292 Specimen X-ray should routinely be performed to confirm the lesion has been excised. Specimen orientation is performed by the surgeon. Additional margins from the surgical bed are taken as needed to provide a histologically negative margin. Requests for determination of ER, PR, and HER2 status are conveyed to the pathologist.It is the surgeon’s responsibility to ensure complete removal of cancer in the breast. Ensuring surgical margins that are free of breast cancer will minimize the chances of local recurrence and will enhance cure rates. If negative margins are not obtainable with reexcision, mastectomy is required. SLN is performed before removal of the primary breast tumor. When indicated, intraoperative assessment of the sentinel node can proceed while the segmental mastectomy is being performed.The use of oncoplastic surgery can be entertained at the time of segmental mastectomy or at a later time to improve the overall aesthetic outcome. The use of oncoplastic techniques range from a simple reshaping of breast tissue to local tissue rearrangement to the use of pedicled flaps or breast reduction techniques. The overall goal is to achieve the best possible aes-thetic result. In determining which patients are candidates for oncoplastic breast surgery, several factors should be considered, including the extent of the resection of breast tissue necessary to achieve negative margins, the location of the primary tumor within the breast, and the size of the patient’s breast and body habitus. Oncoplastic techniques are of prime consideration when (a) a significant area of breast skin will need to be resected with the specimen to achieve negative margins; (b) a large vol-ume of breast parenchyma will be resected resulting in a signifi-cant defect; (c) the tumor is located between the nipple and the inframammary fold, an area often associated with unfavorable cosmetic outcomes; or (d) excision of the tumor and closure of the breast may result in malpositioning of the nipple.Mastectomy and Axillary DissectionA skin-sparing mastectomy removes all breast tissue, the nipple-areola complex, and scars from any prior biopsy pro-cedures.293,294 There is a recurrence rate of less than 6% to 8%, comparable to the long-term recurrence rates reported with stan-dard mastectomy, when skin-sparing mastectomy is used for patients with Tis to T3 cancers. A total (simple) mastectomy without skin sparing removes all breast tissue, the nipple-areola complex, and skin. An extended simple mastectomy removes all breast tissue, the nipple-areola complex, skin, and the level I axillary lymph nodes. A modified radical (“Patey”) mastectomy removes all breast tissue, the nipple-areola complex, skin, and the levels I, II, and III axillary lymph nodes; the pectoralis minor that was divided and removed by Patey may be simply divided, giving improved access to level III nodes, and then left in situ, or occasionally the axillary clearance can be performed with-out dividing pectoralis minor. The Halsted radical mastectomy removes all breast tissue and skin, the nipple-areola complex, the pectoralis major and pectoralis minor muscles, and the levels I, II, and III axillary lymph nodes. The use of systemic che-motherapy and hormonal therapy as well as adjuvant radiation therapy for breast cancer have nearly eliminated the need for the radical mastectomy.Nipple-areolar sparing mastectomy has been popularized over the last decade especially for risk-reducing mastectomy in high risk women. For those patients with a cancer diagno-sis, many consider the following factors for eligibility: tumor located more than 2 to 3 cm from the border of the areola, smaller breast size, minimal ptosis, no prior breast surgeries with periareolar incisions, body mass index less than 40 kg/m2, no active tobacco use, no prior breast irradiation, and no evi-dence of collagen vascular disease.For a variety of biologic, economic, and psychosocial rea-sons, some women desire mastectomy rather than breast con-servation. Women who are less concerned about cosmesis may view mastectomy as the most expeditious and desirable thera-peutic option because it avoids the cost and inconvenience of radiation therapy. Some women whose primary breast cancers cannot be excised with a reasonable cosmetic result or those who have extensive microcalcifications are best treated with Brunicardi_Ch17_p0541-p0612.indd 59101/03/19 5:05 PM 592SPECIFIC CONSIDERATIONSPART IImastectomy. Similarly, women with large cancers that occupy the subareolar and central portions of the breast and women with multicentric primary cancers also undergo mastectomy.Modified Radical MastectomyA modified radical mastectomy preserves the pectoralis major muscle with removal of levels I, II, and III (apical) axillary lymph nodes.293 The operation was first described by David Patey, a surgeon at St Bartholomew’s Hospital London, who reported a series of cases where he had removed the pectoralis minor muscle allowing complete dissection of the level III axil-lary lymph nodes while preserving the pectoralis major and the lateral pectoral nerve. A modified radical mastectomy permits preservation of the medial (anterior thoracic) pectoral nerve, which courses in the lateral neurovascular bundle of the axilla and usually penetrates the pectoralis minor to supply the lateral border of the pectoralis major. Anatomic boundaries of the mod-ified radical mastectomy are the anterior margin of the latissi-mus dorsi muscle laterally, the midline of the sternum medially, the subclavius muscle superiorly, and the caudal extension of the breast 2 to 3 cm inferior to the inframammary fold inferiorly. Skin-flap thickness varies with body habitus but ideally is 7 to 8 mm inclusive of skin and telasubcutanea (Fig. 17-35). Once the skin flaps are fully developed, the fascia of the pectoralis major muscle and the overlying breast tissue are elevated off the underlying musculature, which allows for the complete removal of the breast (Fig. 17-36).Subsequently, an axillary lymph node dissection is per-formed. The most lateral extent of the axillary vein is identified, and the areolar tissue of the lateral axillary space is elevated as the vein is cleared on its anterior and inferior surfaces. The areo-lar tissues at the junction of the axillary vein and the anterior edge of the latissimus dorsi muscle, which include the lateral and subscapular lymph node groups (level I), are cleared. Care is taken to preserve the thoracodorsal neurovascular bundle. The dissection then continues medially with clearance of the central axillary lymph node group (level II). The long thoracic nerve of Bell is identified and preserved as it travels in the investing fascia of the serratus anterior muscle. Every effort is made to preserve this nerve because permanent disability with a winged scapula and shoulder weakness will follow denervation of the serratus anterior muscle. Patey divided the pectoralis minor and removed it to allow access right up to the apex of the axilla. The pectoralis minor muscle is usually divided at the tendinous portion near its insertion onto the coracoid process (Fig. 17-37 inset), which allows dissection of the axillary vein medially to the costoclavicular (Halsted’s) ligament. Finally, the breast and axillary contents are removed from the surgical bed and are sent for pathologic assessment. In his modified radical mastectomy, Patey removed the pectoralis minor muscle. Many surgeons now divide only the tendon of the pectoralis minor muscle at its insertion onto the coracoid process while leaving the rest of the muscle intact, which still provides good access to the apex of the axilla.Figure 17-35. Modified radical mastectomy: eleva-tion of skin flaps. Skin flaps are 7 to 8 mm in thick-ness, inclusive of the skin and telasubcutanea. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Figure 17-36. Modified radical mastectomy after resection of breast tissue. The pectoralis major muscle is cleared of its fascia as the overlying breast is elevated. The latissimus dorsi muscle is the lateral boundary of the dissection. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Brunicardi_Ch17_p0541-p0612.indd 59201/03/19 5:05 PM 593THE BREASTCHAPTER 17Seromas beneath the skin flaps or in the axilla represent the most frequent complication of mastectomy and axillary lymph node dissection, reportedly occurring in as many as 30% of cases. The use of closed-system suction drainage reduces the incidence of this complication. Catheters are retained in the wound until drainage diminishes to <30 mL per day. Wound infections occur infrequently after a mastectomy, and the majority are a result of skin-flap necrosis. Cultures of speci-mens taken from the infected wound for aerobic and anaerobic organisms, debridement, and antibiotic therapy are effective management. Moderate or severe hemorrhage in the postop-erative period is rare and is best managed with early wound exploration for control of hemorrhage and reestablishment of closed-system suction drainage. The incidence of functionally significant lymphedema after a modified radical mastectomy is approximately 20% but can be as high as 50% to 60% when postoperative radiation is employed. Extensive axillary lymph node dissection, the delivery of radiation therapy, the presence of pathologic lymph nodes, and obesity are predisposing factors. Patients should be referred to physical therapy at the earliest signs of lymphedema to prevent progression to the later stages. The use of individually fitted compressive sleeves and complex decongestive therapy may be necessary.Reconstruction of the Breast and Chest WallThe goals of reconstructive surgery after a mastectomy for breast cancer are wound closure and breast reconstruction, which is either immediate or delayed.295 In most cases, wound closure after mastectomy is accomplished with simple approximation of the wound edges. However, if a more radical removal of skin and subcutaneous tissue is necessary, a pedicled myocutane-ous flap from the latissimus dorsi muscle is generally the best approach for wound coverage. A skin graft provides functional coverage that will tolerate adjuvant radiation therapy; however, this is not preferred because poor graft adherence may delay delivery of radiation therapy. Breast reconstruction after risk-reducing mastectomy or after mastectomy for early-stage breast cancer may be performed at the same time as the mastectomy. This allows for a skin-sparing mastectomy to be performed, which offers the best overall cosmetic outcomes. Reconstruc-tion can proceed with an expander/implant reconstruction or with autologous tissue such as a pedicled myocutaneous flap or a free flap using microvascular techniques. In patients with locally advanced breast cancer, reconstruction is often delayed until after completion of adjuvant radiation therapy to ensure that local-regional control of disease is obtained. The expected use of postmastectomy radiotherapy should also be considered as a reason for delayed reconstruction as radiotherapy to a reconstructed breast has been reported to result in inferior cos-metic outcomes. Consideration can be made for placement of a tissue expander to allow for skin-sparing, but this should be discussed with the radiation oncologist and other members of the treatment team. If chest wall coverage is needed to replace a large skin or soft tissue defect, many different types of myo-cutaneous flaps are employed, but the latissimus dorsi and the rectus abdominis myocutaneous flaps are most frequently used. The latissimus dorsi myocutaneous flap consists of a skin paddle based on the underlying latissimus dorsi muscle, which Figure 17-37. Modified radical mastectomy (Patey): axillary lymph node dissection. The dissection proceeds from lateral to medial, with complete visualization of the anterior and inferior aspects of the axillary vein. Loose areolar tissue at the junction of the axillary vein and the anterior margin of the latissimus dorsi muscle is swept inferomedially inclusive of the lateral (axillary) lymph node group (level I). Care is taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space. The lateral lymph node group is resected in continuity with the subscapular lymph node group (level I) and the external mammary lymph node group (level I). Dissection anterior to the axillary vein allows removal of the central lymph node group (level II) and the apical (subclavicular) lymph node group (level III). The superomedial limit of this dissection is the clavipectoral fascia (Halsted’s ligament). Inset depicts division of the insertion of the pectoralis minor muscle at the coracoid process. The surgeon’s finger shields the underlying brachial plexus. (Reproduced with permission from Bland KI, Copeland EMI: The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)Brunicardi_Ch17_p0541-p0612.indd 59301/03/19 5:05 PM 594SPECIFIC CONSIDERATIONSPART IIis supplied by the thoracodorsal artery with contributions from the posterior intercostal arteries. A transverse rectus abdominis myocutaneous (TRAM) flap consists of a skin paddle based on the underlying rectus abdominis muscle, which is supplied by vessels from the deep inferior epigastric artery. The free TRAM flap uses microvascular anastomoses to establish blood supply to the flap. When the bony chest wall is involved with cancer, resection of a portion of the bony chest wall is indicated. If only one or two ribs are resected and soft tissue coverage is pro-vided, reconstruction of the bony defect is usually not necessary because scar tissue will stabilize the chest wall. If more than two ribs are sacrificed, it is advisable to stabilize the chest wall with prosthetic material, which is then covered with soft tissue by using a latissimus dorsi or TRAM flap.NONSURGICAL BREAST CANCER THERAPIESRadiation TherapyRadiation therapy is used for all stages of breast cancer depending on whether the patient is undergoing BCT or mas-tectomy.296-302 Adjuvant radiation for patients with DCIS and early-stage breast cancer have been described previously in this chapter. Those women treated with mastectomy who have cancer at the surgical margins are at sufficiently high risk for local recurrence to warrant the use of adjuvant radiation therapy to the chest wall postoperatively. Women with metastatic disease involving four or more axillary lymph nodes and premeno-pausal women with metastatic disease involving one to three lymph nodes also are at increased risk for recurrence and are candidates for the use of chest wall and supraclavicular lymph node radiation therapy. In advanced local-regional breast can-cer (stage IIIA or IIIB), women are at high risk for recurrent disease after surgical therapy, and adjuvant radiation therapy is used to reduce the risk of recurrence. Current recommenda-tions for stages IIIA and IIIB breast cancer are (a) adjuvant radiation therapy to the breast and supraclavicular lymph nodes after neoadjuvant chemotherapy and segmental mastectomy with or without axillary lymph node dissection, (b) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after neoadjuvant chemotherapy and mastectomy with or without axillary lymph node dissection, and (c) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after segmental mastectomy or mastectomy with axillary lymph node dissection and adjuvant chemotherapy. Data from the EBCTCG has shown improvements in local-regional con-trol and survival in patients treated with mastectomy and post-mastectomy radiation therapy for one to three positive axillary lymph nodes.303 This data is based on clinical trials from the era of axillary lymph node dissection for staging prior to the routine use of sentinel lymph node dissection. It is likely that the vol-ume of disease in the earlier trials was greater overall than what is currently seen in patients who have small volume metastases detected at sentinel node dissection. It is important to include all multidisciplinary team members (medical oncology, plastic surgery, radiation oncology, and surgical oncology) regarding the risks and benefits of postmastectomy radiation therapy in patients with one to three positive nodes.The use of partial breast irradiation (APBI) for patients treated with breast-conserving surgery has also been previously described. APBI can be delivered via brachytherapy, external beam radiation therapy using 3D conformal radiation, or inten-sity-modulated radiation therapy. Although initial results are Table 17-14Adjuvant chemotherapy regimens for breast cancerHER-2 NEGATIVEHER-2 POSITIVEPreferred Dose dense AC → Paclitaxel every 2 weeksDose dense AC → Paclitaxel weeklyTC (T = docetaxel)Other RegimensCMFAC → Docetaxel every 3 weeksAC → Paclitaxel weeklyTAC (T = docetaxel)AC → T + trastuzumab +/pertuzumab (T = paclitaxel)TCH (docetaxel, carboplatin, trastuzumab +/pertuzumab)Other RegimensAC → T + trastuzumab +/pertuzumab (T = docetaxel)Docetaxel + cyclophosphamide + trastuzumabFEC → Docetaxel + trastuzumab + pertuzumabFEC → Paclitaxel + trastuzumab + pertuzumabPaclitaxel + trastuzumabPaclitaxel + trastuzumab + pertuzumab → FECDocetaxel + trastuzumab + pertuzumab → FECA = Adriamycin (doxorubicin); C = cyclophosphamide; E = epirubicin; F = 5-fluorouracil; M = methotrexate; T = Taxane (docetaxel or paclitaxel); → = followed by.Data from NCCN Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network, 2006.promising in highly selected low-risk populations, use of APBI should be based on current guidelines or offered in the setting of a prospective trial.304Chemotherapy AdjuvantChemotherapy. The Early Breast Cancer Trialists’ Collabora-tive Group overview analysis of adjuvant chemotherapy demon-strated reductions in the odds of recurrence and death in women ≤70 years of age with stage I, IIA, or IIB breast cancer.123,305-309 For those ≥70 years of age, the lack of definitive clinical trial data regarding adjuvant chemotherapy prevented definitive rec-ommendations. Adjuvant chemotherapy is of minimal benefit to women with negative nodes and cancers ≤0.5 cm in size and is not recommended. Women with negative nodes and cancers 0.6 to 1.0 cm are divided into those with a low risk of recurrence and those with unfavorable prognostic features that portend a higher risk of recurrence and a need for adjuvant chemotherapy. Adverse prognostic factors include blood vessel or lymph ves-sel invasion, high nuclear grade, high histologic grade, HER2/neu overexpression, and negative hormone receptor status. American Society of Clinical Oncology guidelines suggest that adjuvant chemotherapy should be considered for patients with positive lymph nodes, HER2-positive disease, Adjuvant! Online mortality greater than 10%, grade 3 lymph node negative tumors >5 mm, triple-negative tumors, lympho-vascular invasion, or estimated distant relapse risk of greater than 15% at 10 years based on 21 gene recurrence score.259 Adjuvant chemotherapy is recommended by the NCCN guidelines for women with these unfavorable prognostic features. Table 17-14 lists the frequently used chemotherapy regimens for breast cancer.For women with hormone receptor-negative cancers that are >1 cm in size, adjuvant chemotherapy is appropriate. Brunicardi_Ch17_p0541-p0612.indd 59401/03/19 5:05 PM 595THE BREASTCHAPTER 17However, women with node-negative hormone receptor–positive cancers and T1 tumors are candidates for antiestrogen therapy with or without chemotherapy. Assessment of overall risk using known prognostic factors or additional testing such as the 21-gene recurrence score assay can help to guide deci-sion making regarding chemotherapy in patients with node-negative, ER-positive breast cancer. For special-type cancers (tubular, mucinous, medullary, etc), which are usually strongly estrogen receptor positive, adjuvant antiestrogen therapy should be advised for cancers >1 cm. For women with node-positive tumors or with a special-type cancer that is >3 cm, the use of chemotherapy is appropriate; those with hormone receptor-positive tumors should receive antiestrogen therapy.For stage IIIA breast cancer, preoperative chemotherapy with an anthracycline and taxane-containing regimen followed by either a modified radical mastectomy or segmental mastec-tomy with axillary dissection followed by adjuvant radiation therapy should be considered, especially for estrogen receptor negative disease. While the same regimen may be considered for estrogen receptor positive disease, it is known that these tumors respond less well to chemotherapy with <10% pCR rate overall and <3% pCR rate for lobular cancers. Other options such as neoadjuvant endocrine therapy followed by local-regional treatment or in some cases primary endocrine therapy may be considered depending on other tumor characteristics and the patient’s comorbid conditions and preference.Neoadjuvant (Preoperative) Chemotherapy. In the early 1970s, the National Cancer Institute in Milan, Italy, initiated two prospective randomized multimodality clinical trials for women with T3 or T4 breast cancer.310 The best results were achieved when surgery was interposed between chemotherapy courses, with 82% local-regional control and 25% having a 5-year dis-ease-free survival. The NSABP B-18 trial evaluated the role of neoadjuvant chemotherapy in women with operable stages II and III breast cancer.206 Women entered into this study were randomly assigned to receive either surgery followed by che-motherapy or neoadjuvant chemotherapy followed by surgery. There was no difference in the 5-year disease-free survival rates for the two groups, but after neoadjuvant chemotherapy there was an increase in the number of lumpectomies performed and a decreased incidence of node positivity. It was suggested that neoadjuvant chemotherapy be considered for the initial manage-ment of breast cancers judged too large for initial lumpectomy.Several prospective clinical trials have evaluated the neo-adjuvant approach, and two meta-analyses have been performed, each showing that neoadjuvant vs. adjuvant chemotherapy are equivalent in terms of OS.262,311 These analyses also evaluated local-regional recurrence (LRR) and found that there was an increase in LRR rates for patients receiving neoadjuvant chemo-therapy when radiation therapy was used alone without surgery after completion of chemotherapy. Mittendorf and colleagues evaluated a contemporary series of almost 3000 patients treated with breast conserving surgery and radiation therapy who received either neoadjuvant or adjuvant chemotherapy for breast cancer.312 They found that the risk of LRR was driven by bio-logic factors and disease stage and was not impacted by the timing of chemotherapy delivery. These data high-light the importance of the multidisciplinary management of patients with breast cancer in achieving the best outcomes.The use of neoadjuvant chemotherapy offers the oppor-tunity to observe the response of the intact primary tumor 10and any regional nodal metastases to a specific chemotherapy regimen.279 For patients whose tumors remain stable in size or even progress with the initial neoadjuvant chemotherapy regi-men, a new regimen may be considered that uses another class of agents, although there is no randomized data confirming this will improve outcome.After treatment with neoadjuvant chemotherapy, patients are assessed for clinical and pathologic response to the regimen. Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy have been shown to have statisti-cally improved survival outcomes to those of patients whose tumors demonstrate only a partial response, remain stable, or progress on treatment. Researchers at MD Anderson Cancer Center have shown that residual cancer burden (RCB)—categorized into four classes, RCB-0 or pathologic complete response, RCB-1, RCB-2, and RCB-3—is predictive of 10-year relapse-free survival with neoadjuvant chemotherapy in triple negative, ER-positive, and HER2-positive tumors.313 Patients who experience progression of disease during neoadjuvant che-motherapy have the poorest survival.314,315 This means that while patients who achieve a pCR will have a better prognosis based on their response to neoadjuvant chemotherapy. Equally other patients will have a poorer prognosis compared to when they started neoadjuvant therapy based on the nonresponse to treat-ment. Consequently, the FDA has supported the use of the neo-adjuvant platform and pathologic response rates as an endpoint for mechanism of accelerated approval for new agents in high risk early stage breast cancer, though the short-term endpoints (i.e., pCR) have not been shown to correlate with long-term out-comes (i.e., disease free survival and overall survival).Current NCCN recommendations for treatment of oper-able advanced local-regional breast cancer are neoadjuvant chemotherapy with an anthracycline-containing or taxane-containing regimen or both, followed by mastectomy or lumpec-tomy with axillary lymph node dissection if necessary, followed by adjuvant radiation therapy. For patients with HER2-positive breast cancer, trastuzumab and pertuzumab can be combined with chemotherapy in the preoperative setting to increase patho-logic complete response rates. For inoperable stage IIIA and for stage IIIB breast cancer, neoadjuvant chemotherapy is used to decrease the local-regional cancer burden. This may then permit subsequent modified radical or radical mastectomy, which is followed by adjuvant radiation therapy.Nodal Evaluation in Patients Receiving Neoadjuvant Chemotherapy. The management of the axilla after neoadjuvant chemotherapy has not been specifically addressed in randomized trials. Standard practice has been to perform an axillary lymph node dissection after chemotherapy or to perform a sentinel lymph node dissection before chemotherapy for nodal staging before chemotherapy is initiated. A number of small single-institution studies, one multicenter study, and a recent meta-analysis have explored the use of SLN dissection at the completion of chemo-therapy. The published results from these studies have demon-strated the feasibility of SLN dissection in breast cancer patients after neoadjuvant chemotherapy. A review of 14 studies with 818 patients showed a false negative rate of 11% with an overall accu-racy of 94%.280,281,316 While SLN dissection has been accepted for assessment of the axilla in the clinically node-negative axilla after neoadjuvant chemotherapy, clinicians have been slower to adopt this approach for axillary staging after chemotherapy in patients who started with initial node-positive disease. Several clinical Brunicardi_Ch17_p0541-p0612.indd 59501/03/19 5:05 PM 596SPECIFIC CONSIDERATIONSPART IItrials have been performed to evaluate the accuracy of SLN dis-section in patients with documented axillary metastases at initial presentation, including ACOSOG Z1071, SENTINA, and SN FNAC. ACOSOG Z1071 (Alliance) analyzed women with clini-cal T0-T4, N1-N2, M0 breast cancer who underwent both SLN surgery and axillary lymph node dissection (ALND).317 The pri-mary endpoint was the false-negative rate (FNR) of SLN surgery after chemotherapy with clinically node-positive disease with a prespecified endpoint of 10% considered to be an acceptable rate. However, the FNR was found to be 12.6%, though it was lower when dual-agent mapping technique was used and at least three or more SLNs removed.317 The SENTINA and SN FNAC trials had findings similar to Z1071. The results from Z1071 were further analyzed to determine if a clip was placed in the positive node at initial diagnosis and if the clipped node location at surgery (SLN or ALND) was evaluated. Indeed, this showed that identification of the clipped node during the surgical procedure further decreased the FNR.318 The results from the ACOSOG Z1071 (Alliance) trial, in cases presenting with cN1 disease and at least two SLN resec-tions and clipped node was within the SLN specimen, showed that the FNR was 6.8%.318 Caudle et al at MD Anderson Cancer Center performed a prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the biopsy-proven lymph node, who were treated with neoadjuvant chemotherapy; at the time of surgery these patients underwent SLN dissection with targeting and removal of the clipped node (targeted axillary dis-section [TAD]).319 TAD includes SLN surgery and selective local-ization and removal of the clipped node, with the goal to determine if pathologic changes in the clipped node accurately reflect the status of the nodal basin, and proposing that TAD improves the FNR compared to SLN surgery alone.319 In patients undergoing SLN surgery and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2–19.8), and adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03–7.3; P = .03). TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05–10.7).319 Although the use of dual tracer tech-nique, retrieval of three or more SLNs, and TAD improve axillary staging after neoadjuvant chemotherapy, there is no long-term data about the oncologic safety of omitting ALND in patients who con-vert from cN1 to cN0 disease at this time.Neoadjuvant Endocrine Therapy. While initially used in elderly women who were deemed poor candidates for surgery or cytotoxic chemotherapy, neoadjuvant endocrine therapy is being increasingly evaluated in clinical trials. As clinicians have gained experience with neoadjuvant treatment strategies, it is now clear from examination of predictors of complete pathologic response that ER-positive tumors do not shrink in response to chemotherapy as readily as ER-negative tumors.320 Indeed, the pCR rate in ER-negative tumors is approximately three times that of ER-positive tumors. Fisher et al examined the results of the NSABP B-14 and B-20 trials and found that, as age increased, women obtained less benefit from chemo-therapy. They recommended that factors214 including tumor estrogen receptor concentration, nuclear grade, histologic grade, tumor type, and markers of proliferation should be considered in these patients before choosing between the use of chemotherapy and hormonal therapy. If in fact the tumor is estrogen-receptor rich, these patients may benefit more from endocrine therapy in the neoadjuvant setting than they might if they received stan-dard chemotherapy. Neoadjuvant endocrine therapy has been shown to shrink tumors, enabling breast-conserving surgery in women with hormone receptor-positive disease who otherwise would have to be treated with mastectomy, although long-term recurrence rates have not been reported.265 The IMPACT trial evaluated neoadjuvant use of tamoxifen or anastrozole or both in combination in postmenopausal women with ER-positive operable or locally advanced breast cancer.321 While there were no significant differences in objective tumor response among tamoxifen, anastrozole, or a combination of the two, in patients who were initially deemed as mastectomy candidates, only 31% had breast-conserving surgery with tamoxifen, whereas 44% underwent breast-conserving surgery with anastrozole. Invasive lobular cancers in particular have been shown to respond poorly to neoadjuvant chemotherapy and may have better response to neoadjuvant endocrine therapy.322-324 A meta-analysis evaluating the response rate and rate of breast conservation surgery with the use of neoadjuvant endocrine therapy compared to combi-nation chemotherapy was recently reported. This meta-analysis included nearly 3500 patients across 20 studies.325 Interestingly, aromatase inhibitors had a similar response, and breast conserva-tion rates in comparison with combination chemotherapy albeit with lower toxicity suggest that neoadjuvant endocrine therapy is an appropriate alternative in ER-positive breast cancers. However, the incidence of complete pathological response was low (<10%) with both approaches. Also, aromatase inhibitors were associated with significantly higher response and breast conservation rates compared with tamoxifen. The ALTER-NATE (Alternate Approaches for Clinical Stage II or III Estro-gen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women) trial is currently evaluating neo-adjuvant endocrine therapy with fulvestrant or anastrozole or in combination.Increasing knowledge of secondary resistance mecha-nisms to endocrine therapy and cross talk between ER and the PI3K/Akt/mTOR pathway have led to the evaluation of PI3K pathway inhibitors in combination with endocrine therapy. Post-menopausal women with ER-positive early breast cancers were treated with letrozole or letrozole in combination with everoli-mus, a mTOR inhibitor, in a randomized, phase 2 clinical trial. Clinical response and antiproliferative response, characterized by reduction in Ki67, was superior in the combination arm, sug-gesting that everolimus can increase efficacy of neoadjuvant letrozole.326 The LORLEI study is evaluating the use of taselisib, a PI3K inhibitor in combination with letrozole compared with letrozole alone. With the approval of CDK 4/6 inhibitors in the metastatic setting, clinical trials are evaluating the use of CDK inhibitors in combination with neoadjuvant endocrine therapy. Neoadjuvant anastrozole in combination with palbociclib, a CDK4/6 inhibitor, has been shown to significantly reduce Ki67, suggesting that CDK4/6 inhibition can increase the efficacy of neoadjuvant endocrine therapy.With the use of neoadjuvant chemotherapy or endocrine therapy, observation of the response of the intact tumor and/or nodal metastases to a specific regimen could ultimately help to define which patients will benefit from specific therapies in the adjuvant setting. In adjuvant trials the primary endpoint is typi-cally survival, whereas in neoadjuvant trials the endpoints have more often been clinical or pathologic response rates. There are a number of clinical trials underway comparing neoadjuvant chemotherapy and endocrine therapy regimens with pretreat-ment and posttreatment biopsy samples obtained from the pri-mary tumors in all of the participants. These samples are being subjected to intensive genomic and proteomic analyses that may Brunicardi_Ch17_p0541-p0612.indd 59601/03/19 5:05 PM 597THE BREASTCHAPTER 17help to define a more personalized or individualized approach to breast cancer treatment in the future.Antiestrogen TherapyTamoxifen. Within the cytosol of breast cancer cells are spe-cific proteins (receptors) that bind and transfer steroid moieties into the cell nucleus to exert specific hormonal effects.308,327-331 The most widely studied hormone receptors are the estrogen receptor and progesterone receptor. Hormone receptors are detectable in >90% of well-differentiated ductal and lobular invasive cancers. Although the receptor status may remain the same between the primary cancer and metastatic disease in the same patient in the majority of cases, there are instances where the status is changed in the metastatic focus; therefore, biopsy of newly diagnosed metastatic disease should be considered for assessment of hormone receptor and HER2 status.After binding to estrogen receptors in the cytosol, tamoxi-fen blocks the uptake of estrogen by breast tissue. Clini-cal responses to antiestrogen are evident in >60% of women with hormone receptor-positive breast cancers but in <10% of women with hormone receptor-negative breast cancers. A meta-analysis by the Early Breast Cancer Trialists’ Collabora-tive Group showed that adjuvant therapy with tamoxifen for 5 years reduced breast cancer mortality by about a third through the first 15 years of follow-up.14 This mortality benefit contin-ues to be statistically significant in the second and third 5-year periods (i.e., years 5–9 and 10–15) when the patients are no longer receiving endocrine treatment—the so-called carry-over effect. The analysis also showed a 39% reduction in the risk of cancer in the contralateral breast. The antiestrogens do have defined toxicity, including bone pain, hot flashes, nausea, vom-iting, and fluid retention. Thrombotic events occur in <3% of treated women. Cataract surgery is more frequently performed in patients receiving tamoxifen. The Stockholm trial showed that 5 years of tamoxifen was associated with a significant reduction in locoregional recurrences and distant metastasis in postmenopausal women with ER-positive breast cancer.332 However, an increase in endometrial cancers was observed with long-term tamoxifen use. The NSABP B14 trial evaluated 10 years of tamoxifen compared to 5 years.333 However, the study was terminated based on interim analyses indicating no addi-tional benefit from tamoxifen beyond 5 years. The ATLAS trial also evaluated the use of tamoxifen for 5 years vs. 10 years in nearly 13,000 women across the world. This study showed that continuing tamoxifen for 10 years vs. 5 years produced a significant reduction in recurrence and mortality.334 Interestingly, the benefit was not seen in the second 5 years (i.e., years 5–9) while the patients were on treatment, but it was seen from years 10 to 15. One reason the NSABP B14 study was led to conclude that 10 years of tamoxifen was not beneficial was that the follow-up time was shorter. Results of the ATLAS study were also corroborated by the aTTom study. Similarly, extended adjuvant therapy with letrozole after 5 years of tamoxifen was shown to improve disease-free survival without improvement in overall survival except in node-positive patients.335Tamoxifen therapy is also considered for women with DCIS that is found to be ER-positive. The goals of such ther-apy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event. Consequently, tamoxifen is not recommended for patients who have had bilateral mastectomies with ER-positive DCIS. With the use of aromatase inhibitors in postmenopausal women, use of adjuvant tamoxifen has increasingly been limited to premenopausal women.Aromatase Inhibitors. In postmenopausal women, aromatase inhibitors are now considered first-line therapy in the adjuvant setting. Currently, three third-generation aromatase inhibitors are approved for clinical use: the reversible nonsteroidal inhibitors anastrozole and letrozole and the irreversible steroidal inhibitor exemestane. While all the aromatase inhibitors have been shown to have similar efficacy with a similar spectrum of adverse effects, the Early Breast Cancer Trialists’ Collaborative Group meta-analyses of 31,920 postmenopausal women with ER-positive early breast cancers treated with tamoxifen or aroma-tase inhibitors demonstrated that 5 years of aromatase inhibitors reduced the rate of recurrence by 30% and 10-year breast cancer mortality by about 15% compared to 5 years of tamoxifen.336-339 The NSABP B42 study evaluated whether an additional 5 years of letrozole improved disease-free survival in postmenopausal women who have completed 5 years of tamoxifen or an aromatase inhibitor. After a median follow-up of 6.9 years, while extended letrozole significantly improved breast cancer-free interval, no improvement in disease-free survival, the primary endpoint, was observed. Recently, the results of the MA-17R study, designed to assess the efficacy of adjuvant letrozole for 10 years, were reported.340 Similar to NSABP B42, extended letrozole improved disease-free survival without significant improvement in overall survival. Patients who are node-positive, have received adjuvant chemotherapy, with prior receipt of tamoxifen are likely to ben-efit from long-term use of an aromatase inhibitor.The aromatase inhibitors are less likely than tamoxifen to cause endometrial cancer but do lead to changes in bone mineral density that may result in osteoporosis and an increased rate of fractures in postmenopausal women. The risk of osteoporosis can be averted by treatment with bisphosphonates. Joint pains are a side effect that affects a significant number of patients. Node-negative and node-positive breast cancer patients whose tumors express hormone receptors should be considered for endocrine therapy in the adjuvant setting. Women with hormone receptor–positive cancers achieve significant reduction in risk of recurrence of breast cancer and mortality from breast cancer through the use of endocrine therapies.For postmenopausal women with ER-positive, HER2-negative, metastatic breast cancer, available endocrine thera-pies include nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); serum ER modulators (tamoxifen or toremifene); ER down-regulators (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). A third generation nonsteroidal aromatase inhibitor or palbo-ciclib, the CDK 4/6 inhibitor, in combination with letrozole may be considered as a treatment option for first-line therapy. Activation of CDK4/CDK6 cell cycle signaling axis has been implicated in mediating endocrine resistance. Consequently, PALOMA-1 evaluated the safety and efficacy of palbociclib in combination with letrozole vs. letrozole alone as first-line treat-ment for patients with ER-positive, HER2-negative advanced breast cancer. Median progression-free survival (PFS) was doubled with the combination compared to letrozole alone (20.2 months vs. 10.2 months for the letrozole).341 Based on this, the FDA approved palbociclib in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial treatment. The Brunicardi_Ch17_p0541-p0612.indd 59701/03/19 5:05 PM 598SPECIFIC CONSIDERATIONSPART IIbenefit of palbociclib in combination with letrozole was sub-sequently confirmed in a phase 3 trial (PFS 24.8 months vs. 14.5 months for letrozole).342 Two additional CDK4/6 inhibitors, ribociclib and abemaciclib, have been approved for use in com-bination with endocrine therapy for patients with hormone receptor–positive advanced breast cancer.On the other hand, PALOMA-3 compared the combina-tion of palbociclib and fulvestrant to fulvestrant alone in preor postmenopausal ER-positive, HER2-negative metastatic breast cancer patients, whose disease progressed on prior endocrine therapy. Premenopausal women also received the GNRH ago-nist, goserelin. The median PFS was 9.2 months for the combi-nation compared to 3.8 months with fulvestrant alone.343 Thus, fulvestrant with palbociclib is a potential option for women with metastatic breast cancer who have progressed on prior endo-crine therapy. Additionally, abemaciclib in combination with fulvestrant or as single agent is approved for use in ER-posi-tive advanced breast cancers previously treated with endocrine therapy.In premenopausal women with stage IV ER-positive breast cancer without previous exposure to endocrine therapy, initial treatment with tamoxifen or ovarian suppression/ablation plus aromatase inhibitor with or without CDK4/6 inhibitors are reasonable options.Activation of the PI3K/mammalian target of rapamycin (mTOR) signal transduction pathway has also been implicated in secondary resistance to estrogen targeting. BOLERO-2 eval-uated the use of exemestane in combination with everolimus in postmenopausal women with ER-positive tumors who had progressed or recurred on a nonsteroidal aromatase inhibitor.344 An improvement in PFS was observed with combination com-pared to exemestane alone (11 vs. 4.1 months) leading to FDA approval. Similar improvement in PFS was observed with a combination of tamoxifen and everolimus.345 However, a phase 3 trial of letrozole in combination with temsirolimus, an mTOR inhibitor, did not show any improvement in PFS in aromatase inhibitor–naive metastatic postmenopausal women.346 Trials evaluating the adjuvant use of mTOR inhibitors and CDK 4/6 inhibitors are currently in progress.Women whose tumors respond to an endocrine therapy with either shrinkage of their breast cancer (objective response) or long-term stabilization of disease (stable disease) are con-sidered to represent “clinical benefit” and should receive addi-tional endocrine therapy at the time of progression because their chances of a further response remain high.294-296 Patients whose tumors progress de novo on an endocrine agent have a low rate of clinical benefit (<20%) to subsequent endocrine therapy; the choice of endocrine or chemotherapy should be considered based on the disease site and extent as well as the patient’s general condition and treatment preference.294The adjuvant use of aromatase inhibitors and recent advances in tumor genome sequencing technologies have enabled the identification of secondary ESR1 mutations.347,348 These mutations, typically present in the ligand binding domains, lead to ligand-independent activation of the receptor, mediate resistance to aromatase inhibitors, and are associated with shorter survival.349 Reported incidence of these mutations are variable (20%–30%) based on prior exposure to aroma-tase inhibitors and are uncommon in primary breast cancers. Clinical trials evaluating novel selective estrogen receptor degraders with potential activity against these mutations are in progress.Ablative Endocrine TherapyIn the past, adrenalectomy and/or hypophysectomy were the pri-mary endocrine modalities used to treat metastatic breast cancer, but today these approaches are seldom used. In women who are premenopausal at diagnosis, ovarian ablation can be accomplished by oophorectomy or ovarian radiation. Ovarian suppression can be accomplished by the use of gonadotrophin-hormone releasing hormone agonists, such as goserelin or leuprolide. Evaluation of the combination of goserelin with tamoxifen vs. cyclophospha-mide/methotrexate/fluorouracil chemotherapy in premenopausal ER-positive early-stage breast cancers showed that relapse-free survival was superior with endocrine therapy combination, with a similar trend in overall survival.350 Data from the SOFT and TEXT trials on adjuvant endocrine therapy show that exemes-tane plus ovarian suppression significantly reduces recurrences as compared with tamoxifen plus ovarian suppression.351,352 In these trials, ovarian suppression was achieved with the use of the gonadotropin-releasing hormone agonist triptorelin, oopho-rectomy, or ovarian irradiation. The disease-free survival was 89% in the tamoxifen plus ovarian suppression group, while it was 93% in exemestane plus ovarian suppression group; how-ever, there was no significant differences in overall survival. In the SOFT trial, while tamoxifen plus ovarian suppression was not superior to tamoxifen alone in terms of disease-free survival, improved outcomes were observed in ovarian suppression in women with a high risk of recurrence. In women who received no adjuvant chemotherapy, no meaningful benefit was obtained with ovarian suppression. Thus, ovarian suppression in combi-nation with an aromatase inhibitor can be considered in select premenopausal women with high-risk features (age <40 years, positive lymph nodes) who warranted adjuvant chemotherapy.Anti-HER2 TherapyThe determination of tumor HER-2 expression or gene ampli-fication for all newly diagnosed patients with breast cancer is now recommended.353-356 It is used to assist in the selection of adjuvant chemotherapy in both node-negative and node-positive patients. Trastuzumab was initially approved for the treatment of HER2/neu-positive breast cancer in patients with metastatic disease. Once efficacy was demonstrated for patients with metastatic disease, the NSABP and the North Central Cancer Treatment Group conducted phase 3 trials that evaluated the impact of adjuvant trastuzumab therapy in patients with early-stage breast cancer. After approval from the FDA, these groups amended their adjuvant trastuzumab trials (B-31 and N9831, respectively), to provide for a joint efficacy analysis. The first joint interim efficacy analysis demonstrated an improvement in 3-year disease-free survival from 75% in the control arm to 87% in the trastuzumab arm (hazard ratio = 0.48, P <.0001). There was an accompanying 33% reduction in mortality in the patients who received trastuzumab (hazard ratio = 0.67, P = 0.015). The magnitude of reduction in hazard for disease-free survival events crossed prespecified early reporting boundaries, so the data-monitoring committees for both groups recommended that randomized accrual to the trials be ended, and the results were subsequently published.181While anthracycline-based adjuvant chemotherapy was considered preferable in HER2-positive breast cancer, the BCIRG 006 compared the use of anthracycline with taxane and trastuzumab (AC-TH) versus taxane, carboplatin chemotherapy with trastuzumab (TCH).182 With 10 years of follow-up, no statistical significance with regard to disease-free and overall Brunicardi_Ch17_p0541-p0612.indd 59801/03/19 5:05 PM 599THE BREASTCHAPTER 17survival was observed for anthracycline-based chemotherapy. While anthracycline chemotherapy was numerically superior, this was accompanied by an increase in the incidence of leu-kemia and congestive heart failure. A year of adjuvant trastu-zumab is considered standard of care. Two years of adjuvant trastuzumab has been shown to be more effective, although it is associated with more toxicity than 1 year of trastuzumab.357 On the other hand, the PHARE trial examined 6 months vs. stan-dard 12 months of trastuzumab. After 3.5 years of follow-up, the study failed to demonstrate that 6 months was noninferior com-pared to the standard therapy.358 Patients with HER2-positive tumors benefit if trastuzumab is added to taxane chemotherapy. Because of overlapping cardiotoxicities, trastuzumab is not usu-ally given concurrently with anthracyclines.Buzdar and colleagues reported the results of a random-ized neoadjuvant trial of trastuzumab in combination with sequential paclitaxel followed by FEC-75 (5-fluorouracil, epi-rubicin, cyclophosphamide) vs. the same chemotherapy regimen without trastuzumab in 42 women with early-stage operable breast cancer. The pathologic complete response rates in this trial increased from 25% to 66.7% when chemotherapy was given concurrently with trastuzumab.301 A subsequent report that included additional patients treated with concurrent chemo-therapy and trastuzumab further confirmed the high pathologic complete response rates and continued to show that cardiac function was preserved.302While novel agents have been approved for the treatment of women with metastatic HER2-positive breast cancers, cur-rently trastuzumab is the only HER2-targeted agent approved for use in the adjuvant setting. Lapatinib is a dual tyrosine kinase inhibitor that targets both HER2 and EGFR. It was approved for use with capecitabine in patients with HER2-positive meta-static disease. Adjuvant lapatinib was shown to be inferior to trastuzumab, and the combination of lapatinib with trastuzumab did yield a significant improvement in disease-free survival compared to trastuzumab alone. Ado-trastuzumab emtansine (T-DM1) is approved for HER2-positive metastatic breast cancer patients who have previously received trastuzumab and a taxane either separately or in combination. T-DM1 is an antibody drug conjugate that incorporates the HER2 targeted activity of trastuzumab with the cytotoxic activity of DM1, a microtubule inhibitory agent leading to apoptosis.359Pertuzumab is a humanized monoclonal antibody that binds at a different epitope of the HER2 extracellular domain (subdomain II) and prevents dimerization of HER2 with other members of the family, primarily HER3. In the metastatic setting, it is approved in combination with trastuzumab and docetaxel for patients with metastatic HER2-positive breast cancer who have not received prior HER2-targeted therapy or chemotherapy for metastatic disease.360 In the neoadjuvant setting, pertuzumab is approved in combination with trastu-zumab and docetaxel in HER2-positive, early stage breast cancers that are greater than 2 cm or node-positive. However, this approval is based on improvement in pathologic complete response rate, and not data based on improvement in event free or overall survival.361,362 In the NeoSphere trial, neoadjuvant use of pertuzumab with trastuzumab and docetaxel led to nearly a 17% increase in pathologic complete response in the breast (P = .0141).361 While in the TRYPHAENA study, pathologic complete responses ranging from 57% to 66% were observed with neoadjuvant pertuzumab and trastuzumab combination given with anthracycline-containing or nonanthracycline-containing chemotherapy.362 With the use of dual antibody therapy, cur-rently there is significant interest in identifying patients who can avoid chemotherapy and potentially be treated with HER2-targeted agents alone. The NeoSphere study showed 27% pathologic complete response in HER2-positive, ER-negative, breast cancer patients treated with pertuzumab and trastuzumab alone. Pertuzumab was recently FDA approved in combination with trastuzumab and chemotherapy in the adjuvant setting in HER2 amplified breast cancers with high risk of recurrence. Approval is based on APHINITY trial showing that the addition of pertuzumab improved invasive disease free survival (7.1%) compared to placebo (8.7%) (HR 0.82, 95% CI: 0.67, 1.00; p = 0.047). Overall survival data is not mature.The ExteNET study evaluated the use of neratinib, an irreversible inhibitor of EGFR, HER2, and HER4, in HER2-positive early stage patients who have completed adjuvant trastuzumab. A year of neratinib after completion of chemo-therapy and trastuzumab-based adjuvant therapy significantly improved 2-year disease-free survival, the primary endpoint.363 After two years, invasive disease free survival was 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo (HR 0.66; 95% CI: 0.49, 0.90, p = 0.008) leading to FDA approval for HER2 amplified breast cancers following a year of adjuvant trastuzumab.In addition to amplifications or copy number alterations, activating mutations or single nucleotide variants in HER2 have been described (2%).364 Typically observed in ER-positive breast cancers, a higher prevalence of HER2 mutations have been reported in invasive lobular carcinomas, particularly in the pleomorphic subtype.365 These mutations, usually exclusive with HER2 amplification, are observed in kinase or extracellular domains and predict for responses or resistance to HER2-targeting agents.366,367 A phase 2 trial of neratinib in HER2-mutated meta-static breast cancers showed a clinical benefit rate of 36% with one complete response and one partial response in a heavily pre-treated population. A clinical trial evaluating the combination of neratinib with fulvestrant, in HER2-mutated, ER-positive breast cancers, is in progress.SPECIAL CLINICAL SITUATIONSNipple DischargeUnilateral Nipple Discharge. Nipple discharge is a finding that can be seen in a number of clinical situations. It may be suggestive of cancer if it is spontaneous, unilateral, localized to a single duct, present in women ≥40 years of age, bloody, or associated with a mass. A trigger point on the breast may be present so that pressure around the nipple-areolar complex induces discharge from a single duct. In this circumstance, mammography and ultrasound are indicated for further evalu-ation. A ductogram also can be useful and is performed by can-nulating a single discharging duct with a small nylon catheter or needle and injecting 1.0 mL of water-soluble contrast solu-tion. Nipple discharge associated with a cancer may be clear, bloody, or serous. Testing for the presence of hemoglobin is helpful, but hemoglobin may also be detected when nipple dis-charge is secondary to an intraductal papilloma or duct ecta-sia. Definitive diagnosis depends on excisional biopsy of the offending duct and any associated mass lesion. A 3.0 lacrimal duct probe can be used to identify the duct that requires exci-sion. Another approach is to inject methylene blue dye within Brunicardi_Ch17_p0541-p0612.indd 59901/03/19 5:05 PM 600SPECIFIC CONSIDERATIONSPART IIthe duct after ductography. The nipple must be sealed with collodion or a similar material so that the blue dye does not discharge through the nipple but remains within the distended duct facilitating its localization. Localization with a wire or seed is performed when there is an associated mass that lies >2.0 to 3.0 cm from the nipple.Bilateral Nipple Discharge. Nipple discharge is suggestive of a benign condition if it is bilateral and multiductal in origin, occurs in women ≤39 years of age, or is milky or blue-green. Prolactin-secreting pituitary adenomas are responsible for bilat-eral nipple discharge in <2% of cases. If serum prolactin levels are repeatedly elevated, plain radiographs of the sellaturcica are indicated, and thin section CT scan is required. Optical nerve compression, visual field loss, and infertility are associated with large pituitary adenomas.Axillary Lymph Node Metastases in the Setting of an Unknown Primary CancerA woman who presents with an axillary lymph node metasta-sis that is consistent with a breast cancer metastasis has a 90% probability of harboring an occult breast cancer.303 However, axillary lymphadenopathy is the initial presenting sign in only 1% of breast cancer patients. Fine-needle aspiration biopsy or core-needle biopsy can be used to establish the diagnosis when an enlarged axillary lymph node is identified. When metastatic cancer is found, immunohistochemical analysis may classify the cancer as epithelial, melanocytic, or lymphoid in origin. The presence of hormone receptors (estrogen or progesterone receptors) suggests metastasis from a breast cancer but is not diagnostic. The search for a primary cancer includes careful examination of the thyroid, breast, and pelvis, including the rectum. The breast should be examined with diagnostic mam-mography, ultrasonography, and MRI to evaluate for an occult primary lesion. Further radiologic and laboratory studies should include chest radiography and liver function studies. Additional imaging of the chest, abdomen, and skeleton may be indicated if the extent of nodal involvement is consistent with stage III breast cancer. Suspicious findings on mammography, ultra-sonography, or MRI necessitate breast biopsy. When a breast cancer is found, treatment consists of an axillary lymph node dissection with a mastectomy or preservation of the breast fol-lowed by whole-breast radiation therapy. Chemotherapy and endocrine therapy should be considered.Breast Cancer During PregnancyBreast cancer occurs in 1 of every 3000 pregnant women, and axillary lymph node metastases are present in up to 75% of these women.368 The average age of the pregnant woman with breast cancer is 34 years. Fewer than 25% of the breast nodules developing during pregnancy and lactation will be cancerous. Ultrasonography and needle biopsy specimens are used in the diagnosis of these nodules. Mammography is rarely indicated because of its decreased sensitivity during pregnancy and lac-tation; however, the fetus can be shielded if mammography is needed. Approximately 30% of the benign conditions encoun-tered will be unique to pregnancy and lactation (galactoceles, lobular hyperplasia, lactating adenoma, and mastitis or abscess). Once a breast cancer is diagnosed, complete blood count, chest radiography (with shielding of the abdomen), and liver function studies are performed.Because of the potential deleterious effects of radiation therapy on the fetus, radiation cannot be considered until the fetus is delivered. A modified radical mastectomy can be per-formed during the first and second trimesters of pregnancy, even though there is an increased risk of spontaneous abortion after first-trimester anesthesia. During the third trimester, lumpec-tomy with axillary node dissection can be considered if adju-vant radiation therapy is deferred until after delivery. Lactation is suppressed. Chemotherapy administered during the first tri-mester carries a risk of spontaneous abortion and a 12% risk of birth defects. There is no evidence of teratogenicity resulting from administration of chemotherapeutic agents in the second and third trimesters. For this reason, many clinicians now con-sider the optimal strategy to be delivery of chemotherapy in the second and third trimesters as a neoadjuvant approach, which allows local therapy decisions to be made after the delivery of the baby. Pregnant women with breast cancer often present at a later stage of disease because breast tissue changes that occur in the hormone-rich environment of pregnancy obscure early cancers. However, pregnant women with breast cancer have a prognosis, stage by stage, that is similar to that of nonpregnant women with breast cancer.Male Breast CancerFewer than 1% of all breast cancers occur in men.369,370 The inci-dence appears to be highest among North Americans and the British, in whom breast cancer constitutes as much as 1.5% of all male cancers. Jewish and African-American men have the highest incidence. Male breast cancer is preceded by gyneco-mastia in 20% of men. It is associated with radiation exposure, estrogen therapy, testicular feminizing syndromes, and Kline-felter’s syndrome (XXY). Breast cancer is rarely seen in young males and has a peak incidence in the sixth decade of life. A firm, nontender mass in the male breast requires investigation. Skin or chest wall fixation is particularly worrisome.DCIS makes up <15% of male breast cancer, whereas infil-trating ductal carcinoma makes up >85%. Special-type cancers, including infiltrating lobular carcinoma, have occasionally been reported. Male breast cancer is staged in the same way as female breast cancer, and stage by stage, men with breast cancer have the same survival rate as women. Overall, men do worse because of the more advanced stage of their cancer (stage II, III or IV) at the time of diagnosis. The treatment of male breast cancer is surgi-cal, with the most common procedure being a modified radical mastectomy. SLN dissection has been shown to be feasible and accurate for nodal assessment in men presenting with a clinically node-negative axilla. Adjuvant radiation therapy is appropriate in cases in which there is a high risk for local-regional recurrence. Approximately 80% of male breast cancers are hormone recep-tor–positive, and adjuvant tamoxifen is considered. Systemic che-motherapy is considered for men with hormone receptor-negative cancers and for men with large primary tumors, multiple positive nodes, and locally advanced disease.Phyllodes TumorsThe nomenclature, presentation, and diagnosis of phyllodes tumors (including cystosarcoma phyllodes) have posed many problems for surgeons.371 These tumors are classified as benign, borderline, or malignant. Borderline tumors have a greater potential for local recurrence.Mammographic evidence of calcifications and morpho-logic evidence of necrosis do not distinguish between benign, borderline, and malignant phyllodes tumors. Consequently, it is difficult to differentiate benign phyllodes tumors from the Brunicardi_Ch17_p0541-p0612.indd 60001/03/19 5:05 PM 601THE BREASTCHAPTER 17malignant variant and from fibroadenomas. Phyllodes tumors are usually sharply demarcated from the surrounding breast tissue, which is compressed and distorted. Connective tissue composes the bulk of these tumors, which have mixed gelati-nous, solid, and cystic areas. Cystic areas represent sites of infarction and necrosis. These gross alterations give the gross cut tumor surface its classical leaf-like (phyllodes) appearance. The stroma of a phyllodes tumor generally has greater cellular activity than that of a fibroadenoma. After microdissection to harvest clusters of stromal cells from fibroadenomas and from phyllodes tumors, molecular biology techniques have shown the stromal cells of fibroadenomas to be either polyclonal or mono-clonal (derived from a single progenitor cell), whereas those of phyllodes tumors are always monoclonal.Most malignant phyllodes tumors (Fig. 17-38) contain liposarcomatous or rhabdomyosarcomatous elements rather than fibrosarcomatous elements. Evaluation of the number of mitoses and the presence or absence of invasive foci at the tumor mar-gins may help to identify a malignant tumor. Small phyllodes tumors are excised with a margin of normal-appearing breast tissue. When the diagnosis of a phyllodes tumor with suspicious ABFigure 17-38. A. Malignant phyllodes tumor (cystosarcoma-phyllodes). B. Histologic features of a malignant phyllodes tumor (hematoxylin and eosin stain, ×100).malignant elements is made, reexcision of the biopsy specimen site to ensure complete excision of the tumor with a 1-cm mar-gin of normal-appearing breast tissue is indicated. Large phyl-lodes tumors may require mastectomy. Axillary dissection is not recommended because axillary lymph node metastases rarely occur.Inflammatory Breast CarcinomaInflammatory breast carcinoma (stage IIIB) accounts for <3% of breast cancers. This cancer is characterized by the skin changes of brawny induration, erythema with a raised edge, and edema (peau d’orange).372 Permeation of the dermal lymph vessels by cancer cells is seen in skin biopsy specimens. There may be an associated breast mass (Fig. 17-39). The clinical differentia-tion of inflammatory breast cancer may be extremely difficult, especially when a locally advanced scirrhous carcinoma invades dermal lymph vessels in the skin to produce peau d’orange and lymphangitis (Table 17-15). Inflammatory breast cancer also may be mistaken for a bacterial infection of the breast. More than 75% of women who have inflammatory breast cancer present with palpable axillary lymphadenopathy, and distant metastases also are frequently present. A PET-CT scan should be considered at the time of diagnosis to rule out concurrent metastatic disease. A report of the SEER program described distant metastases at diagnosis in 25% of white women with inflammatory breast carcinoma.Surgery alone and surgery with adjuvant radiation therapy have produced disappointing results in women with inflamma-tory breast cancer. However, neoadjuvant chemotherapy with an anthracycline-containing regimen may affect dramatic regres-sions in up to 75% of cases. Tumors should be assessed for HER2 and hormone receptors with treatment dictated based on receptor status. Modified radical mastectomy is performed after demonstrated response to systemic therapy to remove residual cancer from the chest wall and axilla. Adjuvant chemotherapy may be indicated depending on final pathologic assessment of the breast and regional nodes. Finally, the chest wall and the Figure 17-39. Inflammatory breast carcinoma. Stage IIIB cancer of the breast with erythema, skin edema (peau d’orange), nipple retraction, and satellite skin nodules.Brunicardi_Ch17_p0541-p0612.indd 60101/03/19 5:06 PM 602SPECIFIC CONSIDERATIONSPART IIsupraclavicular, internal mammary, and axillary lymph node basins receive adjuvant radiation therapy. This multimodal approach results in 5-year survival rates that approach 30%. Patients with inflammatory breast cancer should be encouraged to participate in clinical trials.Rare Breast CancersSquamous Cell (Epidermoid) Carcinoma. Squamous cell (epidermoid) carcinoma is a rare cancer that arises from metaplasia within the duct system and generally is devoid of distinctive clinical or radiographic characteristics.373 Regional metastases occur in 25% of patients, whereas distant metastases are rare.Adenoid Cystic Carcinoma. Adenoid cystic carcinoma is very rare, accounting for <0.1% of all breast cancers. It is typically indistinguishable from adenoid cystic carcinoma arising in sali-vary tissues. These cancers are generally 1 to 3 cm in diameter at presentation and are well circumscribed. Axillary lymph node metastases are rare, but deaths from pulmonary metastases have been reported.Apocrine Carcinomas. Apocrine carcinomas are well-differentiated cancers that have rounded vesicular nuclei and prominent nucleoli. There is a very low mitotic rate and little variation in cellular features. However, apocrine carcinomas may display an aggressive growth pattern.Sarcomas. Sarcomas of the breast are histologically similar to soft tissue sarcomas at other anatomic sites. This diverse group includes fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, malignant schwannoma, rhab-domyosarcoma, osteogenic sarcoma, and chondrosarcoma. The clinical presentation is typically that of a large, painless breast mass with rapid growth. Diagnosis is by core-needle biopsy or by open incisional biopsy. Sarcomas are graded based on cellular-ity, degree of differentiation, nuclear atypia, and mitotic activity. Primary treatment is wide local excision, which may necessitate mastectomy. Axillary dissection is not indicated unless there is biopsy proven lymph node involvement. Angiosarcomas are classified as de novo, as postradiation, or as arising in associa-tion with postmastectomy lymphedema. In 1948, Stewart and Treves described lymphangiosarcoma of the upper extremity in women with ipsilateral lymphedema after radical mastectomy.374 Angiosarcoma is now the preferred name. The average interval between modified radical or radical mastectomy and the devel-opment of an angiosarcoma is 7 to 10 years. Sixty percent of women developing this cancer have a history of adjuvant radia-tion therapy. Forequarter amputation may be necessary to palli-ate the ulcerative complications and advanced lymphedema.Lymphomas. Primary lymphomas of the breast are rare, and there are two distinct clinicopathologic variants. One type occurs in women ≤39 years of age, is frequently bilateral, and has the histologic features of Burkitt’s lymphoma. The second type is seen in women ≥40 years of age and is usually of the B-cell type. Breast involvement by Hodgkin’s lymphoma has been reported. An occult breast lymphoma may be diagnosed after detection of palpable axillary lymphadenopathy. Treatment depends on the stage of disease. Lumpectomy or mastectomy may be required. Axillary dissection for clearance of disease may be necessary. Recurrent or progressive local-regional disease is best man-aged by chemotherapy and radiation therapy. The prognosis is favorable, with 5and 10-year survival rates of 74% and 51%, respectively. More recently anaplastic large cell lymphoma has been described in association with breast implants for cosmetic or reconstructive purposes. This disease is treated with complete excision of the implant capsule with any associated soft tissue mass. More advanced cases may require systemic therapy and radiation treatment.REFERENCESEntries highlighted in bright blue are key references. 1. Breasted JH. The Edwin Smith Surgical Papyrus. University of Chicago Press, 1930;405. 2. Celsus AC. De Medicina (ed Loeb Classical Library Ed). Cambridge: Harvard University Press; 1935;131. 3. Beenken SW. History of the therapy of breast cancer. 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Disorders of the Head and NeckAntoine Eskander, Stephen Y. Kang, Michael S. Harris, Bradley A. Otto, Oliver Adunka, Randal S. Weber, and Theodoros N. Teknos 18chapterCOMPLEX ANATOMY AND FUNCTIONThe anatomy of the head and neck is complex because of the proximity of vital structures such as framework, nerves, and arteries. Functionally, these structures afford most of the human senses: vision, taste, smell, and hearing. Even more fundamental, the upper aerodigestive tract is critical for breathing, speech, and swallowing. Otolaryngology—head and neck surgery is the field that predominantly deals with disorders of the head and neck; however, a multidisciplinary approach is required to achieve optimal outcomes. The multidisciplinary team can include audi-ology, speech language pathology, allergy/immunology, neurol-ogy, neurosurgery, radiation, and medical oncology. This chapter aims to provide an overview of the most common diseases pre-senting to and treated by the otolaryngologist—head and neck surgeon. It reviews benign conditions, trauma, malignancies, reconstruction, tracheotomy, and rehabilitation.BENIGN CONDITIONS OF THE HEAD AND NECKOtologyInfectious. Infectious processes of the ear may be consid-ered by their location (external, middle, or inner ear), their time course (acute or chronic), and the presence of complications. The external ear or pinna consists of a cartilaginous frame-work, perichondrium, and a relatively thin layer of skin. Ery-sipelas (St Anthony’s Fire) or impetigo are causes of external ear infection affecting the dermis or hypodermis of the auricle, typically caused by Streptococcus pyogenes or Staphylococcus aureus, respectively, that may be encountered posttraumatically or related to ear piercing. Treatment is oral antibiotic therapy targeting these organisms. History and clinical features such as presence of bullae and golden crusting distinguish erysipelas and impetigo from other benign entities causing erythema and edema of the auricle, such as relapsing polychondritis, which is typically diffuse, lobule-sparing, and steroid-responsive.Acute otitis externa, often referred to as “swimmer’s ear,” denotes infection of the skin of the external auditory canal.1 Typically, the pathology is incited by moisture within the canal leading to skin maceration and pruritus. Subsequent trauma to the canal skin by scratching (i.e., instrumentation with a cot-ton swab or fingernail), erodes the normally protective skin/cerumen barrier. Hearing aid use and comorbid dermatologic conditions such as eczema or other forms of dermatitis may similarly serve as predisposing factors. The milieu of the exter-nal ear canal—dark, warm, humid—is ideal for rapid microbial proliferation. The most common offending organism is Pseu-domonas aeruginosa, although other bacteria and fungi may also be involved. Symptoms and signs of otitis externa include itching during the initial phases and pain with marked swelling of the canal soft tissues as the infection progresses. Treatment involves removal of debris under otomicroscopy and applica-tion of appropriate ototopical antimicrobials, such as neomycin/polymyxin or quinolone-containing eardrops. The topical ste-roid component of these drops (e.g., hydrocortisone or dexa-methasone) addresses swelling and, as a result, decreases the often intense pain associated with this infection. In cases of marked ear canal edema, the use of an otowick is required to facilitate delivery of ototopical medication medially into the ear canal. Fungal infections may call for the addition of 2% acetic acid to reestablish the premorbid pH balance. Patients with otitis externa should also be instructed to keep the ear dry. Systemic antibiotics are reserved for those with severe infections, diabet-ics, and immunosuppression.Complex Anatomy and Function 613Benign Conditions of the Head  and Neck 613Otology / 613Sinonasal Inflammatory Disease / 617Pharyngeal and Adenotonsillar Disease / 622Benign Conditions of the Larynx / 624Vascular Lesions / 626Trauma of the Head and Neck 627Soft Tissue / 627Facial Fractures / 628Temporal Bone Fractures / 629Tumors of the Head and Neck 629Etiology and Epidemiology / 630Anatomy and Histopathology / 630Second Primary Tumors in the Head and Neck / 631Staging / 632Upper Aerodigestive Tract / 632Nose and Paranasal Sinuses / 643Nasopharynx / 644Ear and Temporal Bone / 645Neck / 646Salivary Gland Tumors / 650Reconstruction 651Local Flaps and Skin Grafts / 651Regional Flaps / 651Free Tissue Transfer / 651Tracheotomy 652Indications and Timing / 652Technique and Complications / 652Speech with Tracheotomy and Decannulation / 653Long Term Management  and Rehabilitation 654Palliative Care / 654Follow-Up Care / 654Brunicardi_Ch18_p0613-p0660.indd 61301/03/19 5:22 PM 614Figure 18-1. Acute otitis media.Malignant otitis externa, a fulminant necrotizing infec-tion of the soft tissues of the external ear canal combined with osteomyelitis of the temporal bone, is a potentially life-threatening form of otitis externa seen most commonly among elderly patients with insulin-dependent diabetes mellitus or immunodeficiency.2,3 The classic physical finding is granulation tissue along the floor of the external auditory canal near the bony cartilaginous junction. Symptoms include persistent otalgia for longer than one month and purulent otorrhea. Biopsy is called for in order to exclude malignancy. Computed tomography (CT) and magnetic resonance imaging (MRI) define the extension of disease. Technetium 99-m scans are useful in gauging extend of bony involvement in early disease. Gallium-67 scans are valu-able for monitoring disease during the course of treatment and for determining duration of antibiotic therapy. These patients require aggressive medical therapy including ototopical and IV antibiotics targeting Pseudomonas. Other gram-negative bacteria and fungi are occasionally implicated, necessitating culturedirected therapy. Patients who do not respond to medical management require surgical debridement. This condition may progress to involvement of the adjacent skull base and soft tissues, meningitis, brain abscess, and death.Acute otitis media (AOM) typically implies a bacterial infec-tion of the middle ear.4 This diagnosis accounts for 25% of pedi-atric antibiotic prescriptions and is the most common bacterial infection of childhood. Most cases occur before 2 years of age and are secondary to immaturity of the Eustachian tube. Well-recog-nized contributing factors include upper respiratory viral infection and daycare attendance, as well as craniofacial conditions affect-ing Eustachian tube function, such as cleft palate.It is important to distinguish between acute otitis media and otitis media with effusion (OME). The later denotes unin-fected serous fluid accumulation within the middle ear space. In children not already considered “at risk” for developmen-tal difficulties, OME is generally observed for resolution for a period of 3 months.5 Age-appropriate hearing testing should be performed when OME persists for ≥3 months or at any time when language delay, learning problems, or a significant hear-ing loss is suspected. In the absence of these factors, the child with OME should be reexamined at 3to 6-month intervals until the effusion is no longer present or until significant hear-ing loss is identified or structural abnormalities of the eardrum or middle ear are suspected. When hearing, speech, or structural concerns exist, myringotomy with tympanostomy tube place-ment is indicated.Signs and symptoms of infectious otitis media occurring for <3 weeks denote AOM. In this phase, otalgia and fever are the most common symptoms and physical exam reveals a bulging, opaque tympanic membrane (Fig. 18-1). If the process lasts 3 to 8 weeks, it is deemed subacute. Chronic otitis media, lasting more than 8 weeks, usually results from an unresolved acute otitis media. The most common organisms responsible are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.In order to minimize antibiotic resistance and obviate complications of antimicrobial therapy such as allergic reaction and diarrhea, guidelines have been established for the treatment of AOM.6,7 Pain associated with AOM should be recognized and treated with oral analgesics. In children older than 6 months who are not otherwise considered “high risk” for complications (e.g., immunocompromised, previous cochlear implantation, developmental anomalies of the inner ear) with symptoms con-sistent with unilateral AOM without otorrhea, an initial period of observation is offered. If initial observation is selected by the physician and family, a mechanism for reexamination in 48 to 72 hours to evaluate for clinical improvement must be in place. When these criteria are not met, or clinical improvement is not observed within 48 to 72 hours, oral antibiotics are begun. First-line therapy is high-dose amoxicillin or amoxicillin-clavulanate, for β-lactamase coverage. Chronic otitis media is frequently Key Points1 One of the most common benign head and neck disorders includes sinonasal inflammatory disease which can present as acute or chronic rhinosinusitis.2 Acute adeno-tonsillitis is a major cause of morbidity in children and adenotonsillectomy can significantly improve symptoms of both sleep disordered breathing and of symp-toms during acute infections.3 Squamous cell carcinoma comprises >90% of all of the malignant pathology of the mucosal lining of the upper aerodigestive tract.4 The ideal treatment protocol for these cancers varies by subsite, stage, patient comorbidity, and center preference/experience. Early stage disease is treated with unimodality and late stage disease is treated with multiple modalities in the form of primary surgery with adjuvant radiotherapy or primary concurrent chemoradiotherapy.5 Free flap reconstruction of head and neck defects is integral to help improve patient-reported quality of life and to re-establish form and function.Brunicardi_Ch18_p0613-p0660.indd 61401/03/19 5:22 PM 615DISORDERS OF THE HEAD AND NECKCHAPTER 18treated with myringotomy and tube placement (Fig. 18-2). This treatment is indicated for frequent acute episodes and in the set-ting of COME as discussed previously. The purpose of this pro-cedure is to remove the effusion and provide a route for middle ear ventilation. Episodes of AOM following tube placement are still possible. Myringotomy tubes, however, allow for preven-tion of painful tympanic membrane distension, risk of perfora-tion and other complications, and permit delivery of ototopicals into the middle ear space, in most cases obviating the need for systemic antibiotic therapy.Spontaneous tympanic membrane perforation during acute otitis media provides for drainage of purulent fluid and middle ear ventilation and frequently results in immediate resolution of severe pain. In the majority of cases, these perforations will heal spontaneously after the infection has resolved.8 Chronic otitis media, however, may be associated with nonhealing tympanic membrane perforations. Patients may have persistent otorrhea, which is treated with topical drops. Preparations containing ami-noglycoside are avoided because this class of drugs is toxic to the inner ear. Solutions containing alcohol or acetic acid may be irritating or caustic to the middle ear and are also avoided in the setting of a perforation. Nonhealing perforation requires surgical closure (tympanoplasty) after medical treatment of any residual acute infection.Chronic inflammatory changes from otitis media intersect with and share common etiological factors with cholesteatoma. Cholesteatoma is an epidermoid cyst of the middle ear and/or mastoid cavity that develops as result of Eustachian tube dysfunction. While several theories exist regarding causes of cholesteatoma, most cholesteatoma arises from squamous epi-thelium drawn into the middle ear via retraction pockets, most commonly in the pars flaccida.9 Squamous epithelium may also migrate into the middle ear via a perforation. Chronic mastoid-itis that fails medical management or is associated with cho-lesteatoma is treated by mastoidectomy. Chronic inflammation and destruction of middle ear structures by osteolytic enzymes of cholesteatoma matrix may also be associated with erosion of the ossicular chain, which can be reconstructed with various prostheses or autologous ossicular replacement techniques.Complications of otitis media with or without cholestea-toma may be grouped into two categories: intratemporal (oto-logic) and intracranial.10 Fortunately, complications are rare in the antibiotic era, but mounting antibiotic resistance necessitates an increased awareness of these conditions. Intratemporal com-plications include acute coalescent mastoiditis, petrositis, facial nerve paralysis, and labyrinthitis. In acute coalescing mastoid-itis, destruction of the bony lamellae by an acute purulent pro-cess results in severe pain, fever, and fluctuance behind the ear. The mastoid air cells coalesce into one common space filled with pus. Mastoid infection may also spread to the petrous apex, causing retro-orbital pain and sixth-nerve palsy. These diagno-ses are confirmed by computed tomographic scan. Facial nerve paralysis may also occur secondary to an acute inflammatory process in the middle ear or mastoid.11Intratemporal complications of otitis media are managed by myringotomy tube placement in addition to appropriate IV antibiotics. In acute coalescent mastoiditis and petrositis, mas-toidectomy is also performed as necessary to drain purulent foci. Labyrinthitis refers to inflammation of the inner ear. Most cases are idiopathic or are secondary to viral infections of the endolymphatic space. The patient experiences vertigo together with sensorineural hearing loss, and symptoms may smolder over several weeks. Labyrinthitis associated with middle ear infection may be serous or suppurative. In the former case, bac-terial products and/or inflammatory mediators transudate into the inner ear via the round window membrane, establishing an inflammatory process therein. Total recovery is eventually pos-sible after the middle ear is adequately treated.Suppurative labyrinthitis, however, is a much more toxic condition in which the acute purulent bacterial infection extends into the inner ear and causes marked destruction of the sensory hair cells and neurons of the eighth-nerve ganglion. This con-dition may be a harbinger for meningitis and must be treated rapidly. The goal of management of inner ear infection, which occurs secondary to middle ear infection, is to “sterilize” the middle ear space with antibiotics and the placement of a myr-ingotomy tube.The most common intracranial complication of otitis media is meningitis. Otologic meningitis in children is most commonly associated with an H. influenzae type B infection. Other intra-cranial complications include epidural abscess, subdural abscess, brain abscess, otitic hydrocephalus, and sigmoid sinus thrombo-phlebitis. In these cases, the otogenic source must be urgently treated with antibiotics and myringotomy tube placement. Mas-toidectomy and neurosurgical consultation may be necessary.Facial Nerve Disorders. Bell’s palsy is the most common etiology of facial nerve weakness/paralysis and is clinically dis-tinct from that occurring as a complication of otitis media in that the otologic exam is normal.12 Bell’s palsy is rapid, unilat-eral and, historically, considered idiopathic. It is now accepted, however, that the majority of these cases represent a viral neu-ropathy caused by herpes simplex. It is critical that clinicians distinguish Bell’s palsy from other causes of facial weakness/palsy. Alternative diagnoses are suggested by weakness/paraly-sis that arise gradually (rather than <72 hours), is bilateral, is accompanied by other neurological deficits, or does not show some recovery within 2 to 3 weeks and complete recovery at 3 to 4 months. Treatment includes oral steroids plus antiviral ther-apy (i.e., valacyclovir). Complete recovery is the norm, but it does not occur universally, and selected cases may benefit from surgical decompression of the nerve within its bony canal. Elec-trophysiologic testing has been used to identify those patients in whom surgery might be indicated.13 The procedure involves decompression of the nerve via exposure in the mastoid and middle cranial fossa.Figure 18-2. Myringotomy and tube.Brunicardi_Ch18_p0613-p0660.indd 61501/03/19 5:22 PM 616SPECIFIC CONSIDERATIONSPART IIVaricella zoster virus may also cause facial nerve paraly-sis when the virus reactivates from dormancy in the nerve. This condition, known as Ramsay Hunt syndrome, is characterized by severe otalgia followed by the eruption of vesicles of the external ear and the soft palate. Treatment is similar to Bell’s palsy, but full recovery is only seen in approximately two-thirds of cases.Traumatic facial nerve injuries may occur secondary to accidental trauma or surgical injury. Iatrogenic facial nerve trauma most often occurs during mastoidectomy, most com-monly to the vertical segment of the nerve.14 Detailed knowl-edge of facial nerve anatomy and adjunctive use of nerve integrity monitoring systems are imperative in this context. When the facial nerve is injured during an operative procedure, it is explored. Injury to >50% of the neural diameter of the facial nerve is addressed either with primary reanastomosis or recon-structed with the use a nerve graft. Complete recovery of nerve function is uncommon in these cases.Lesions of the Internal Auditory Canal and Cerebello-pontine Angle. The most common lesion affecting the inter-nal auditory canal (IAC) and the cerebellopontine angle (CPA) is vestibular schwannoma (formerly referred to as “acoustic neuroma”). Less commonly encountered lesions of the IAC and CPA include meningioma and epidermoid tumors. Vestibular schwannomas are benign tumors that comprise 60% to 92% of all CPA lesions and 6% to 10% of intracranial tumors. They demon-strate an average growth rate of 1 to 2 mm per year.15 Vestibular schwannomas are most commonly unilateral and sporadic; bilat-eral tumors are the hallmark of neurofibromatosis type 2 (NF2), an autosomal dominant condition linked to mutation of a tumor suppressor gene mapped to chromosome 22. The most common presenting symptoms of vestibular schwannoma are asymmetric sensorineural hearing loss and speech perception deficits often out of proportion to degree of hearing loss indicated by audiom-etry. Unilateral tinnitus is also frequently reported. Disequilib-rium or, less commonly, episodic vertigo may be present. Facial nerve weakness or paralysis is rare. Larger tumors may feature facial numbness and loss of the cornea reflex from compression of the trigeminal nerve. Very large lesions can lead to brainstem compression, obstructive hydrocephalus, and death.Gadolinium-enhancement on T1-weighted MRI is the gold standard for diagnosis and detects even very small tumors (Fig. 18-3) The conventional armamentarium for vestibular Figure 18-3. A. Axial T1 magnetic resonance imaging (MRI) post-contrast showing left cerebellopontine angle tumor with avid gadolinium enhancement. Minimal internal auditory canal involvement is noted. B. Axial T2 MRI showing left cerebellopontine angle tumor with thin cerebrospinal fluid cleft between tumor and brainstem/cerebellum. C. Axial T1 MRI post-contrast showing left cerebellopontine angle tumor with avid gadolinium enhancement. The lesion is confined to the internal auditory canal with minimal cerebellopontine angle involvement. D. Intraoperative phono during microsurgical resection via translabyrinthine approach. Black arrow indicates cochlear nerve.ABCDBrunicardi_Ch18_p0613-p0660.indd 61601/03/19 5:22 PM 617DISORDERS OF THE HEAD AND NECKCHAPTER 18schwannoma includes observation, microsurgical resection, and stereotactic radiation.16 Management of patients with ves-tibular schwannomas involves weighing a multitude of vari-ables particular to the tumor (location, size, growth pattern), the patient (age, overall health, individual wishes), and the inter-action between tumor and patient (symptoms currently expe-rienced, symptoms likely to develop with lesion progression, degree of residual hearing). For patients who have hearing that may still benefit from acoustic amplification using a hearing aid, either a retrosigmoid or a middle fossa approach may be offered, depending on tumor location, size, patient preference, and provider experience. For patients without serviceable hear-ing preoperatively, a translabyrinthine approach is most com-monly offered.Sinonasal Inflammatory DiseaseRhinosinusitis. Rhinosinusitis is defined as symptomatic inflammation of the nasal cavity and paranasal sinuses. Rhi-nosinusitis is preferred over sinusitis because sinusitis almost always is accompanied by inflammation of the contiguous nasal mucosa. Rhinosinusitis is a significant health burden, affect-ing nearly 12% of the population.17 Rhinosinusitis is the fifth most common diagnosis responsible for antibiotic prescription and accounts for more than 20% of all antibiotics prescribed to adults. Rhinosinusitis may be broadly classified based on duration of symptomatology. Symptoms lasting <4 weeks may be classified as acute rhinosinusitis (ARS), while symptoms lasting >12 weeks may be classified as chronic rhinosinusitis (CRS). Rhinosinusitis lasting between 4 and 12 weeks has his-torically been defined as “subacute,” although the current clini-cal practice guideline published by the American Academy of Otolaryngology—Head and Neck Surgery does not distinguish rhinosinusitis in this time frame, noting that this group likely represents crossover symptoms from one of the other two sub-classes. Hence, the decision on how to manage this group of patients must be individualized.18 Because common conditions such as atypical migraine headache, laryngopharyngeal reflux, and allergic rhinitis frequently mimic rhinosinusitis, diagno-sis of rhinosinusitis is based not only on symptomatic criteria but also on objective evaluation with either imaging and/or endoscopy.Acute Rhinosinusitis. Acute rhinosinusitis most commonly occurs in the setting of a viral upper respiratory tract infection (URI). Although it is believed that acute bacterial rhinosinusitis (ABRS) typically follows a viral URI, it has been estimated that only up to 2% of viral URIs lead to ABRS.19 The most common viruses involved in ARS include rhinovirus, influenza virus, and parainfluenza virus. It is not known whether the viral URI precedes or only occurs along with ABRS. Regardless, viral infection leads to mucosal edema with sinus ostium obstruction, mucus stasis, tissue hypoxia, ciliary dysfunction, and epithelial damage, which may enhance bacterial adherence.20 Other con-ditions that may contribute to ABRS should be investigated, especially in the setting of recurrent ABRS. Such conditions include foreign body, sinus fungal ball (with bacterial secondary infection), and periapical dental disease (Figs. 18-4 and 18-5).The symptomatic criteria used to define ABRS include up to 4 weeks of purulent nasal drainage accompanied by nasal obstruction, facial pain with pressure and fullness, or both.18 ABFigure 18-4. A. Right periapical abscess (arrow) leading to acute bacterial rhinosinusitis. B. Follow-up scan of the same patients after administration of antibiotics demonstrating resolution of the sinonasal inflammatory changes. Therapy subsequently directed at the offending tooth will prevent recurrent symptoms.Figure 18-5. Computed tomography scan demonstrating a fungal ball of the right maxillary sinus, characterized by heterogeneous opacification of the sinus.Brunicardi_Ch18_p0613-p0660.indd 61701/03/19 5:22 PM 618SPECIFIC CONSIDERATIONSPART IIOther historical factors that may predict the development of ABRS include persistence of symptoms beyond 10 days, or worsening of symptoms, following initial improvement, within 10 days (“double worsening”). Although routine head and neck examination may identify anteriorly or posteriorly draining purulent secretions, the utilization of a rigid endoscope may improve diagnostic sensitivity and may also facilitate culture acquisition (Fig. 18-6).The management of ABRS is heavily dependent on anti-biotics, either culture-directed or empirically chosen to cover the most common isolates of ABRS, including S pneumoniae, H influenza, and M catarrhalis. Nosocomial ABRS more com-monly involves P aeruginosa or S aureus. Methicillin-resistant S aureus (MRSA) has been isolated with increasing frequency.20 Other treatments include topical and systemic decongestants, nasal saline spray, topical nasal steroids, and oral steroids in selected cases. In the acute setting, surgery is reserved for com-plications or pending complications, which may include exten-sion to the eye (orbital cellulitis or abscess) or the intracranial space (meningitis or intracranial abscess).Chronic Rhinosinusitis. Chronic rhinosinusitis (CRS) is characterized by symptomatic inflammation of the nose and paranasal sinuses lasting over 12 weeks. CRS has been clini-cally classified into two main groups: those with CRS with nasal polyps (CRSwNP) tend to exhibit a Th2-biased inflammatory profile, and those with CRS without nasal polyps (CRSsNP) tend to exhibit a Th1-biased profile. Although the etiology of CRS is unclear and the development of the clinical subtypes may be distinct, there exists significant overlap not only in phys-iologic manifestations but also in symptomatology. Hence, the sinonasal cavities of patients with both subtypes of CRS tend to exhibit mucosal edema, ostial obstruction, ciliary dysfunction, and an abhorrent inflammatory milieu.Two of the following symptomatic criteria must be pres-ent to diagnose CRS: purulent nasal drainage, nasal obstruc-tion, facial pain-pressure-fullness, and decreased sense of smell. These patients may also experience acute exacerbation, generally signified by an escalation of symptoms. Frequently, this is due to bacterial infection. However, patients with acute exacerbation of CRS may be distinguished from patients with recurrent acute bacterial rhinosinusitis (four or more episodes of ABRS per year) through baseline comparison: patients with CRS are symptomatic, even while at baseline, while patients with recurrent acute bacterial sinusitis are normal at baseline. As with ARS, the diagnosis of CRS requires objective confirmation utilizing either nasal endoscopy, CT scans, or, less commonly, MRI.Nasal endoscopy is a critical element of the diagnosis of CRS. Abnormalities that may confirm the diagnosis of CRS include• Purulent mucus in the middle meatus or anterior ethmoid region• Edema in the middle meatus or ethmoid region• Polyps in nasal cavity or the middle meatusIn addition to establishing the diagnosis, nasal endoscopy can be valuable in antibiotic selection by facilitating specific culture acquisition. Furthermore, simple polypectomy or ste-roid injection can be performed under topical anesthesia in the appropriate clinical setting.Imaging is also an important clinical tool in the diagnosis of CRS. In general, CT is the modality of choice for diagno-sis and management of CRS. Usual diagnostic criteria include mucosal thickening, sinus opacification, and bony remodeling (erosion or hyperostosis). It should be underscored, however, that CT scan is not the positive gold standard because many asymptomatic patients will demonstrate findings on a sinus CT scan, and many patients with presumed sinusitis will have negative findings.19 CT scan has excellent negative predic-tive value when performed in the setting of active symptoms. Thus, if a patient complains of rhinosinusitis-like symptoms but has no specific physical (endoscopic) findings, and the scan Figure 18-6.  Nasal endoscopy is commonly performed in the clinic setting to aid in the diagnosis and management of rhinosinusitis.Brunicardi_Ch18_p0613-p0660.indd 61801/03/19 5:22 PM 619DISORDERS OF THE HEAD AND NECKCHAPTER 18Figure 18-7. Point-of-care computed tomography system. All components can be fit within an 8′ × 10′ room in an outpatient office setting.Figure 18-8.  Triplanar imaging revealing proximity to critical structures such as the orbital wall and skull base. This can be used for diag-nosis of sinus opacification as well as stereotactic intraoperative navigation, where endoscope view (lower right) can be radiologically cor-related with location in the three cardinal planes. This case reflects classic allergic fungal sinusitis where the opacified sinuses are filled with heterogeneous whitish material on computed tomography images. Polyps in the ethmoid cavity are seen on the endoscope image.is negative, other diagnoses (e.g., allergic rhinitis, migraine headache, tension headaches, and laryngopharyngeal reflux) should be sought. This has led to the utility of point-of-care CT (POC-CT) scan that can be performed in the physician’s office. POC-CT utilizes cone beam technology,21 which acquires the equivalent of >100 axial slices in approximately 1 minute at an effective resolution of 0.3 mm or less. The equipment occupies a room of 8’ × 10’ and can thus be accommodated in almost any office setting (Fig. 18-7). Perhaps most important, the radiation dosing for even the most sophisticated protocol is 0.17 mSv, which is <10% the dose of a conventional head CT and equivalent to approximately 20 days of background radia-tion. One theoretical shortcoming of this technology is that it does not permit soft tissue imaging. This is seldom a concern in sinonasal evaluation, as this is typically undertaken in bone windows. The acquired data are immediately formatted into triplanar (axial, sagittal, coronal) reconstructions and is also compatible with devices used for intraoperative stereotactic navigation, which can be used to confirm relationships between the disease process, medial orbital wall, and skull base during surgery (Figs. 18-8 and 18-9).Medical management of CRS is heavily dependent on topical intranasal therapy. The reasons for this lie not only in established effectiveness but also in tolerability and safety—the chronic nature of CRS generally lends to requisite long-term medication administration despite other measures such as surgery. Nasal irrigation and topical nasal steroids are commonplace in the management of CRSwNP and CRSsNP. Oral steroids have demonstrated effectiveness in patients with CRSwNP, although the role in CRSsNP is less clear. Although otolaryngologists commonly utilize antibiotics in the man-agement of CRS, indications and administration practices are not uniform. Oral antibiotic therapy given for short duration (<4 weeks) is generally useful in the management of acute exac-erbation related to bacterial infection. Long-term utilization of antibiotics may be necessary in the setting of chronic infection or osteomyelitis. Additionally, long-term macrolide administra-tion may be utilized for anti-inflammatory effects in the appro-priate clinical setting.In most cases, patients considering endoscopic sinus surgery (ESS) for CRS should have significant residual Brunicardi_Ch18_p0613-p0660.indd 61901/03/19 5:22 PM 620SPECIFIC CONSIDERATIONSPART IIsymptomatology despite medical therapy. However, there cur-rently exists no consensus regarding what constitutes a “maxi-mum” course of medical therapy. It should be noted that unless there is suspicion of neoplasm or pending complication of rhinosinusitis, the decision to proceed with surgery is highly individualized. This is because surgery for uncomplicated CRS is elective, and patients who “fail” medical management will exhibit significant variability in symptoms, physical signs, and CT findings. Furthermore, ESS is not necessarily curative—the intent of ESS is to remove the symptoms related to CRS rather than cure the underlying condition itself.Surgery is typically preformed endoscopically where the goals are to remove polyps, enlarge or remove obstruct-ing tissue surrounding the natural sinus ostia (Fig. 18-10), and remove chronically infected bone and mucosa to promote both ventilation and drainage of the sinus cavities. Inspissated mucin or pus is drained and cultured. Eventual resolution of the chronic inflammatory process can be attained with a com-bination of meticulous surgery and directed medical therapy, although the patient must understand that surgery may not alter the underlying immunologic pathophysiology. In cases where resection of inflammatory tissue and polyps are not required, recent trends have also included use of angioplasty-type balloons to dilate sinus ostia. The exact role for this tech-nology is unclear, but it appears to have promise in outpatient office management of patients with focal or limited obstruc-tive pathology.Endoscopic Skull Base Surgery. Over the past three decades, the development and expansion of multidisciplinary skull base teams has become somewhat commonplace at large academic institutions. Facilitated mainly by growing cooperation between otolaryngologists and neurosurgeons, a variety of approaches that utilize the sinonasal corridor to treat a plethora of patho-logic processes of the anterior skull base have been developed.Technological advances in endoscopy, instrumentation, and imaging have also facilitated the development of endo-scopic endonasal approaches (EEAs), allowing team members to work simultaneously while maintaining optimal visualization of the relevant anatomy and freedom of movement within the corridor. Although historically the sphenoid sinus has been the common access route in the management of sellar pathology, a series of modular approaches of varied complexity have been developed that have broadened the reach of EEAs to address lesions at virtually all comportments of the ventral skull base, from the crista galli to the anterior arch of C2.22One of the key tenets of the EEA is that the sinonasal cor-ridor presents the most prudent and safest path to the lesion of interest. Accordingly, the EEA is generally chosen for lesions adjacent to the skull base, without intervening brain parenchyma, cranial nerves, major vessels, or other important anatomical structures. Currently, EEAs are utilized to treat a significant number of pathologic process involving the skull base, including: cerebrospinal fluid leaks, encephaloceles, meningoceles, pseudomeningoceles, benign intracranial tumors (Fig. 18-11), benign sinonasal tumors, malignant sinonasal tumors, and inflammatory or traumatic conditions leading to compression at the craniovertebral junction. Although EEAs tend to be considered “minimally invasive,” the corridor created in the sinonasal cavity is nonetheless comprehensive enough to Figure 18-9. Sphenoid sinus fungal ball. The sinus has been opened revealing cheesy material during this intraoperative endoscopic view (lower right). The crosshairs stereotactically confirm location within the sphenoid sinus radiologically in the cardinal planes.Brunicardi_Ch18_p0613-p0660.indd 62001/03/19 5:22 PM 621DISORDERS OF THE HEAD AND NECKCHAPTER 18ABFigure 18-10. A. Endoscopic view of the right nasal cavity demonstrating the uncinate process (U), ethmoid bulla (EB), middle turbinate (MT), inferior turbinate (IT), and nasal septum (S). B. Endoscopic view of a microdebrider being used to widen the right maxillary sinus ostium.ABCDFigure 18-11. Preoperative coronal (A) and sagittal (B) magnetic resonance images of a large olfactory groove meningioma removed using endoscopic endonasal approach. Postoperative coronal (C) and sagittal (D) images demonstrating removal of the tumor. The skull base can be reconstructed using local flaps (most commonly a nasoseptal flap pedicled on the posterior nasal artery).Brunicardi_Ch18_p0613-p0660.indd 62101/03/19 5:23 PM 622SPECIFIC CONSIDERATIONSPART IIprovide maximal freedom of movement for the critical compo-nent of the case (i.e., tumor resection near vital structures). Once the corridor is created by the otolaryngologist, the neurosurgeon joins, and a two-person, threeto four-hand technique is utilized to address the lesion of interest and reconstruct the skull base (Fig. 18-12).Despite the relatively confined aperture provided by the nostrils, even large tumors can be removed using EEAs, albeit via piecemeal removal. For malignant tumors, this has required a philosophical shift whereby en bloc resection of the entire tumor is replaced by piecemeal removal of the bulk of the tumor followed by complete resection of the pedicle with sufficient margins. Outcomes utilizing EEAs for resection of malignant tumors, when chosen appropriately, parallel those of traditional open approaches. However, EEAs are not favored over tradi-tional approaches when oncological principles would otherwise need to be violated.Pharyngeal and Adenotonsillar DiseaseWaldeyer’s ring consists of the palatine tonsils between the anterior and posterior tonsillar pillars, the lingual tonsils (lym-phoid tissue in the base of tongue), and the adenoid located in the nasopharynx. These four main sites of Waldeyer’s ring are connected by other minor lymphoid tissue along the posterior and lateral pharyngeal wall completing the ring. These are all considered mucosa-associated lymphoid tissue (MALT). These tissues react to inflammatory disease, infection, trauma, acid reflux, and radiotherapy. Even the vibratory effects of chronic snoring have been implicated in the development of adenoton-sillar disease. Inflammation of these tissues can lead to referred pain through cranial nerves IX and X to the throat and ear. Adenotonsillar tissue does not have any afferent lymphatics and receives antigen presentation directly, with appropriate produc-tion of memory cells. However, there is no clear immune com-promise after removal.Figure 18-12.  Two-surgeon, threeto four-hand technique uti-lized in endoscopic endonasal surgery.Microbiology and Complications. Adenotonsillar infections present with three temporal patterns: acute, recurrent acute, and chronic. Acute infection is typically viral in origin but second-ary bacterial invasion may initiate chronic disease. Viruses do not cause chronic infections; however, Epstein-Barr Virus (EBV) can cause significant hypertrophy. Systemic EBV infection, also known as mononucleosis, can mimic bacterial pharyngitis, but the progression of signs and symptoms demonstrates lymphade-nopathy, splenomegaly, and hepatitis. This can be diagnosed on bloodwork (heterophile antibody or atypical lymphocytes). The most common bacterial causes of acute tonsillitis are group A β-hemolytic streptococcus species (GABHS) and S pneumoniae.23 If GABHS is confirmed, then antibiotic therapy is warranted in the pediatric population to decrease the risk (3%) of developing rheu-matic fever. A positive test for GABHS historically meant a throat swab with culture and sensitivity; however, rapid antigen assays have been demonstrated to be reasonably sensitive and specific (85% and 95%, respectively), thus largely replacing cultures.24 If the rapid assay is negative, then a culture is warranted. The remainder of the bacteriology for adenotonsillar disease is similar to otitis media and sinusitis, which includes H influenzae and M catarrhalis. Atypical infections include Corynebacterium diph-theria, Neisseria gonorrhoeae, and Chlamydia trachomatis.Complications of GABHS pharyngitis, typically from S pyogenes, can be systematic and include poststreptococcal glomerulonephritis, scarlet fever, and rheumatic fever. Anti-biotic therapy does not decrease the incidence of glomerulo-nephritis. Scarlet fever, caused by blood-borne streptococcal toxins, causes a strawberry tongue and a punctate rash on the trunk that spreads distally while sparing the palms and soles. Peritonsillar abscess is also a common complication that is treated in an ambulatory setting through a transoral approach after appropriate topicalization and local anesthetic. Deep neck space infections are rare from pharyngitis but can occur from odontogenic and salivary gland infections. These typically require a transcervical approach for incision and drainage.Adenoids and Adenoidectomy. Acute adenoiditis typically presents with purulent rhinorrhea, nasal obstruction, and fever and can be associated with otitis media, particularly in the pedi-atric population. Recurrent acute adenoiditis is defined as four or more acute infections in a 6-month period, but in an adult, this may be difficult to distinguish from recurrent acute sinus-itis, and endoscopy with or without imaging of the sinuses may be warranted to distinguish between the two diagnoses. Chronic adenoiditis presents with persistent nasal discharge, halitosis, chronic congestion, and postnasal drip. In children, obstructive adenoid hyperplasia often requires surgical intervention to help relieve obstructive symptoms such as snoring, obligate mouth breathing, and hyponasal voice.The management of adenoid disease is slightly different than that for tonsillar disease. Chronic infection can be treated with antibiotics, although this often does not lead to a full reso-lution of symptoms. If the adenoid bed appears hyperplastic on lateral X-ray imaging or endoscopy, a 2-month trial of nasal steroids may be helpful. Adenoidectomy is indicated for recur-rent and chronic infections that have failed conservative man-agement. These infections are not limited to the adenoid bed but also involve the sinuses and the middle year. Adenoidectomy with a myringotomy and ventilation tube placement is benefi-cial for recurrent or chronic otitis media in children because the Brunicardi_Ch18_p0613-p0660.indd 62201/03/19 5:23 PM 623DISORDERS OF THE HEAD AND NECKCHAPTER 18adenoid functions as a reservoir for bacteria that can enter the middle ear through the Eustachian tube.25Adenoidectomy is also the first line of surgical manage-ment for children with chronic sinusitis because the adenoid can obstruct mucociliary clearance from the sinonasal tract into the choana and ultimately into the pharynx. Patients with obstruc-tive systems attributable to the adenoids and suspected benign or malignant neoplasms of the adenoid bed are also candidates. However, the procedure is contraindicated in patients with vel-opalatine insufficiency (VPI) and in patients with a cleft pal-ate. Prior to adenoidectomy, patients should be examined for a submucous cleft, a lack of midline muscular tissue of the soft palate. Clinical signs of this include a bifid uvula, a translucent portion of the muscular diastasis of the soft palate (zona pel-lucida), and a palpable notched hard palate.26 A number of dif-ferent methods can be used to perform an adenoidectomy: cold steel, suction coagulator, microdebrider, and coblation. Adenoid regrowth and bleeding rates are both low, and no study has been able to demonstrate the superiority of one technique over the other for either outcome.27,28 Adenoidectomy is not without complications though, beyond VPI and bleeding, halitosis and adenoid bed regrowth (∼1%) are common complications. Rare complications include torticollis secondary to inflammation of the prevertebral fascia, nasopharyngeal stenosis, and cervi-cal spine subluxation, which is more common in patients with Down syndrome.Tonsils and Tonsillectomy Patients with acute tonsillitis present with sore throat, fever, dysphagia, and tender cervi-cal nodes with erythematous or exudative tonsils. The Centor Criteria is used to identify the likelihood of bacterial infection in adult patients complaining of sore throat in the emergency department or walk-in clinic, a point is given for each of the following: fever, tonsillar exudate, lymphadenopathy, and lack of cough.29-31 A score of 0 to 1 warrants no treatment, a score of 2 to 3 warrants GABHS testing, and a score of 4 warrants initiation of antibiotic therapy. First-line treatment is with peni-cillin or a cephalosporin; however, in those with an allergy, a macrolide can be considered. Documentation of recurrent acute infections should include a temperature (>38.3oC), cervical adenopathy, tonsillar exudate, and a positive test for GABHS. According to the American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) clinical practice guideline on tonsillectomy in children, tonsillectomy is indicated when chil-dren have more than 7 documented episodes per year, 5 epi-sodes per year in the past 2 years, or 3 episodes per year in the past 3 years.23 Tonsillectomy can still be considered in children who do not meet these criteria if they have multiple antibiotic allergies or intolerances, have a history of peritonsillar abscess after the acute inflammation has resolved, or have PFAPA (peri-odic fever, aphthous stomatitis, pharyngitis, and adenitis). A peritonsillar abscess is an infection of the peritonsillar salivary gland (Weber’s gland), located between the tonsil capsule and the muscles of the tonsillar fossa. In selected cases of active peritonsillar abscess, tonsillectomy is required in the acute set-ting to treat systemic toxicity or impending airway compromise. Multiple techniques have been described, including electrocau-tery, sharp dissection, laser, and radiofrequency ablation. There is no consensus as to the best method.Sleep Disordered Breathing and Adenotonsillar Disease.  Patients with sleep-disordered breathing (SDB) and tonsil-lar hypertrophy may also benefit from tonsillectomy if they have growth retardation, poor school performance, enuresis, or behavioral problems. The benefits may be accentuated in children with abnormal polysomnography; however, DB may require further treatment after tonsillectomy when it is multifac-torial. Clinical documentation of tonsillar grade/size is based on the percentage of the transverse oropharyngeal space measured between the anterior tonsillar pillars: grade 1+ <25%; grade 2+ 25% to 49%; grade 3+ 50% to 74%; grade 4+ ≥75% or more sometimes referred to as “kissing tonsils.”32 Tonsillectomy is effective for control of SDB in 60% to 70% of patients with tonsillar hypertrophy, although this much lower (10%–25%) in obese children, and it is therefore not curative in obese chil-dren but may improve some of their symptoms nonetheless. In patients with Down syndrome, obesity, craniofacial abnormali-ties, neuromuscular disorders, sickle cell disease, or mucopoly-saccharidoses, polysomnography (PSG) should be performed prior to tonsillectomy.33 When the need for surgery is uncertain or when there is a discordance between tonsillar size on physi-cal examination and the reported severity of SDB, physicians should advocate for PSG prior to tonsillectomy. Tonsillectomy, usually with adenoidectomy if the adenoids are enlarged, is often performed on an outpatient basis unless the patient has documented or strongly suspected obstructive sleep apnea (OSA), is <3 years of age, or has severe OSA (in children, an apnea-hypopnea index ≥10 or more, oxygen saturation <80%, or both). Other reasons for admission include a home >1 hour from a hospital, patients with craniofacial abnormalities, or any other medical issue. There is strong evidence to suggest the routine administration of a single intraoperative dose of IV dexametha-sone in children undergoing tonsillectomy, though antibiotics should not be administered or prescribed perioperatively in children. The complications from tonsillectomy include peri-operative bleeding (3%–5%), airway obstruction, death, and readmission from postoperative dysphagia leading to dehydra-tion.34 It is recommended that surgeons calculate and quote their own primary and secondary posttonsillectomy hemorrhage rates yearly.23 A rare but serious complication in patients with obstructive adenotonsillar disease post adenotonsillectomy is postobstructive pulmonary edema syndrome, which presents with decreased oxygen saturation and frothy, blood-tinged oral secretions. Patients usually recover with reintubation, positive pressure, diuresis, and supportive care.Multilevel Sleep Surgery. SDB surgery is often multilevel and is not limited to adenotonsillar disease. Patients with nasal obstruction may benefit from septoplasty and trubinate reduc-tion, although in the adult population this is most commonly used to allow patients to tolerate their OSA appliances. Simi-larly, patients with significant lingual tonsillar hypertrophy and a large base of tongue may benefit from a base of tongue reduction, tongue base advancement, or geniohyoidopexy. A base of tongue reduction alone does not often provide enough apnea-hypopnea index reduction (30%–60%) for resolution of symptoms and is fraught with a high morbidity rate.35 Rarely, maxillomandibular advance is required to open up the retrolin-gual space. In patients with life threatening symptoms (right heart failure/cor pulmonale, oxygen saturation <70%, comorbid cardiopulmonary disease) who have failed other measures, the only “cure” for OSA is a tracheotomy.Other Tonsillar Pathology. Unilateral tonsillar hypertrophy is mostly likely benign but can also be the result of Mycobac-terium tuberculosis, atypical mycobacterium, fungi, or Actino-myces. With the epidemic rise in incidence of oropharyngeal Brunicardi_Ch18_p0613-p0660.indd 62301/03/19 5:23 PM 624SPECIFIC CONSIDERATIONSPART IIcancers, neoplasms (squamous cell carcinoma and lymphoma) have increasingly also presented as tonsillar asymmetry.36 Man-agement of these lesions is dependent on the pretest probability of malignancy and the type of malignancy. If squamous cell car-cinoma is suspected, then a biopsy alone is sufficient so as to not impact the possibility of other future surgical interventions such as transoral robotic surgery. If lymphoma or a nonmalignant pathology is suspected, tonsillectomy is often recommended for diagnostic and therapeutic reasons, and the specimen should be sent fresh to pathology for a lymphoma protocol workup, bacte-rial and fungal culture, and gram stain. Pharyngitis may also be seen in immune-mediated conditions such as erythema multi-forme, bullous pemphigoid, and pemphigus vulgaris.Benign Conditions of the LarynxHoarseness is the most common presenting symptom for patients with a voice complaint. Other complaints include breathiness, weakness/hypophonia, aphonia, and pitch breaks. Voice disor-ders affect a large range of patient ages, occupations, and socio-economic statuses and affect both genders equally. They can be associated with dysphagia, globus sensation, laryngopharyngeal reflux (LPR) disease and, rarely, airway obstruction.37 Smoking can both cause and aggravate preexisting benign laryngeal con-ditions and raises the suspicion of malignancy often requiring a biopsy to exclude this diagnosis.Any discussion of laryngeal disorders should start with a review of the anatomy of the vocal cords (Fig. 18-13). The true vocal cords are formed from stratified squamous epithelium, beneath which is the superficial lamina propria (in Reinke’s space). Beneath this is the ligament that includes the middle and deep lamina propria. Beneath this ligament is the muscular layer that includes the thyroarytenoid muscle or vocalis. The cover-body theory describes the freely mobile cover (mucosa and Reinke’s space) over the more rigid body (vocal ligament and vocalis).38Membranous vocal cord lesions have been notoriously dif-ficult to classify reliably; however, increased availability of vid-eostroboscopic examination and standardized definitions have improved the classification of these lesions.39 These lesions are usually mid cord because that is the site of maximal lateral displacement and amplitude. Vocal fold nodules are typically bilateral, fairly symmetric, and with normal or mild impairment of the mucosal wave, and they almost always resolve with voice therapy. A vocal fold polyp is more often unilateral than bilat-eral, is exophytic, and is associated with unorganized gelatinous debris in the subepithelial space. These can be hemorrhagic as is often seen in males secondary to capillary rupture within the mucosa by shearing forces during voice abuse. Hemorrhagic polyps are seen more often in patients on anticoagulants. These lesions usually fail conservative measures (voice rest, voice therapy, smoking cessation, and reflux management) usually requiring micorlaryngeal surgery to remove the lesion while preserving normal mucosa. Vocal fold cyst is an encapsulated lesion within the subepithelial or ligamentous space and is asso-ciated with reduced mucosal wave. It typically does not resolve with voice therapy. These lesions require microlaryngeal sur-gery for complete removal of the cyst while preserving the over-lying mucosa, and this surgery can be performed with cold steel or carbon dioxide (CO2) laser. A fibrous mass of the vocal fold is amorphous fibrous material within the subepithelial space or EpiglottisEpitheliumLayers oflamina propriaSuperficialIntermediateDeepVocalisHyoid boneCushion ofepiglottisThyroidcartilageFalse vocal cordLaryngealsinusTrue vocalcordThyroarytenoidmuscleCricoid cartilageAryteno-epiglottideanfoldFigure 18-13. Coronal view of the larynx demonstrate the supraglottic, glottic and subglottis (LEFT) and the layers of the true vocal cord (RIGHT).Brunicardi_Ch18_p0613-p0660.indd 62401/03/19 5:23 PM 625DISORDERS OF THE HEAD AND NECKCHAPTER 18ligament often associated with reduced mucosal wave, and it also does not resolve with voice therapy.Reinke’s edema is characterized by edema in the superfi-cial lamina propria of the vocal cord. Edema is thought to arise from injury to the capillaries that exist in this layer, with sub-sequent extravasation of fluid. The etiology is multifactorial: smoking, LPR, hypothyroidism, and vocal misuse.40 This pathol-ogy is more common in women (because they present early due to a deep vocal pitch change in their voice) and heavy smokers. The physical examination findings are typically bilateral. Sur-gery typically involves microlaryngoscopy with removal of the gelatinous debris in Reinke’s space with trimming of the excess mucosa. However, smoking cessation and surgery do not fully reverse the structural abnormalities due to the presence of pos-sible structure alterations in fibroblasts caused by the toxicity of cigarette components, resulting in uncontrolled production of fibrous matrix in the lamina propria, thus preventing complete vocal recovery.41Laryngeal granulomas typically occur in the posterior lar-ynx on the arytenoid mucosa (Fig. 18-14). These lesions are typically multifactorial: chronic throat clearing, phonotrauma, endotracheal intubation, compensatory supraglottic squeeze from vocal fold paralysis, and LPR.42 The majority of these lesions (82%) disappear within 48 weeks with conservative measures such as voice therapy, vocal rest, oral steroids, inhaled steroids, and proton pump inhibitors.42 Botulinum toxin of thy-roarytenoid and lateral cricoarytenoid muscles can be used as first-line treatment in patients who prefer a chemically activated voice rest regiment.42 LPR appears to be the most important contributing factor,42 and when aggressive conservative and medical therapy has failed, a Nissen fundoplication may be indicated. Surgery is rarely required for patients with laryngeal granulomas because it does not address the underlying etiol-ogy and is frequently associated with recurrence. Nonetheless, excision is sometimes required in patients with airway obstruc-tion or the suspicion of malignancy. Careful preservation of the arytenoid perichondrium intraoperatively is required to assist with reepithelialization and to decrease the risk of recurrence postoperatively.Recurrent respiratory papillomatosis (RRP) is pathophysi-ologically associated with human papillomavirus (HPV) within the mucosa of the upper aerodigestive tract. The glottis and supra-glottis are the two most common involved subsites. HPV 6 and 11 are the most often implicated types; however, LPR and herpes simplex virus (HSV) type-2 are risk factors of adult-onset RRP.43 The disorder typically presents in early childhood (juvenile-onset RR; JoRRP) secondary to HPV acquisition during vaginal deliv-ery; however, children born by caesarean section are also at risk for the disease. JoRRP usually resolves around puberty but can progress into adulthood. Adult-onset RRP is less severe and is more likely to involve extralaryngeal subsites. There is no cure for RRP. Surgery excision is used to improve voice and airway symptoms in a palliative fashion. Surgical excision in the operat-ing room involves microlaryngoscopy with the use of the laser (CO2 for bulky disease or KTP for more superficial disease) or the use of a microdebrider. The microdebrider has been dem-onstrated to have superior voice outcomes in JoRRP; however, CO2 laser is the most commonly used operative ablative tech-nique used in adults.44 Recent advances have made it possible to treat a select group of adult RRP patients in the office using the KTP laser, typically for those with a lower disease burden.45 Several adjuvant treatments are used to increase the intersurgical interval, including intralesional cidofovir injection, oral indole-3-carbinol, oral methotrexate, and retinoic acid. In addition to preventing RRP in some patients, the HPV vaccine has also been demonstrated to increase the intersurgical interval in the most aggressive JoRRP patients.46,47Leukoplakia is a white patch seen on mucosa that can be wiped off on physical examination. This can be seen anywhere in the upper aerodigestive tract. In the larynx, this is typically seen on the superior surface of the true vocal cords and may represent squamous hyperplasia, dysplasia, and/or carcinoma with an associated risk of malignant transformation of 1% to 3% in hyperplastic lesions and 10% to 30% in dysplastic lesions. Lesions that are not overtly suspicious for malignancy, particularly in patients without a strong smoking or alcohol history, can be managed conservatively (increased hydration, elimination of poor vocal habits, phonotrauma, and manage-ment of LPR) for 1 month before reevaluation with fiberoptic laryngoscopy. Any lesions that progress, persist, or recur could have microlaryngoscopy with complete excision. Similarly, because erythroplasia and ulceration are more suggestive of malignancy, these lesions also require an excisional biopsy in the operating room.The most common cause of unilateral vocal cord paresis is iatrogenic in origin, following surgery to the thyroid, parathy-roid, carotid, spine through an anterior approach,48 or cardiotho-racic structures.49 It is therefore very important that all patients undergoing thyroid surgery receive preoperative visualization of the larynx, usually in the form of fiberoptic nasolaryngos-copy, although an indirect mirror exam can be used if adequate visualization is possible.50 Postthyroidectomy visualization may also be required to document normal vocal cord move-ment. Less common causes include malignancy of structures near the recurrent laryngeal nerve (RLN) from the skull base jugular foramen to the mediastinum. In the pediatric population, there can be neurologic causes, the most common of which is the Arnold-Chiari malformation.51 Overall, the left vocal cord is more commonly involved secondary to the longer course of the RLN on that side. Other rare etiologies include trauma, intu-bation injury, atypical infections, and neurotoxic medications. Patients typically present with a weak breathy voice and may have aspiration secondary to diminished supraglottic sensa-tion if the proximal vagal nerve or superior laryngeal nerve is involved. RLN injury is also associated with delayed relaxation Figure 18-14. Laryngeal granuloma.Brunicardi_Ch18_p0613-p0660.indd 62501/03/19 5:23 PM 626SPECIFIC CONSIDERATIONSPART IIof the cricopharyngeus muscle that can lead to dysphagia and decreased sensation in the hypopharynx, which can cause pool-ing of secretions. In children, stridor, weak cry, and airway com-promise may be presenting symptoms, whereas in adults this is rarely the case unless there is bilateral vocal cord paralysis. When an obvious cause is not identified after a thorough history and physical examination including fiberoptic nasolaryngos-copy, then a more comprehensive workup is required. A workup should not include autoimmune serology as a screen because this is low yield, but this can be included if there is a suspicion of autoimmune disorders. Imaging, in the form of a CT scan, is the mainstay of the workup and should include the skull base to the mediastinum. Repeat imaging is beneficial in this population within a 2-year period because many patients have undiagnosed small malignancies as the primary cause of their paralysis that are too small to detect on initial imaging.52 Laryngeal electro-myography can assist with identifying whether the paresis is a result of a paralysis or cricoarytenoid joint fixation/disloca-tion. It can also help prognosticate a paralysis. This is, however, rarely used in practice. Despite an extensive workup, 20% to 35% of cases are idiopathic.The management of bilateral vocal cord paralysis almost always requires a tracheotomy because the cords are left in a paramedian position leaving a slit light glottic aperture. If the paralysis is permanent, then a cordectomy with or without ary-tenoidectomy can be used to open up the airway in an attempt to eventually decannulate the patient. However, this has obvi-ous implications for voice with a weak and breathing voice. Many patients with a unilateral paralysis compensate when the cord is in the paramedian position using supraglottic structure and the contralateral cord on their own or with speech therapy. However, in patients with a less than adequate voice-related quality of life, four techniques have been used to surgically manage patients with a unilateral vocal cord paralysis: injection laryngoplasty, medialization thyroplasty, arytenoid adduction, and laryngeal reinnervation. Injection laryngoplasty involves injecting a temporary filler medial to the vocalis into the liga-ment at the posterior and midmembranous vocal cord. This can be performed in the office or in the operating room, depend-ing on the comfort of the surgeon and patient characteristics. Materials used include autologous (fat, collagen) or alloplastic (hydroxyapatite, hyaluronic acid, micronized cadaveric human collagen) compounds. Early medialization is recommended in patients with mediastinal and thoracic malignancies because it is safe and has been shown to improve quality of life in a palli-ative setting.53 Teflon is historic and is no longer used because of its granulomatous side effects on the larynx. A more per-manent medialization can be performed using a medialization thyroplasty, during which a small window is created in the inferolateral aspect of the thyroid cartilage and a submucosal-carved silastic block is placed in the operating room with the patient under neurolept anesthetic so that vocalization and flex-ible laryngoscopic visualization of the larynx can be improved (Fig. 18-15). In some cases, this is not enough of a medialization due to a large posterior glottic chink, and an arytenoid adduction is required to provide better closure of the posterior glottis and supraglottis with ensuing improved vocal outcomes. This is a technically challenging procedure that is rarely required, but in select patients it is associated with significant improvements in voice. Lastly, laryngeal reinnervation, typically with the ansa cervicalis that supplies motor function to the strap muscles, can also be performed. This is the best approach in patients who have had a recurrent laryngeal nerve severed during a central or upper mediastinal neck procedure because it is in the field.54 Multiple studies demonstrate favorable outcomes; however, no significant differences between treatment arms has been demon-strated based on perceptual, acoustic, quality of life, and laryn-goscopic outcomes.55Vascular LesionsVascular lesions can be broadly classified into two groups: hem-angiomas and vascular malformations.56Hemangiomas. Hemangiomas are the most common vascular lesion present in infancy and early childhood. Infantile heman-giomas present largely within the first few weeks of life. Initially they proliferate (2 weeks to 1 year), and then they begin to invo-lute (1–7 years) until they have fully involuted, leaving the child with redundant skin, scar, or a fatty lesion. Children with large facial infantile hemangiomas benefit from regular neurological examinations and brain MRI to rule out PHACES syndrome (Posterior fossa malformations, Hemangiomas, Arterial lesions, Cardiac abnormalities/aortic coarctation, Eye abnormalities). Only 10% of these lesions require early intervention because of impairment of vision or swallowing, or airway compromise. Early intervention can include medical management, such as systemic steroids, intralesional steroids, intralesional interferon α-2a, or photocoagulation therapy, and surgical management, including excision with CO2 laser/microdebrider and tracheot-omy. Systemic steroids assist with rapidly proliferating lesions until the child reaches approximately one year of age; however, it is associated with growth retardation and immune suppres-sion. Intralesional interferon α-2a has been largely abandoned because it is a daily subcutaneous injection and is associated Figure 18-15.  Hand carved silastic block for thyroplasty.Brunicardi_Ch18_p0613-p0660.indd 62601/03/19 5:23 PM 627DISORDERS OF THE HEAD AND NECKCHAPTER 18with significant neurological side effects, including spastic diplegia. Photocoagulation therapy with either the flashlamp-pumped pulsed-dye laser (FPDL), the potassium titanyl phos-phate (KTP) laser, or the neodymium yttrium-aluminum garnet (Nd:YAG) laser, is repeated every 4 to 6 weeks until the lesion disappears. A randomized trial recently demonstrated that pro-pranolol was effective at a dose of 3mg/kg per day for 5 months in the treatment of infantile hemangioma with a very acceptable and low side-effect profile.57 Other groups have had success at discontinuing propranolol at 1 year of age with excellent out-comes.58 For patients who do not require early intervention, the lesion is observed every 3 months for involution after the pro-liferative phase has ended. Surgery is considered if regression has not occurred by 5 years of age because the cosmetic result is less likely to be satisfactory.Congenital hemangiomas differ from infantile heman-giomas in that they reach their maximal size at birth and do not have a proliferative phase. There are two subtypes: rapidly involuting (RICH), which typically disappears by 1 of age with minimal fatty appearance upon resolution, and noninvoluting (NICH). The management is similar to infantile hemangiomas with the exception that medical management is not typically necessary.Vascular Malformations. Vascular malformations, in contrast to infantile hemangioma, are always present at birth, although they may not be apparent for a few months. Although they do not have a proliferative phase, they grow with the patient, have hormonal growth spurts and do not involute.59 Vascular mal-formations can be classified as low flow (capillary, venous, lymphatic, and mixed), which comprise approximately two-thirds of all vascular malformations, or high flow (arteria and arteriovenous).Capillary malformations arise from the cutaneous super-ficial plexus and are made up of capillary and postcapillary venules with a pink, red, or purple macular-papular appearance. Venous malformations arise from dilated vascular channels lined by normal endothelium; therefore, they are soft, compress-ible, and nonpulsatile. If they are superficial, they will increase in size with Valsalva or dependent positioning. They can grow suddenly with trauma or in association with hormonal changes. Lymphatic malformations typically present at birth with the majority (90%) being identified by 2 years of age. They can be macrocystic (>2 cm), microcystic (≤2 cm), or a combina-tion. They are most commonly found in the head and neck, particularly on the neck, and on physical examination they are soft and doughy with normal overlying skin. Infrahyoid lesions tend to be macrocystic, well circumscribed, and discrete and can be totally excised, whereas suprahyoid lesions are typically microcystic, infiltrative, and excision is usually incomplete. On MRI, the best imaging modality for this malformation, a sep-tated mass with low-intensity signal on T1 and high-intensity signal on T2 is noted. They grow slowly with the patient but can have a sudden increase in size with hemorrhage or infection. Rarely, they cause airway compromise, feeding difficulties, and failure to thrive.Treatment of vascular malformations is based on depth, size, and growth pattern. Capillary malformations are typically treated with the pulsed dye laser (585 nm). Venous lesions can be treated with the KTP laser (532 nm) or the Nd:YAG laser (1064 nm), sclerotherapy, and, in select cases, complete surgi-cal excision is possible. Arteriovenous malformations are rare but typically require surgical excision with negative margins often after embolization. Lymphatic malformations are typically treated at least in part with surgical excision, although this is less successful for microcystic lesions. OK-432 is lyophilized low virulence S pyogenes cultured in penicillin. It is used as a sclerotherapy agent for lymphatic malformations and has a 94% response rate in macrocystic lesions, a 63% response rate in mixed macromicrocystic lesions, and no response in micro-cystic lesions.60TRAUMA OF THE HEAD AND NECKSoft TissueSoft tissue trauma of the head and neck is managed with the same general surgical principles as any other body subsite with a few particularities. Most lacerations can be closed primarily if there is not soft tissue loss; even some devitalized soft tis-sue should be preserved because of the excellent blood sup-ply to head and neck tissue that allows it to recover at a higher rate. Thus, minimal debridement is usually required. Thor-ough irrigation to remove foreign bodies and clean the tissue is required. This is followed by a careful layered closure. On the face, the deep layers are usually closed with a 3-0 or 4-0 Vicryl/Polysorb after a minimal amount of undermining, and interrupted 5-0 or 6-0 Prolene or Nylon is used for the skin. These sutures are removed at 5 days on the face. Antibiotics are reserved for through-and-through mucosal lacerations, con-taminated wounds, bite injuries, and when delayed closure is performed (>72 hours). The chosen antibiotic should cover S aureus. Patients are instructed to avoid sunlight because this can cause pigmentary abnormalities in the suture line as it heals and matures over the first year.Eyelid lacerations are closed in layers with careful reap-proximation of the orbicularis oculi as a separate layer. Another important layer to reapproximate separately is the gray line (con-junctival margin) so as to avoid height mismatch or lid notching. Lip injuries follow the same principle with a three-layer closure involving the orbicularis oris, which is the strength layer, fol-lowed by careful reapproximation of the vermillion border to avoid a step-deformity (Fig. 18-16). Of course, a mucosal layer closure may also be required for through-and-through defects. Rarely, locoregional flaps or grafts are required for closure when greater than one-fourth of the eyelid width or one-third of the lip width is missing. Auricular hematoma is managed with prompt incision and drainage followed by bolstering technique; anteriorly and posteriorly placed dental pledgets secured with through-and-through sutures. These are to remain in place for at least 4 days to prevent reaccumulation of the hematoma and to prevent a cauliflower ear deformity. Auricular lacerations are typically closed primarily with perichondrial sutures to preserve the precarious cartilage blood supply followed by a primary clo-sure of the skin, making sure to cover the cartilage to prevent chondritis. Given the rich vascular supply to the face and neck, many soft-tissue components that appear devitalized will indeed survive, and therefore minimal debridement of devitalized tissue is required.Facial lacerations resulting in facial nerve injury are not explored if they are anterior to a vertical line dropped from the lateral cantus as there is excellent collateral innervation in the anterior midface. Posterior to this line, the nerve should be repaired, primarily if possible, using 8-0 to 10-0 monofila-ment suture to approximate the epineurium under the operative Brunicardi_Ch18_p0613-p0660.indd 62701/03/19 5:23 PM 628SPECIFIC CONSIDERATIONSPART IImicroscope. If primary reapproximation is not possible due to a missing segment, cable nerve grafts can be performed using the sural nerve or the greater auricular nerve. If the buccal branch is injured, this raises suspicion regarding injury to the parotid duct, which lies along an imaginary line drawn from the tragus to the midline upper lip. The duct should be repaired over a 22-gauge stent or marsupialized into the oral cavity.Facial FracturesThe most common facial fracture involves the mandible. Fig. 18-17 demonstrates the most common sites of fracture, which include the condyle (36%), body (35%), and angle (20%). In most cases, more than one site is involved due to reciprocating forces. The vector forces from the muscles of mastication, vertical from the masseter and horizontal from the pterygoid muscles, can cause a fracture to be favorable or unfavorable depending on the angle of the fracture line. After taking a history and performing a physical examination, imaging is performed in the form of a Panorex or a CT scan. Where closed reduction can be achieved, patients are placed in maxillomandibular fixation (MMF) with arch bars applied via circumdental wiring, and these are left in place for 4 to 6 weeks depending on patient factors and the fracture location. In elderly patients, this is kept in for 6 to 8 weeks. In children and patients with condylar fractures only 2 to 3 weeks is required, and this is important to prevent condylar ankylosis. During this time, patients are placed on a liquid diet and are provided with wire cutters in case of aspiration or airway emergency. Open reduction and fixation is indicated in patients with open, comminuted, displaced, or unfavorable fractures. In these patients, MMF is usually only temporary with a soft diet starting almost immediately in the postoperative setting. Because the MMF is temporary with rigid fixation, it is per-formed usually using the 4-point fixation technique, where the maxilla and mandible are held in occlusion by wires attached to intraoral cortical bone screws, with two screws above and below the occlusal line anteriorly. This is a benefit of open reduction and internal fixation because prolonged MMF is associated with gingival and dental disease, as well as with significant weight loss and malnutrition, during the fixation period. After fixation, the fracture is exposed, more commonly from a transcervical compared to a transoral approach. Care is made not to injure the marginal mandibular branch of the facial nerve during this exposure. A rigid, locking, load-bearing mandibular plate is used. In edentulous patients, determining the baseline occlusion is of less significance because dentures may be refashioned once healing is complete.Midface fractures are rarely isolated and include multiple subsites. However, isolated zygoma fractures are typically dis-placed inferior inferiorly and medially with disruption of the suture lines between the temporal, frontal, and maxillary bones and the zygoma. If multiple zygoma fractures are present or if the zygomatic arch is significantly displaced, a coronal incision is required to perform the reduction and fixation. However, if it is an isolated depressed fracture, a Gilles reduction can be achieved inferiorly (transorally) or superiorly (along temporalis muscle). The pathophysiology of orbital blow-out fractures is (a) hydraulic from increased intraocular pressure or (b) buckling from direct bone conduction. This requires surgical intervention if there is a defect of >2 cm2 or >50% of the floor with herniation.61 A forced duction test, where the muscular attachment of the inferior oblique is grasped with forceps and manipulated to determine passive ocular mobility, is performed to ensure that there is not inferior rectus entrapment. If there is entrapment, this would also result in diploplia with upward gaze. Blowout fractures demonstrating significant entrapment or enophthal-mos are treated by orbital exploration and reinforcement of the floor with titanium mesh, hydroxyapatite, or split calvarial bone grafts. Sometimes, the anterior maxillary bone that has been fractured and is accessed in the process of repairing other factures can also be used.62There are three classic patterns of more extensive mid-face fractures: Le Fort I, II, and III. However, fractures rarely follow this exact pattern, and the two sides of the face may have different Le Fort fractures. Nonetheless, a full under-standing of midface buttresses is central in understanding these fractures (Fig. 18-18). There are three vertical buttresses: the nasofrontal-maxillary, the frontozygomaticomaxillary, and Key stitchFigure 18-16.  Approximation of the vermilion border is the key step in the repair of lip lacerations.3%3%36%2%20%21%14%Figure 18-17.  Sites of common mandible fractures.Brunicardi_Ch18_p0613-p0660.indd 62801/03/19 5:23 PM 629DISORDERS OF THE HEAD AND NECKCHAPTER 18pterygomaxillary. There are five horizontal buttresses: the fron-tal bone, nasal bones, upper alveolus, zygomatic arches, and the infraorbital region.63 Signs of midface fractures include subcon-junctival hemorrhage, ocular signs/symptoms, malocclusion, facial asymmetry, midface hypoesthesia (V2), hematoma, and a mobile maxillary complex. Transverse maxillary alveolus frac-tures above the teeth are Le Fort I fractures, which may result in a mobile hard palate. When this fracture extends superiorly to include the nasofrontal buttress, medial orbital wall, and even as high as the infraorbital rim and zygomaticomaxillary articula-tion laterally, it is considered a Le Fort II. Mobility includes the palate, nasal dorsum, which is separated from the upper face, and the inferomedial aspect of the orbital rim. When the frac-ture disrupts the frontozygomaticomaxillary, frontomaxillary, and frontonasal suture line, there craniofacial disjunction, a Le Fort III fracture. Of note, all of the Le Fort fractures involve the pterygoid plates posteriorly (Fig. 18-19).Temporal Bone FracturesTemporal bone fractures occur in approximately one fifth of skull fractures. Temporal bone fractures were previously clas-sified as longitudinal or transverse describing the path along the temporal bone of the fracture line, but this has been largely replaced by the more relevant otic capsule sparing or involv-ing classification given that most fractures are oblique.64 Otic capsule sparing fractures present with conductive hearing loss, ossicular injury, bloody otorrhea, and labyrinthine concussion.65 The facial nerve is rarely injured nor cerebrospinal fluid (CSF) leak common with this fracture pattern. However, in patients with otic capsule involving temporal bone fractures, typically caused by occipitomastoid impact, sensorineural hearing loss, vestibular dysfunction, facial nerve paralysis, and CSF leak are far more common.65 Regardless of the fracture pattern, when CSF leak is suspected, it usually resolves with conservative measures including bed rest, elevation of the head of the bed, stool softeners, and avoiding sneezing or straining. In some cases, a CSF drain can be placed if there is a delay in spontane-ous resolution. Rarely will surgical repair be required. Unlike CSF leaks with temporal bone fractures, the facial nerve needs to be assessed and managed urgently. An incomplete or delayed facial nerve paralysis almost always resolves spontaneously with conservative measures, including oral steroids. An imme-diate complete paralysis that does not recover within 1 week should be prognosticated to consider nerve decompression. Electroneurography (ENoG), EMG, and nerve stimulation tests have been used to help determine which patients with delayed-onset complete paralysis will benefit from surgical decompres-sion. The finding of >90% degeneration more than 72 hours after the onset of complete paralysis is considered an indica-tion for surgery.66 A nerve excitability test, where thresholds are increased to elicit visible muscle contraction on each side, can indicate advanced degeneration when there is a difference of >3.0 to 3.5 mA between sides. Whether surgical intervention is indicated or not for facial nerve paresis, it is crucial to pro-tect the eye because a corneal drying and abrasion can lead to blindness in the abscess of eye closure and a blink reflex. This requires application of ocular lubricant at night with the eye taped shut, frequent artificial tears application while awake, and a humidity chapter.67TUMORS OF THE HEAD AND NECKSquamous cell carcinoma (SCC) comprises >90% of all of the malignant pathology of the mucosal lining of the upper aerodi-gestive tract. Naturally, a discussion of tumors of the head and neck typically focuses on this pathology presenting from the lips and oral cavity to the larynx and hypopharynx. Management of these tumors requires a systematic approach.The ideal treatment protocol varies by subsite, stage, patient comorbidity, and center preference/experience. Given the relative rarity of these tumors, multidisciplinary management is of the utmost importance to provide the patient with a balanced perspective. This can be performed in the form of a multidisciplinary clinic where radiation and surgical oncologists simultaneously see the patient or through a tumor board where a new patient’s history, physical examination findings, imaging, and prior pathology Frontal barLateralzygomatico-maxillarybuttressesMedial nasomaxillary buttressesFigure 18-18.  Major buttresses of the midface.IIIIIIFigure 18-19.  Classic Le Fort fracture patterns.Brunicardi_Ch18_p0613-p0660.indd 62901/03/19 5:23 PM 630SPECIFIC CONSIDERATIONSPART IIspecimens are reviewed. This encourages discussion from multiple points of view concerning the most appropriate treatment options available. In addition to radiation and surgical oncology, medical oncology, dentistry, speech language pathologists, radiologists, and pathologists contribute to the decision-making in this patient population. Some of the greatest advances in head and neck oncology over the last several decades include the development of standardized organ preservation protocols, advances in free flap reconstruction with microvascular techniques, and vaccinations. The future of head and neck oncology is bright with advances in molecular biology, immunotherapy, and preventative methods with vaccination. These have the potential of significantly decreasing incidence rates and improving survival and quality of life for those with the disease.Etiology and EpidemiologyThe main etiological factors associated with head and neck cancers are tobacco products and alcohol. Overall, there has been a decline in incidence of head and neck cancers of the oral cavity and larynx/hypopharynx subsites,68 likely related to public health campaigns and government taxation policies as it relates to cigarette consumption.69 Similarly, the incidence of head and neck cancer between countries varies widely and is strongly associated with the incidence of cigarette smok-ing. Cigarette smoking triples the likelihood of developing an oral cavity cancer, while the addition of alcohol synergistically increases the likelihood by 10to 15-fold.70 The risk increases as the number of years smoking and number of cigarettes smoked per day increases. Individuals who both smoke (two packs per day) and drink (four units of alcohol per day) had a 35-fold increased risk for the development of a carcinoma compared to controls.71The preoperative and perioperative periods are excellent opportunities for head and neck oncologists to pursue a smok-ing cessation intervention. Continued smoking after completion of treatment is associated with a 3to 4-fold increased risk of developing a second primary or recurrent tumor.72-74 A study assessing patients diagnosed with a new head and neck cancer demonstrated that of the patients that were smoking at diagno-sis, only 54% were able to quit, highlighting the difficulty this population has with smoking cessation.75Betel nut/quid chewing, which is a product of the areca catechu tree, is endemic to some parts of Asia and India, and in these regions oral cavity cancer is one of the most common can-cers.76,77 Betel nut when chewed acts as a mild stimulant similar to that of coffee but can be associated with submucous fibrosis that adds an additional challenge in the management of patients who present with a concurrent oral cavity cancer.77 These prod-ucts are associated with particular subsites secondary to direct contact (e.g., buccal mucosa) as well as subsites with depen-dent saliva drainage (e.g., floor of mouth, mandibular alveolus, and wet lip). Reverse smoking, where the lighted portion of the tobacco product is placed within the mouth during inhalation is also associated with oral cavity cancer, specifically hard palate carcinoma. The risk for this cancer is 47 times greater in patients that exhibit this behavior compared to nonsmokers.78In Europe and North America there has been an increas-ing interest in decriminalizing marijuana smoking. There is a strong correlation between this activity and head and neck can-cers (OR 2.5; 95% CI 1.1–6.6) when compared to nonusers.79 Furthermore, there is a dose-response relationship that is stron-ger in young patients (55 years of age or less). Ultraviolet light VermilionBuccal mucosaHard palateSoft palateRetromolar trigoneCircumvallate papillaeLower gingivaPalatine raphePalatine tonsilFigure 18-20.  Oral cavity landmarks.exposure is associated with cutaneous malignancies of the head and neck as well as lip cancer. The lower lip is at a higher risk due to its increased anterior-posterior projection, and the major-ity of squamous cell carcinomas of the lip arise along the ver-milion border of the lower lip. Immunocompromised patients, particularly those who have received solid organ and bone mar-row transplants are at an increased risk of head and neck can-cers.80 Similarly, HIV-infected patients have a higher incidence of head and neck cancers, and despite aggressive treatment have poorer results compared to HIV-negative patients.81,82 Other conditions associated with oral cancer include Plummer-Vinson syndrome (iron-deficiency anemia, dysphagia, glossitis, cheilo-sis, and esophageal webs), dyskeratosis congenita,83,84 Bloom’s syndrome,85,86 and Fanconi anemia.87HPV is a double stranded DNA virus that is transmitted through sexual contact. Over the last two decades, this virus, specifically the 16 and 18 subtypes,88 has been associated with an epidemic rise in oropharyngeal squamous cell carcinoma.89,90 The p16 protein is a surrogate for HPV positivity. HPV status in oropharynx cancer has prognostic and therefore treatment-related implications.91,92Anatomy and HistopathologyThe upper aerodigestive tract is divided into several distinct sites that include the oral cavity, pharynx, larynx, and nasal cav-ity/paranasal sinuses. Each of these sites has separate subsites as alluded to earlier with specific etiological, pathological, prog-nostic, and treatment-related peculiarities. Locoregional tumor spread is determined by weaknesses in the framework, fascial planes, and the course of neurovascular and lymphatic channels.The oral cavity extends from the vermilion border of the lip to the hard-palate/soft-palate junction superiorly, to circumval-late papillae inferiorly, and to the anterior tonsillar pillars later-ally. It is divided into eight subsites including the (a) mucosal lip, (b) the mandibular alveolus, (c) floor of mouth, (d) tongue (ante-rior two-thirds), (e) buccal mucosa, (f) retromolar trigone, (g) maxillary alveolus, and (e) hard palate (Fig. 18-20). Advanced oral cavity cancer can present with mandibular and/or maxillary invasion requiring resection, at least in part, of these structures. Oral cavity cancers typically metastasize to the submental, sub-mandibular, and upper jugular lymph nodes (levels I-III).Brunicardi_Ch18_p0613-p0660.indd 63001/03/19 5:23 PM 631DISORDERS OF THE HEAD AND NECKCHAPTER 18The pharynx is divided into three regions: nasopharynx, oropharynx, and hypopharynx (Fig. 18-21). The nasopharynx extends from the posterior nasal septum and choana to the skull base and includes the fossa of Rosenmüller and torus tubarius of the Eustachian tubes laterally. The inferior margin of the nasopharynx is the superior surface of the soft palate. In adults, the adenoids are typically absent secondary to invo-lution during late adolescence, but these can be seen in some adults in the posterior aspect of this subsite. Isolated posterior triangle (level V) lymphadenopathy in an adult should be con-sidered nasopharyngeal carcinoma (NPC) until proven other-wise. Due to its midline location, bilateral regional metastatic spread is common in nasopharyngeal carcinoma. Given the epi-demic rise oropharyngeal cancers, isolated level V adenopathy in an adult may also represent oropharyngeal cancer, although cancers at this site typically drain to the upper and lower cervi-cal nodes (levels II–IV) as well as the retropharyngeal nodes. The oropharynx has a number of subsites including the tonsillar region, base of tongue, soft palate, and posterolateral pharyn-geal walls. The hypopharynx extends from the vallecula to the lower border of the cricoid posterior and lateral the larynx. It includes several subsites as well including the pyriform fossa, the postcricoid space, and the posterior pharyngeal wall. Lym-phatic drainage is to the mid and lower cervical nodes (levels III–IV); however, usually the upper cervical nodes (level II) are addressed at the same time for tumors at this site.The larynx is divided into three regions: the supraglottis, glottis, and subglottis (Fig. 18-22). The supraglottis includes sev-eral subsites: the epiglottis, false vocal cords, medial surface of the aryepiglottic folds, and the upper half of the laryngeal ventri-cles. The glottic larynx includes the true vocal cords, the anterior and posterior commissure, and the lower half of the laryngeal ventricles. The subglottis extends from below the true vocal SoftpalateHardpalateUvulaNasopharynxOropharynxLaryngopharynxPalatinetonsilsLingualtonsilsEpiglottisOesophagusTracheaLarynxHyoid boneFigure 18-21. Sagittal view of the head and neck demonstrating the distinction between the nasopharynx, oropharynx and larynx/hypopharynx including the boundaries of each.SupraglottisGlottisHyoid boneLarynxSubglottisCricoidcartilageArytenoidcartilageFalse cordVocal cordPre-epiglotticspaceThyroid cartilageVentricle of MorganiFigure 18-22.  Sagittal view of the larynx with the divisions of the supraglottis, glottis, and subglottis demonstrated.cords to the superior cricoid border from within. The supraglottis has a high rate of bilateral metastatic spread secondary to its rich lymphatic drainage, whereas isolated glottic cancers rarely have lymphatic spread. Laryngeal cancers, in addition to having the propensity for lymphatic spread, particularly in advanced cases, can have preepiglottic and paraglottic invasion as well as inva-sion of the laryngeal framework (thyroid and cricoid cartilage). Furthermore, glottic and subglottic lesions, in addition to poten-tial spread to the upper and lower cervical nodes (levels II–IV), have the propensity for spread to the central neck (level VI) in the paralaryngeal and paratracheal region.Second Primary Tumors in the Head and NeckPatients with head and neck squamous cell carcinoma (HNSCC) are at increased risk for the development of a second primary malignancy (SPM), which is defined as a second malignancy that presents either simultaneously or after the diagnosis of an index tumor. A synchronous SPM is diagnosed simultaneously or within 6 months of the index tumor, while a metachronous SPM is diagnosed >6 months after the index tumor. SPMs need to be distinguished from local recurrences or metastasis of the primary tumor. The incidence of SPM ranges from 2% to 7% per year,93-95 and this risk remains constant from the time of initial diagnosis throughout the lifetime of the patient.93 Sec-ond primary malignancies represent the second leading cause of death in patients with HNSCC.96 One-quarter to one-third of deaths in these patients are attributable to SPM,96-98 highlight-ing the importance of SPM in the successful management of HNSCC.The classic criteria for defining second primary malig-nancy (SPM) were proposed by Warren and Gates and are: (a) histologic confirmation of malignancy in both the index and secondary tumors; (b) two malignancies that are anatomically Brunicardi_Ch18_p0613-p0660.indd 63101/03/19 5:23 PM 632SPECIFIC CONSIDERATIONSPART IIseparated by normal mucosa; and (c) the possibility of the SPM being a metastasis from the index tumor must be excluded. Most investigators use these criteria to define an SPM. However, dis-agreement exists regarding the application of the second and third criteria. For example, when both tumors appear in the same anatomic subsite, there is no agreement on the distance that should exist between the tumors, with some investigators favoring 1.5 cm99 and others requiring 2 cm.100 Furthermore, when the tumors occur in the same anatomic subsite, some investigators add that the SPM must present at least three years after the diagnosis of the index tumor,100 while others require that the SPM present at least five years after the index tumor.101 Others suggest that molecular analysis is required to classify a tumor as an SPM.102Treatment of SPMs of the upper aerodigestive tract is site specific. In general, the SPM should be treated as a sep-arate entity, in the same manner as a primary index tumor at the anatomic subsite. In many cases, particularly in metachro-nous SPMs, patients have already received a full complement of treatment, including primary or adjuvant radiation and/or chemoradiation treatment. In these cases, surgical treatment of the SPM is often indicated when feasible. Reirradiation is an option in carefully selected cases when salvage surgery is not possible. Proper patient selection for reirradiation is criti-cal, and only patients with minimal comorbidity and toxicity of previous radiation treatment should be considered.103 Patients at high risk for local recurrence after salvage surgery may benefit from increased locoregional control from adjuvant reirradiation, although there is no survival advantage compared with salvage surgery alone.103 Survival in patients with SPM depends upon the stage and location of the primary site of the SPM. Patients with SPM arising in the head and neck have significantly improved survival when compared with patients with SPM aris-ing in the lung and esophagus.104StagingStaging for upper aerodigestive tract malignancies is defined by the American Joint Committee on Cancer and follows the TNM (primary tumor, regional nodal metastases, distant metastasis) staging format which was recently updated in the 8th edition in 2017.105 The T stage for each subsite incorporates relevant anatomy; for instance, T3 lesions of the glottis are associated with vocal cord immobility. Recent changes have incorporated HPV/P16 status for oropharynx cancer (Tables 18-1 and 18-2) and depth of invasion for oral cavity cancers (Table 18-3).The N classification for head and neck sites is nearly uni-form for all sites (Tables 18-4 and 18-5) except for the nasophar-ynx and for HPV-associated (p16-positive) oropharynx cancer. Recent changes have also incorporated extracapsular extension into this nodal staging to improve the discrimination and prog-nostication of the classification.Upper Aerodigestive TractThere are similarities in the initial assessment and manage-ment of all patients with a newly diagnosed upper aerodiges-tive tract malignancy. The frequently reviewed clinical practice guidelines (National Comprehensive Cancer Network; NCCN) provide valuable information by site and stage with regard to workup and management and should be used to direct care.106 After a thorough history that should include assessment of the previously discussed risk factors, a comprehensive physical examination should follow. A full head and neck examination including inspection and palpation is critical for nearly all head and neck cancers. Oral cavity and oropharyngeal cancers should be palpated when possible to provide additional tactile informa-tion regarding depth of invasion, mobility, and invasion into adjacent structures. A cranial nerve (CN) examination with a focus on the assessment of trigeminal (V2/V3) parasthesia/Table 18-1Clinical and pathologic T category for HPV-associated (p16-positive) oropharyngeal cancerT CATEGORYT CRITERIAT0No primary identifiedT1Tumor 2 cm or smaller in greatest dimensionT2Tumor larger than 2 cm but not larger than 4 cm in greatest dimensionT3Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottisT4Moderately advanced local diseaseTumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond**Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of the larynx.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Table 18-2Clinical and pathologic T category for non–HPV-associated (p16-negative) oropharyngeal cancerT CATEGORYT CRITERIATXPrimary tumor cannot be assessedTisCarcinoma in situT1Tumor 2 cm or smaller in greatest dimensionT2Tumor larger than 2 cm but not larger than 4 cm in greatest dimensionT3Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottisT4Moderately advanced or very advanced local disease T4aModerately advanced local diseaseTumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible* T4bVery advanced local diseaseTumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery*Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of the larynx.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Brunicardi_Ch18_p0613-p0660.indd 63201/03/19 5:23 PM 633DISORDERS OF THE HEAD AND NECKCHAPTER 18anesthesia, CN VII, CN XI, and CN XII function. Flexible fiber-optic nasolaryngoscopy should be carried out to better charac-terize tumor extent, assess vocal cord mobility in laryngeal cancers, assess airway patency, and rule out any synchronous second primary tumors, as previously discussed.Investigations should include a diagnostic laryngoscopy and esophagoscopy to rule out second primaries and obtain tis-sue of any concerning lesions. A pathologic specimen is nearly always required before initiation of treatment. A metastatic work up including a CT of the neck and chest with contrast is indicated in all patients with a newly diagnosed head and neck cancer. In certain jurisdictions, a positron emission tomography (PET)-CT is used to rule out any distant metastases; however, this approach does lead to a high false positive rate.107Patients are then assessed in a multidisciplinary manner with radiation and surgical oncology. A dental evaluation is initiated before treatment because many patients undergoing primary or adjuvant radiotherapy require dental extraction to decrease the risk of osteoradionecrosis in the posttreatment period. Assessment by speech language pathology in the pre-operative period is imperative in all patients, but it is especially important in patients with laryngeal/hypopharyngeal pathology because speech and swallowing dysfunction needs to be charac-terized and often helps drive management. Smoking cessation is initiated as early as possible.Lip. The lips starting at the vermillion border represent a tran-sition between external skin to internal mucosa. The sphincter function of the lip is created by activation of the circumferen-tial musculature of the orbicularis oris, a critical structure in lip form and function. Lip cancers are most common in men and are often seen in those with fairer complexions. In addition to tobacco use and immunosuppression, UV exposure is an addi-tional important risk factor unique to this head and neck subsite. The majority (>90%) of lip cancers present on the lower lip due to its increased protrusion and increased sun exposure.108 Although the vast majority of lip cancers are SCC, other cuta-neous malignancies such as basal cell carcinoma and malignant melanoma are not uncommon at this subsite.Basal cell carcinoma presents more frequently on the upper lip than lower.Negative prognostic factors for lip cancers include peri-neural invasion, invasion into bone (maxilla or mandible), upper Table 18-3Clinical and pathologic T category for oral cavity cancerT CATEGORYT CRITERIATXPrimary tumor cannot be assessedTisCarcinoma in situT1Tumor ≤2 cm, ≤5 mm depth of invasion (DOI)DOI is depth of invasion and not tumor thickness.T2Tumor ≤2 cm, DOI >5 mm and ≤10 mmor tumor >2 cm but ≤4 cm, and DOI ≤10 mmT3Tumor >4 cmor any tumor with DOI >10 mm but ≤20 mmT4Moderately advanced or very advanced local disease T4aModerately advanced local diseaseTumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla, or involves the maxillary sinus or skin of the face) or extensive tumor with bilateral tongue involvement and/or DOI >20 mm.Note: Superficial erosion of bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4. T4bVery advanced local diseaseTumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid arteryUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Table 18-4Clinical N category for non–HPV-associated (p16-negative) oropharyngeal cancerN CATEGORYN CRITERIANXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-)N2Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-); or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-) N2aMetastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-) N2bMetastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-) N2cMetastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-)N3Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-); or metastasis in any node(s) and clinically overt ENE(+) N3aMetastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-) N3bMetastasis in any node(s) and clinically overt ENE(+)ENE = extranodal extension.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Brunicardi_Ch18_p0613-p0660.indd 63301/03/19 5:23 PM 634SPECIFIC CONSIDERATIONSPART IIlip or oral commissure involvement, positive regional metasta-sis, and young age at diagnosis.The primary management of lip cancer is a surgical resection of the primary site with an adequate margin (1 cm). This provides margin analysis and additional pathologic information that can help stratify which patients may benefit from adjuvant treatment. The primary regional nodal drainage basin for lip cancers is the submandibular, submental, and perifacial nodes (level I), and metastases occur in <10% of patients with a higher incidence in those with upper lip cancers.109 When there are clinical evident notes, a neck dissection is indicated. Otherwise, in the clinically and radiographically negative neck observation is acceptable.109 Unfortunately, many lip cancers are not appropriately staged, and advanced regional failure is not infrequently seen. Adjuvant (postoperative) radiotherapy is indicated in patients with close (<5 mm) or positive margins, lymph node metastases, tumors with perineural invasion, and in thick (>4 mm) tumors.110 The overall 10-year survival rate is 84% to 92% for early stage disease but drops precipitously (11%–28%) for advanced stage disease predicted by regional and distant metastases.111The goals of lip reconstruction include providing oral competence, maintaining dynamic function, and achieving acceptable cosmesis, while avoiding severe microstomia. The proportion of the lip excised and whether the defect involves the oral commissure determines the reconstructive options. Regardless of the reconstructive technique, realignment of the vermilion border and reapproximation of the orbicularis oris are critical steps to a successful outcome. Defects of less than one-third of the lip are closed primarily, while defects between one-third and two-thirds of the lip borrow tissue from surrounding regions, mainly the upper lip and cheek to recreate the lip. This can be accomplished using an Abbe (lip switch) (Fig. 18-23) or Karapandzic flap (Fig. 18-24), if the commissure is preserved, or an Estlander flap (lip switch) if the commissure is resected. If there is insufficient lip tissue, rectangular excisions can be closed using upper Burrow’s triangles in combination with bilateral advancement flaps made possible by mental crease relaxing incisions; this technique is called Bernard-Burrow (Fig. 18-25).112 When more than two-thirds of the lip is excised, the Karapandzic can still be used when the defect is up to 80% as this provides a sensate lip with sphincter-like function; however, microstomia becomes a serious concern, and larger defects require free flap reconstruction. This typically does not achieve sphincter function even when a sling is used. Microstomia can be a problem in patients that are edentulous who then cannot insert their dentures and in the dentulous who may not be able to get dental work performed with significant negative impact on their dental health.Oral Cavity. As previously mentioned, the oral cavity is com-posed of several sites. The anatomy of each subsite can uniquely impact the aggressiveness of disease, the function after resec-tion, and the surgical approach. We therefore in this next section briefly review each subsite with a focus on the relevant anatomy and treatment options.The preferred approach to management of these tumors is a surgical resection with adequate (1 cm) surgical margins with management of the regional nodal basin. In general, tumors of the oral cavity metastasize to the submandibular, submental, and upper cervical nodes and are almost always treated with a supra-omohyoid neck dissection at the time of primary resection with a few rare exceptions (T1 oral tongue lesions that have less than 4 mm depth of invasion). In the “Neck” section of this chapter, we will discuss this in more detail. Adjuvant radiotherapy is indicated in patients with close margins, regional lymphade-nopathy, advanced stage tumors (T3/T4), perineural invasion, and lymphovascular invasion, while adjuvant chemoradiother-apy is reserved for those with positive margins or extracapsular invasion.113,114Oral Tongue The oral tongue is a muscular structure composed of intrinsic (longitudinal, vertical, and transverse muscle fibers) and extrinsic (genioglossus, hyoglossus, styloglossus, and pala-toglossus) muscles separated by a midline raphe and has overly-ing nonkeratinizing squamous epithelium. The posterior limit of the oral tongue is the circumvallate papillae beyond which the oropharynx begins while the ventral portion is contiguous with the anterior floor of mouth.Table 18-5Clinical N category for oral cavity, larynx, and hypopharynx cancerN CATEGORYN CRITERIANXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension ENE(-)N2Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-); or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, and ENE(-) N2aMetastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension, and ENE(-) N2bMetastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension, and ENE(-) N2cMetastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension, and ENE(-)N3Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-); or metastasis in any node(s) and clinically overt ENE(+) N3aMetastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-) N3bMetastasis in any node(s) and clinically overt ENE(+)ENE = extranodal extension.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Brunicardi_Ch18_p0613-p0660.indd 63401/03/19 5:23 PM 635DISORDERS OF THE HEAD AND NECKCHAPTER 18Tumors of the tongue typically start along the epithelial surface and can be endophytic or exophytic with or without ulceration (Fig. 18-26) and are typically seen on the lateral and ventral surfaces of the tongue. Lesions on the dorsal aspect of the tongue, particularly along the midline, are less likely to be malignant. What is seen on the surface is typically the tip of the iceberg, and palpation can provide further information regarding the depth of invasion of the tumor. These tumors can be extensive, and when they cross the midline and start to involve the base of tongue an extensive surgical resection including a total glossectomy may be required. However, most tumors present at an early stage due to significant pain, otal-gia, voice change secondary to difficulties with articulation, and dysphagia, which may lead to weight loss. On history and physical examination, ipsilateral paresthesias and deviation of the tongue protrusion with fasciculations or atrophy may indicate lingual nerve and hypoglossal nerve tumor invasion respectively (Fig. 18-27).Early lesions (T1–T2) can be closed primarily, allowed to heal by secondary intention, or reconstructed with a split thickness ACBDFigure 18-23.  Estlander flap. A. Intra-operative image of lower lip squamous cell carcinoma with buccal and cutaneous extension pre-excision; B. Intra-operative defect and Estlander flap design. C. Immediate post-operative flap. D. One year post-operative image.ABCFigure 18-24.  A-C. Karapandzic labiaplasty for lower lip carcinoma.Brunicardi_Ch18_p0613-p0660.indd 63501/03/19 5:23 PM 636SPECIFIC CONSIDERATIONSPART IIskin graft after partial glossectomy. This procedure allows rea-sonable speech and swallowing function as long as there is not significant tethering in the floor of the mouth if this has been resected. Articulation is determined by premaxillary contact of the tongue, and dental appliances can be used in the postoperative setting to improve this. Tongue protrusion and lateral movement predicts a patient’s ability to swallow, and this is less difficult to repair secondarily. Therefore, many patients, even with small tongue cancers that require significant floor of mouth resection, receive soft pliable fasciocutaneous free flap reconstruction to improve these functional outcomes.115 Advanced lesions that require a more radical resection require free flaps, which obliter-ate the oral cavity dead space while creating bulk in the posterior oropharynx to improve the pharyngeal swallowing phase.116ABFigure 18-25. Bernard burrow flap reconstruction for a total lower lip defect involving upper and lip advancement rotation flap and cheek advancement.Figure 18-26.  Oral tongue squamous cell carcinoma.ABSubmandibular glandDigastric m.(anterior belly)Myohyoid m.Stylopharyngeus,stylohyoid andstyloglossus mm.Digastric muscle(posterior belly)Styloid processHypoglossal n.Middleconstrictor m.External carotid a.Hyoid boneHyoglossus m.Lingual n.Deep lingual a.Dorsal lingual a.Genioglossus m.Geniohyoid m.Sublingual a.Lingual n.Hyoid boneHypoglossal n.Figure 18-27.  A and B. Anatomy of the floor of mouth and submandibular space. a. = artery; m. = muscle; n. = nerve.Brunicardi_Ch18_p0613-p0660.indd 63601/03/19 5:24 PM 637DISORDERS OF THE HEAD AND NECKCHAPTER 18Floor of Mouth The floor of mouth is a mucosal-covered semilu-nar area that extends from the anterior tonsillar pillar posteriorly to the frenulum anteriorly, and from the inner surface of the mandible to the ventral surface of the oral tongue. The ostia of the submax-illary and sublingual glands are contained in the anterior floor of mouth. The muscular floor of mouth is composed of the sling-like genioglossus, mylohyoid, and hyoglossus muscles, which serve as a barrier to the spread of disease. Invasion into these muscles can result in decreased tongue mobility and poor articulation.The floor of mouth begins just below the lingual surface of the mandibular alveolus and ends at the ventral tongue where the frenulum connects the floor of mouth to the tongue along the mid-line and at the anterior tonsillar pillars posteriorly. Just deep to the floor of mouth mucosa is the submandibular (Wharton’s) duct and sublingual minor salivary glands followed by the genio-glossus, hyoglossus, and mylohyoid muscles. Direct invasion of these structures is not uncommon and can result in direct spread to the sublingual and submandibular spaces as well as decreased tongue mobility, leading to articulation complaints. The lingual nerve (a branch of V3) provides sensory innerva-tion to this subsite and is in close proximity to it, often requir-ing resection of this structure. The contiguity of the floor of mouth mucosa with the lingual surface of the mandible can lead to mandibular invasion. This needs to be carefully examined bimanually on physical examination and using imaging (CT, MRI, or Panorex) because a marginal or segmental mandibu-lectomy may be required to excise these tumors (Fig. 18-28). If the lesion is not fixed to the mandibular cortex on physical examination, then a mandible-sparing procedure is feasible.117 Extension to the sublingual and submandibular ducts and spaces requires that the neck dissection specimen be removed en bloc with the primary tumor. Invasion of the intrinsic tongue muscu-lature requires a partial glossectomy. In our experience, except for the smallest (T1) very superficial floor of mouth lesions, cancers at this subsite nearly always require a reconstructive procedure to separate the floor of mouth from the neck and to avoid tethering of the tongue using a pliable fasciocutaneous flap. If a segmental resection is performed, the vascularized osteocutaneous free flap is used. Given the anterior location of this tumor, a lip-splitting incision is rarely used unless resection of lip and chin skin is required as part of the resection in a select group of T4a tumors with through-and-through involvement.Mandibular Alveolus and Gingiva The alveolar mucosa overlies the bone of the mandible and extends from the gin-givobuccal sulcus to the mucosa of the floor of mouth to the second and third molar, which is the anterior border of the ret-romolar trigone subsite. Treatment of these lesions requires at the very least marginal resection of the mandibular bone given the proximity and early invasion of the periosteum in this region. A marginal resection is acceptable if there is only very early bony invasion (Fig. 18-29). If the inferior alveolar canal or the medullary cavity is invaded on physical examination or preoperative imaging, a negative locoregional prognostic fac-tor, a segmental resection is recommended with appropriate reconstruction.118,119Retromolar Trigone The retromolar trigone (RMT) is bor-dered medially by the anterior tonsillar pillar, anteriorly by the ABIncisionTissue excisedFigure 18-28.  A and B. Differences in the transoral resection of a floor of mouth and alveolar ridge lesion.Brunicardi_Ch18_p0613-p0660.indd 63701/03/19 5:24 PM 638SPECIFIC CONSIDERATIONSPART IIsecond or third molar, posteriorly by the maxillary tuberosity, inferiorly by the posterior mandibular alveolus, superiorly by the coronoid process of the mandible, and laterally by the buc-cal mucosa. Negative margin resection often requires a mar-ginal shave mandibulectomy, even when there is no evidence of mandibular cortical invasion, because of the close proxim-ity to the mandibular periosteum. This is typically achieved through a transoral approach while carefully protecting the lips and cheek.120 Extension to adjacent subsites including the buccal mucosa, maxillary tuberosity, floor of mouth, and posterolateral tongue often requires these structures be resected as part of the margin. Trismus at this and other subsites is an advanced indica-tion of involvement of the muscles of mastication in the masti-cator space, which can extend to the skull base. These tumors are aggressive. Infiltration into the masticator space and bony invasion (maxilla more often than mandible) significantly wors-ens the prognosis.121Buccal Mucosa The buccal mucosa includes all of the mucosal lining from the inner surface of the lips to the line of attachment of mucosa of the alveolar ridges and pterygomandibular raphe. The mucosa includes the parotid (Stenson’s) duct opening adja-cent to the first and second maxillary molars. An understanding of the layers of the cheek from medial to lateral is important because these layers are very closely adherent to the buccal mucosa. Therefore, tumors in this region have a high propensity for early deep invasion and early lymphatic spread. The layers of the cheek from medial to lateral are: (a) buccal mucosa, (b) pharyngobasilar fascia, (c) buccinator muscle, (d) buccopha-ryngeal fascia, (e) buccinator fat pad, (f) masseter muscle, (g) muscles of facial expression and the superficial muscular apo-neurotic system (SMAS), (h) subcutaneous tissue, and (i) facial skin. It is not uncommon for tumors with deep invasion into the cheek to require a through-and-through resection. Reconstruc-tion aimed at providing both an internal and external lining may be accomplished with a folded fasciocutaneous free flap or a combination of a local flap for the external component and a free flap for the internal component. Marginal bone resection is often required in tumors that extend to the mandibular or maxil-lary alveolus.Maxillary Alveolus and Hard Palate The hard palate and maxillary alveolus have classically been considered two sepa-rate subsites, but due to their anatomic contiguity and the simi-larities in their oncologic outcomes these two subsites should be discussed together.122 The junction between the hard palate and soft palate is the posterior border, while the maxillary tuberos-ity is the posterolateral border separating the retromolar trigone from the maxillary alveolus. The periosteum is at this subsite is closely adherent to the mucosa, and as such, superficial lesions require resection of the bone to achieve a clear margin. An infrastructure maxillectomy may be required for larger lesions involving the palate or maxillary antrum. The greater palatine nerve and foramen can be a pathway for neuropathic spread, and it is important to identify perineural invasion on these tumors in the biopsy specimen.Although SCC continues to be the primary malignant pathology at this subsite, minor salivary gland tumors such as adenoid cystic carcinoma, mucoepidermoid carcinoma, and adenocarcinoma can also present in this location. Minor sali-vary gland tumors tend to arise at the junction of the hard and soft palate.Nonmalignant pathology includes necrotizing sialometa-plasia, which appears as a butterfly-shaped ulcer on the hard palate that otherwise looks like a neoplasm. Treatment is symp-tomatic as these lesions typical disappear with time; however, a biopsy is warranted to confirm the diagnosis. A torus palatini is a benign bony outgrowth seen on midline of the hard palate. This does not require biopsy to confirm the diagnosis and only requires treatment to relieve symptoms.Reconstruction of the maxillectomy defect depends on a number of variables, including patient preference, dentition, patient comorbidity, and extent of defect. A partial palatectomy or partial infrastructure palatectomy can often be reconstructed with a dental obturator or a soft tissue flap alone to separate the oral cavity from the nasal cavity and maxillary sinus. More extensive suprastructure maxillectomies can be reconstructed with a free flap composed only of soft tissue, although this will leave the patient with a significant malar asymmetry over an osseous free flap. The layered fibular free flap and the scapular tip have been recently popularized to reconstruct more extensive orbitomaxillary reconstruction.123,124 Supporting the orbital floor when it is resected is critical in supporting the orbital contents and avoiding eventual diploplia because there can be a drop in these contents when they are not supported.Oropharynx The borders of the oropharynx start at the soft pal-ate superiorly, the hyoid (vallecular root) inferiorly, the anterior tonsillar pillar anterolaterally, and the cricumvallate papilla at the junction between the anterior two-thirds and posterior third of the tongue. There are five subsites in the oropharynx: the tonsillar region that includes the anterior and posterior tonsillar pillars, the soft palate, the posterior pharyngeal wall, the lateral pharyngeal wall, and the base of tongue. Tumors at this subsite can have direct extension laterally in the parapharyngeal space, posteriorly into the retropharyngeal space, anteriorly into the oral cavity, superiorly into the nasopharynx, or inferiorly into Figure 18-29.  Anterior mandibulotomy with mandibular swing to approach a posterior lesion.Brunicardi_Ch18_p0613-p0660.indd 63801/03/19 5:24 PM 639DISORDERS OF THE HEAD AND NECKCHAPTER 18the supraglottic larynx. Laterally, through the superior con-strictor, invasion of the jugular vein, carotid artery, and cranial nerves IX to XII, as well as the sympathetic chain, is possible. The pharyngobasilar fascia (resectable) deep to the constrictor muscles is a natural barrier from invasion into the prevertebral fascia (unresectable). The ascending ramus of the mandible can be involved when tumors invade the medial pterygoid muscle.Although SCC is the predominant pathology, minor sali-vary gland tumors can present as submucosal lesions in the soft palate or tongue base, and lymphoma can present in the tonsils as an asymmetric enlargement, underlying the importance of a tissue diagnosis before treatment.Oropharyngeal cancers, other than those on the soft palate or tonsils, are often not obvious on oral cavity exam inspection; therefore, a high degree of suspicion should exist in patients with a muffled voice as would be experienced in tongue base tumors, patients with dysphagia and weight loss, or referred otalgia from the tympanic branches of CN IX and X. Trismus may indicate advanced disease with pterygoid involvement. As previously mentioned, because of the epidemic rise in incidence of oropharyngeal cancers, secondary to HPV-associated tumors, and the high regional metastatic rate for these tumors, the pre-senting symptom is often a nontender cervical lymphadenopa-thy, which should be investigated with a fine-needle aspiration (FNA) biopsy. Approximately 50% of patients have metastases at the time of diagnosis. Bilateral metastases are common in patients with soft palate and base of tongue tumors. Treatment of the neck should include the upper jugulodigastric nodes to which these tumors most commonly metastasize to, followed by levels II, IV, V, and the retropharyngeal lymph nodes.A discussion about oropharyngeal cancer cannot be had without discussing the important prognostic information pro-vided by the HPV status of these tumors. The incidence of oro-pharyngeal squamous cell carcinoma has increased significantly over the last four decades secondary to HPV-16 related develop-ment of this tumor.125 HPV infection can induce the production of two viral oncoproteins, E6 and E7, which inactivate tumor suppressors p53 and Rb leading to tumor promotion.126 HPV-positive tumors are more common in younger male patients and are associated with a history of a higher lifetime number of sexual partners and oral sex.127 Ang et al demonstrated that oropharyngeal cancers can be stratified on overall survival into low risk (HPV-positive tumors in patients with ≤10 pack years of smoking or >10 pack years of smoking but N0-N2a), intermediate risk (HPV-positive tumors with >10 pack years of smoking and N2b-N3 or HPV-negative tumors in patients with ≤10 pack years of smoking and T2-T3 tumors), and high risk (HPV-negative tumors in patients with ≤10 pack years of smok-ing and T4 tumors or HPV-negative tumors in patients with >10 pack years of smoking).92 The rate of distant metastases in the HPV-positive and HPV-negative tumors does not differ, and therefore the survival benefit in the HPV-positive group is due to improved locoregional control.Management of squamous cell cancers of this region includes single modality (surgery or radiotherapy alone) treat-ment for early stage disease (stage I/II) and multimodality treatment for advanced stage (stage III/IV) disease (surgery followed by postoperative radiotherapy or concurrent chemora-diotherapy).106 Historically, from 1971 to 2000, oropharyngeal cancers, at the time mostly HPV-negative, were treated hetero-geneously with surgery followed by radiotherapy or primary radiotherapy similar survival until Parsons et al demonstrated in a meta-analysis similar survival rates between the two treatment groups with improved locoregional control in the radiation-alone group and much higher complication rates in the surgery group (32% severe complications, 3.5% mortality) compared to the radiotherapy group (3.8% severe complications, 0.4% mortal-ity).128 For this reason, for many years, advanced-stage tumors were treated with primary concurrent chemoradiotherapy. How-ever, this is now a moving target given the excellent results in early and some intermediate-stage HPV-positive disease regardless of treatment. More recently, there has been a push to study de-escalation, particularly in the aforementioned low and intermediate risk groups given the excellent survival rates. The standard of care, regardless of HPV status, for advanced tumors (T3/T4 or N2b-N3 or evidence of gross ECE) continues to be concurrent chemoradiotherapy.129The high complication and mortality rate in the surgi-cal group analyzed by Parsons et al was associated not just with HPV-negative tumors but also with open resections for advanced tumors that necessitated a lip-splitting mandibulotomy approach. More recently, particularly for early stage tumors (T1, T2, N0-N2a), there has been a push towards minimally invasive transoral robotic surgery (TORS) using the da Vinci Surgical System. Oncologic outcomes are similar between surgery and radiotherapy in this group, and TORS has been demonstrated to be cost-effective in this setting.130-132 Functional outcomes related to swallowing (G-tube dependency) and airway (tra-cheotomy dependency) are also similar between the groups.130 These outcomes are heavily dependent on the surgeon’s abil-ity to achieve negative margins, which can be challenging, and on good preoperative predictive value of imaging to stage the neck, given that advanced nodal disease, particularly with ECE, continues to benefit from adjuvant chemoradiotherapy. Positive margins or ECE ultimately leads to adjuvant chemoradiother-apy. This results in triple modality treatment with its associated higher morbidity. Therefore, clinical recommendations based on these favorable early retrospective poorly controlled studies with small sample sizes is not yet possible. Meanwhile, clinical trial evidence is pending to help elucidate in which settings and patients this new approach may be beneficial.133Extensive oropharyngeal cancers that fail concurrent chemoradiotherapy are treated with resection. If the mandible is involved, a marginal mandibulectomy or segmental man-dibulectomy may be required depending on the extent of bony invasion. Tongue base resection may necessitate total glossec-tomy depending on the contralateral extent of the tumor and the ability to save the lingual artery and to a lesser extent the hypo-glossal nerve on that side. When the larynx is preserved many patients, if careful reconstruction is performed, 90% of patients can be decannulated and have acceptable voice outcomes.134 However, it is not uncommon to have to perform a total laryn-gectomy at the same time as the total glossectomy for tumors with supraglottic extent, and this is associated with poor quality of life. Generally, these patients also have poorer survival.135-137The primary goal of oropharyngeal reconstruction is swal-lowing rehabilitation. For soft palate defects, palatal obturators may assist in providing a seal between the nasopharynx and the posterior pharyngeal wall. The modified Gehanno technique sutures the posterior wall of the remaining soft palate to the remaining incised pharyngeal mucosa to close off the ipsilateral hemi-nasopharyngeal port.138,139 A flap can then be inset overly-ing this defect, which has effectively separated the nasopharynx from the oropharynx. This prevents nasal regurgitation of air Brunicardi_Ch18_p0613-p0660.indd 63901/03/19 5:24 PM 640SPECIFIC CONSIDERATIONSPART IIand liquids, therefore impacting both speech and swallowing. Similarly, total glossectomy reconstruction has several goals, including filling the oral cavity dead space, allowing the neo-tongue to reach the premaxilla to assist with articulation, and, most importantly, creating posterior bulk to allow the base of tongue to touch the posterior pharyngeal wall, which assists with the pharyngeal phase of swallowing. This is often achieved with a large rectus abdominis or anterolateral thigh free flap.138 If the neotongue does not successfully touch the premaxilla and hard palate and speech is impeded, a palatal obturator can be used to bring down the palate and achieve better contact.Hypopharynx and Cervical Esophagus The hypopharynx, which extends from the vallecular to the lower border of the cricoid cartilage (Fig. 18-30), has three subsites; the pyriform sinuses, the lateral and posterior pharyngeal walls, and the post cricoid space. SCC of the hypopharynx typically presents with progressive dysphagia, first to solids then to liquids, fol-lowed by weight loss. Similar to oropharyngeal tumors, patients can also present with voice change, referred otalgia or a neck mass. Rarely, when the larynx is involved, patients may pres-ent with stridor and airway compromise necessitating an urgent tracheotomy.Unfortunately, there is significant delay in diagnosis of patients with hypopharyngeal cancer and late presentation is common.140 Routine physical examination will not typically detect the tumor. Fiberoptic nasolaryngoscopy is important in assessing the extent of the tumor and laryngeal function. Vocal cord paralysis is a poor prognostic factor and indicates fixation of the cricoarytenoid joint from direct extension of the tumor or recurrent laryngeal nerve invasion. A Valsalva maneuver dur-ing laryngoscopy allows for a better evaluation of the opened pyriform sinuses and postcricoid space. Functional endoscopic evaluation of swallowing (FEES) can be useful to assess laryn-geal penetration and aspiration, but a modified barium swal-low (MBS) is better at assessing inferior extent of the disease, multifocality within the esophagus, and aspiration. A thorough metastatic workup is required, with special attention paid to paratracheal and upper mediastinal metastases.This site has the poorest survival outcomes of all head and neck subsites. There is no difference in survival when surgery is used as the primary modality of treatment followed by radio-therapy or chemoradiotherapy compared to primary radiother-apy or concurrent chemoradiotherapy followed by surgery.141 Concurrent chemoradiotherapy appears to be the modality of choice for laryngeal preservation; however, when surgical sal-vage is required, there is a low cure rate and increased wound complications.142 Early T1 lesions without clinical or radio-graphic evidence of adenopathy can be treated with primary radiotherapy, but this is relatively rare for this subsite due to a high rate of adenopathy and an advanced T stage at presentation.Surgical resection, typically in the salvage setting, involves a total laryngopharyngectomy typically with a circumferential defect or a very small strip of mucosa preserved in continuity with the cervical esophagus. A total thyroidectomy and cen-tral neck dissection (level VI) is simultaneously performed and removed en bloc with the specimen. Bilateral neck dissection of levels II to IV is indicated. Careful dissection of the central neck, and in some cases the upper mediastinum (level VII), is required to clear regional disease, and this is critical in prevent-ing a peristomal recurrence.Given the circumferential or near circumferential defect, reconstruction is required to prevent saliva from accumulating in the wound and to create a neopharynx. A pedicled pectoralis major flap sutured to the prevertebral fascia has been described, but advances in free flap reconstruction has popularized a num-ber of fasciocutaneous flaps for reconstruction of this defect, namely the radial forearm flap and the anterolateral thigh free flap.143-146 When total laryngopharyngoesophagectomy is required, a gastric pull-up may be performed for the pharyngeal reconstruction.Larynx Laryngeal carcinoma typical presents with a progres-sive voice complaint in a long-time smoker (Fig. 18-31). A thorough understanding of laryngeal anatomy is critical in the proper diagnosis, staging, and treatment of laryngeal cancers. The larynx is divided into the supraglottis, glottis, and subglottis as previously described (Fig. 18-32). The larynx starts superi-orly at the epiglottis and ends inferiorly at the inferior border of the cricoid cartilage of the larynx span from the epiglottis supe-riorly to the cricoid cartilage inferiorly. Laterally, it is separated from the hypopharynx by the aryepiglottic folds.The supraglottis includes all of the laryngeal structures above the inferior half of the ventricle, and this includes the upper half of the ventricle, the false vocal cords, the arytenoids, the aryepiglottic folds, and the epiglottis. The membranes and cartilages of the larynx act as barriers to laryngeal spread: the thyroid and cricoid cartilage, conus elasticus, the quandrangular membrane, the ventricle, the hyoepiglottic ligament, thyrohyoid membrane, and cricothyroid membrane. Although the majority of tumors of the larynx are SCC, minor salivary glands, and their associated malignancies, can be found in the supraglot-tis and subglottis. Other rarer pathologies include granular cell EpiglottisNasopharynxOropharynxEustachiantube orificeSoft palateHyoid boneLarynxHypopharynxPalatine tonsilAdenoidThyroid glandCricoidcartilageFigure 18-30.  Relationship of nasopharynx, oropharynx, and hypopharynx.Brunicardi_Ch18_p0613-p0660.indd 64001/03/19 5:24 PM 641DISORDERS OF THE HEAD AND NECKCHAPTER 18tumors and laryngeal framework tumors, typically arising from the cricoid, such as chondroma and chondrosarcoma.The larynx functions to (a) phonate, (b) protect the air-way during swallowing, and (c) maintain airway patency. This is a fine balance. For instance, if the glottic aperture is enlarged and/or supraglottic structures are excised, phonation and air-way protection suffer while airway patency is improved. It is therefore not surprising that patients with laryngeal tumors can present with dysphonia (hot potato voice in supraglottic tumors and hoarseness in glottic tumors), dysphagia, and airway con-cerns. These patients can also present with dysphagia, weight loss, referred otalgia, and a neck mass. Vocal cord fixation can be a result of a mass effect from large obstructing masses, sec-ondary to direct extension into the paraglottic space or through direct invasion of the cricoarytenoid joint involving either the muscle or the recurrent laryngeal nerve (RLN). Although sub-glottic tumors represent <1% of laryngeal cancers, they can also present with vocal cord paralysis and/or airway compromise.Direct laryngoscopy is beneficial in the assessment of laryngeal tumors to assess the local extent of tumor spread. This is particularly important in assessing vallecula and base of tongue as there can be direct extension to the oropharynx. Simi-larly, glottic cancers can have subglottic extension, which neces-sitates a wider radiation field and/or a more extensive resection. Esophagoscopy and bronchoscopy are also recommended to assess second primary tumors. Furthermore, when a laryngec-tomy is planned, the direct laryngoscopy provides information about the best possible site of entry into the pharynx. Entry can be achieved through (a) a suprahyoid pharyngotomy, (b) ) lat-eral pharyngotomy (lateral to the thyroid cartilage), or (c) infe-riorly through a postcricoid or hypopharyngeal pharyngotomy.Appropriate preoperative staging with a CT scan with contrast is critical in assessing cervical lymphadenopathy and extralaryngeal spread. Erosion or invasion of the thyroid and cri-coid cartilage can significantly impact outcomes and treatment as can extension into the preepiglottic or paraglottic spaces. The supraglottic and subglottic sites are lymphatic rich, and bilateral lymphadenopathy is not uncommon, whereas the glottic site has relatively poor lymphatic drainage (1%–4% regional metasta-sis for isolated larynx cancer). The supraglottis drains through the neurovascular bundle to the thyrohyoid membrane, mainly draining to the upper and lateral cervical nodes (levels II–IV), whereas the glottis and subglottis drain through the cricothyroid membrane and can have spread to the prelaryngeal (Delphian nodes), paratracheal, and lower cervical nodes (levels IV and VI), although in these cases we still treat levels II to IV surgi-cally because of the significant occult nodes in this region.The primary management of laryngeal cancer depends on a variety of factors, including tumor extent, patient comorbidi-ties, and surgeon/center experience. In general, similar to other subsites, early-stage disease can be treated with single modality treatment (surgery or radiotherapy) while advanced stage dis-ease is treated with at least two modalities, typically either sur-gery followed by radiotherapy (with or without chemotherapy) or concurrent chemoradiotherapy. Supraglottic and subglottic lesions are typically treated with primary concurrent chemo-radiotherapy in an attempt to preserve the organ; however, in patients where the primary functions of the larynx are not being fulfilled preoperatively (tracheotomy– and gastrostomy tube–dependent), primary surgical management with a total lar-yngectomy (Fig. 18-33) can be considered. The original trials that popularized organ preservation techniques with concurrent chemoradiotherapy either excluded or had a very small sample size of large (T4) tumors.147,148 Similarly, advanced glottic can-cers (T3/T4a), even when there is no evidence of nodal disease or supraglottic tumors of all stages, have superior survival out-comes when surgery is used as the primary treatment modality.149,150 This is particularly true for tumors that extend beyond the endolarynx or with cartilage destruction, for which total Figure 18-31.  Endoscopic view of a laryngeal squamous carcinoma.Figure 18-32.  Total laryngectomy specimen featuring a locally invasive advanced stage glottic squamous carcinoma.Brunicardi_Ch18_p0613-p0660.indd 64101/03/19 5:24 PM 642SPECIFIC CONSIDERATIONSPART IIlaryngectomy followed by postoperative radiotherapy continues to be the standard of care. When primary chemoradiotherapy is used, surgical salvage is available if there is treatment failure or recurrent disease.The early glottic and supraglottic lesions can be safely treated with CO2 laser transoral microlaryngoscopic resection with excellent oncologic outcomes and laryngeal preservation rates.151,152 Patients with limited involvement of the arytenoid or anterior commissure are the best candidates for a good posttreat-ment vocal quality result with this approach. One of the benefits of this approach is that it does not burn any bridges to more inva-sive treatment. Often, multiple procedures are required to control the disease. Nonetheless, for early stage cancers of the glottis and the supraglottis, radiation therapy is equally as effective as surgery in controlling disease with excellent voice outcomes.Laryngeal Preservation Techniques Beyond CO2 laser tran-soral microlaryngoscopic resection for the most early of lesions, more advanced open laryngeal preservation techniques have been developed for the resection of select, moderately advanced supraglottic and glottic tumors. These techniques can be divided into vertical and horizontal partial laryngeal procedures.Vertical partial larygnectomy (VPL) (Fig. 18-34) involves a midline thyrotomy followed by dissection of the inner peri-chondrium off of the thyroid cartilage with resection of the entire true cord and a portion of the false cords, followed by reconstruction with pedicle strap muscles and bipedicled outer perichondrial flaps. A temporoparietal fascial free flap has also been used to reconstruct these defects with excellent voice outcomes.153 This can be extended to include a frontal verti-cal VPL where the excision crosses the midline as far laterally as to leave only the posterior commissure and one functional cricoarytenoid unit. This procedure is best reserved for recurrent glottic T1/T2 lesions involving only one vocal cord (although anterior commissure involvement is not a contraindication), <5 mm sublottic extension, with a mobile cord, and no cricoid cartilage or extralaryngeal extension. This technique leads to excellent locoregional control with improvements in voice related quality of life with advanced reconstructive techniques.153Supraglottic and supracricoid partial laryngectomies are horizontally oriented resections. In a supraglottic laryngectomy, a laryngectomy is performed below the hyoid and includes the upper portion of the thyroid cartilage while preserving a lower portion approximately the height of the cricoid cartilage. This is reserved for lesions not involving the vocal cords, false cords, or the arytenoids. Cartilage invasion and extensive base of tongue involvement are contraindications. Most lesions amenable for resection using this procedure are typically small enough that a laser or TORS procedure is adequate for resection, and there-fore this procedure is rarely performed. For T3 glottic lesions without preepiglottic space or cricoarytenoid joint involvement, a supracricoid laryngectomy with a cricohyoidopexy or crico-hyoidoepiglottopexy (CHEP) are options. A single cricoaryte-noid unit is preserved to allow for phonation through apposition with the remnant epiglottis or base of tongue. The procedure is associated with excellent oncologic outcomes, tracheostomy decannulation rates, and swallowing function.154 Phonation is reasonable after this procedure but can be characterized as breathy and coarse. Many surgeons prefer not to decannulate patients until the patient has had a significant period of time with good oral intake to allow for pulmonary toilet given the high initial rate of aspiration with this procedure.All partial laryngeal procedures are associated with a high risk of aspiration. Therefore, patients should have excellent pul-monary reserve through pulmonary function tests. When this is not possible, a simple measure includes whether patients can climb two flights of stairs without stopping.PerichondriumUnilaterallesionThyroidcartilageFigure 18-33.  Example of the resection of a vertical partial laryn-gectomy for an early stage glottic carcinoma.Angle of mandibleOhngren'slineMaxillarysinusMedial canthusFigure 18-34.  Example of the Ohngren’s line and the relationship to the maxilla.Brunicardi_Ch18_p0613-p0660.indd 64201/03/19 5:24 PM 643DISORDERS OF THE HEAD AND NECKCHAPTER 18Speech and Swallowing Rehabilitation Speech and lan-guage pathology (SLP) assessment is critical in the manage-ment of patients with laryngeal and hypopharyngeal cancer. It is a critical part of the preoperative assessment and counseling and postoperative therapy. In the elderly larynx cancer popula-tion, Starmer et al demonstrated that SLP care is underutilized and is largely reserved for select patients in anticipation of total laryngectomy or after the onset of impaired airway and swal-lowing function. SLP care was, however, strongly associated with improved outcomes (lower rates of dysphagia, stricture, weight loss, and pneumonia).155SLP often discusses with the patient speech rehabilita-tion options after total laryngectomy, which include esophageal speech, tracheoesophageal puncture, and use of an electrolar-ynx. Esophageal speech is produced by actively swallowing and releasing air from the esophagus, resulting in vibrations of the esophageal walls and pharynx that can then be articulated into words. This requires a very motivated patient, and unfor-tunately, <20% of postlaryngectomy patients develop fluent esophageal speech.The electrolarynx is a device that creates vibratory elec-tric type sounds when held against the neck or cheek that the patient can articulate into speech. This device is typically used in the postoperative inpatient setting, but it can also be used by patients who are not able to create esophageal speech.The ultimate speech rehabilitation for patients with laryn-gectomy is a tracheoesophageal puncture (TEP) with insertion of a voice prosthesis. This prosthesis is a one-way valve that allows air from the trachea to enter the upper esophagus while preventing retrograde passage of food or saliva into the trachea. Patients who undergo placement of a tracheoesophageal punc-ture have a success rate of >90% in achieving functional speech. Many surgeons do not like to place a TEP at the time of the primary laryngectomy, particularly in the salvage setting after radiotherapy due to wound complication concerns. However, primary and secondary TEP patients experience similarly high complication rates, and the extent of the pharyngeal reconstruc-tion rather than preoperative exposure to radiotherapy appear to be more important factors in selection of TEP timing.156 Free flap patients used their TEP more commonly for primary com-munication after secondary versus primary TEP.Postoperative swallowing rehabilitation is another impor-tant task performed by SLPs. Modified barium swallows where the consistency and amount of food provided is varied to mini-mize aspiration can be critical particularly in the management of patients with partial laryngeal procedures. This is performed under fluorosocopy in the radiology suite to allow for the assess-ment of all phases of swallowing. A more limited examination in FEES utilizes the fiberoptic nasolaryngoscope to visualize the larynx during swallow and directly visualize whether there is any laryngeal penetration.Unknown Primary Tumors Patients with cervical nodal metas-tases confirmed to be carcinoma without clinical or radiologic evidence of an upper aerodigestive tract primary tumor are referred to as having carcinoma of unknown primary (CUP). CUP comprise 2% to 5% of all head and neck cancers, although the true incidence is probably lower given advances in surgical visualization and radiological imaging to identify the primary site.157-159 Recently, there has been a rise in CUP likely related to the increase in HPV-associated oropharyngeal cancer, although CUP could also be from a primary thyroid or skin malignancy.160 After a thorough history and physical examination including fiberoptic nasolaryngoscopy, an FNA biopsy is used to confirm carcinoma in the cervical metastases. This is preferred over an open biopsy to avoid the risk of tumor spillage, challeng-ing revision surgery secondary to disruption of fascial planes, and increased risk of recurrence and distant metastases.161 If the primary is not identified on physical examination, patients should undergo a PET-CT scan. A recent systematic review of 7 studies (246 patients) demonstrates an overall sensitivity of 44% and specificity of 97% with this technique, which can often detect tumors >1 cm in size.162 This should be followed by thorough diagnostic operative endoscopy (nasopharyngos-copy, direct laryngoscopy, esophagoscopy, and bronchoscopy). Operative manipulation of the tissues in the upper aerodiges-tive tract specifically with biopsy may lead to false positive results on the PET-CT scan, and therefore PET-CT should be performed before endoscopy. Furthermore, having the PET-CT results prior to operative endoscopy allows the surgeon to focus on specific high-risk sites for biopsy, particularly as it relates to the base of tongue.163 When the primary site is not evident, bilat-eral tonsillectomies and bilateral base of tongue biopsies can be performed to try to identify the primary site. Patients in whom a primary is identified proceed to receive appropriate treatment, and if radiotherapy is part of this treatment regimen, a more limited radiation field is administered, highlighting the impor-tance of identifying a primary site. When the primary site is not identified, primary chemoradiotherapy is advocated, treating all of the mucosal sources of the upper aerodigestive tract at risk (from nasopharynx to hypopharynx) and the cervical regional basin bilaterally. For patients with advanced neck disease (N2a or greater) or with persistent lymphadenopathy after radiation, a neck dissection may be necessary. In the preradiation setting, a neck dissection is preferred over radiotherapy for patients with N1 disease, according to the NCCN guidelines, because some of these patients will be upstaged, ECE is not accurately diagnosed on imaging alone, and because some patients without ECE and a pathologically N1 node benefit from radiation alone without chemotherapy.106,164 The additional prognostic information pro-vided by a neck dissection can significantly impact treatment algorithms and is also associated with lower morbidity com-pared to postoperative neck dissection.Nose and Paranasal SinusesCancers of the nasal cavity and paranasal sinuses are exceed-ingly rare, and pathology in this anatomic subsite is dominated by infectious and inflammatory sources as previously discussed in the “Sinonasal Inflammatory Disease” section of this chapter. Malignant pathology at this site is often diagnosed after failed repeated treatment of suspected benign inflammatory sinona-sal pathology. Concerning preoperative imaging findings (uni-lateral disease; extensive disease; bony, orbital or intracranial invasion) and unusual clinical features may raise concerns about malignancy, and in these cases referral to a tertiary head and neck oncology center is preferred. A concerning history is one that involves a slow progression and worsening of symptoms, which may include nasal obstruction, facial pain, headache, epistaxis, and facial numbness. Most tumors at this site pres-ent with advanced stage given the inevitable delay in diagnosis. Numbness in the V2 distribution suggests invasion of pterygo-palatine fossa, and V3 distribution numbness can be an indi-cation of extension to the infratemporal fossa and skull base invasion to foramen ovale. Proptosis, epiphora, diploplia, and change in vision (typically starting with loss of color vision) are Brunicardi_Ch18_p0613-p0660.indd 64301/03/19 5:24 PM 644SPECIFIC CONSIDERATIONSPART IIall signs of advanced orbital invasion. Maxillary sinus tumors, the most common site for cancers of this site, can be prognos-ticated simply using Ohgren’s line (Fig. 18-35), an imaginary line from medial canthus to the angle of the mandible, which divides maxillary sinus into anterior-inferior and posterior-superior parts. Tumors from the anterior-inferior are more prognostically favorable.Although the most common pathology at this site continues to be squamous cell carcinoma, a brief discussion of other histo-pathology is warranted given significant variety, prognostic, and treatment-related differences between these at this subsite. Benign pathology at this site includes inverted papilloma, hemangiomas, hemangiopericytomas, angiofibromas, minor salivary tumors, and benign fibrous histiocytomas. Fibro-osseous and osseous lesions, such as fibrous dysplasias, ossifying fibromas, osteo-mas, and myxomas, can also arise in this region. Additionally, encephaloceles and meningo-encephaloceles with herniation of intracranial content into the nasal cavity can present as sinonasal lesions; therefore, imaging, typically with an MRI, is warranted before biopsy of any sinonasal mass to prevent an iatrogenic CSF leak. In the evaluation of sinonasal malignant pathology, both CT and MRI are required because they provide complimentary information. MRI provides improved skull base, intracranial, and orbital invasion assessment, while CT provides better assessment of bony anatomy and invasion.Beyond squamous cell carcinoma, the next two most com-mon malignancies at this site include adenoid cystic carcinoma and adenocarcinoma. Other pathologies include sinonasal undif-ferentiated carcinoma (SNUC), mucosal melanoma, lymphoma, esthesioneuroblastoma (previously known as olfactory neuro-blastoma), rhabdomyosarcoma, and angiosarcoma. Unlike other head and neck cancers, metastases to the regional lymphatic basis are extremely rare, and rarely will patients require or receive pri-mary or adjuvant treatment to the neck unless there is clinical or radiographic evidence of neck disease (approximately 15%).165The standard treatment for malignant tumors of the para-nasal sinuses is driven by the primary pathology; however, for most pathology, including SCC, the standard of care includes surgical resection followed by adjuvant radiotherapy.166 Advances in EEAs has led to a shift in management of these tumors with minimally invasive approaches that are associated with significantly lower complication and morbidity rates with comparable oncologic outcomes.167,168 Open approaches are, however, indicated when there is tumor abutting the anterior wall of the frontal sinus, anterior extension into nasal bones, anterior maxillary wall invasion, facial skin or soft tissue inva-sion, dural involvement above the orbit or periorbital invasion, tumors with significant inratemporal fossa invasion, and exten-sion into the oral cavity, including the hard palate or the floor of the maxillary sinus. Many tumors can be treated with an endo-scopic approach such a medial maxillectomy when the tumor arises from the medial wall of the maxilla. Multidisciplinary assessment and treatment should include a skull base tumor board discussion with a head and neck oncologist/surgeon, a neurosurgeon, opthalmologist including oculoplastic surgeons, prosthodontists, and reconstructive surgeons. Preoperative embolization within 24 hours of tumor excision can be useful for vascular tumors.Extent of surgery and prognosis is dependent on the tumor location and extension. For tumors limited to the hard palate and lower maxillary sinus, an infrastructure maxillectomy is sufficient. A total maxillectomy without removal of the orbital floor may be warranted for more extensive tumors limited to the maxillary sinus. When the orbital periosteum is not invaded but tumor abuts this region, removal of the orbital floor with appro-priate reconstruction is warranted. When there is invasion of periorbita, an orbital exenteration is warranted for most pathol-ogy. Tumors originating in the ethmoid sinuses may require excision of the cribriform plate and repair of subsequent skull base defect if the tumor originates or invades through the bony skull base. This is performed through an anterior craniofacial resection, where a neurosurgeon performs a frontal craniotomy for exposure of the anterior cranial fossa floor, while the head and neck surgeon performs a transfacial or endoscopic resection of the inferior bony and soft tissue structures. This approach often requires resection of dura and a dural repair to achieve negative margins. A less extensive surgery including a sphe-noethmoidectomy or medial maxillectomy can be entertained for smaller tumors originating in the lateral nasal wall through endoscopic or open approaches.Tumors are deemed to be unresectable if both optic nerves are involved, if there is carotid artery invasion, or if there is extensive intracranial extension. Chemotherapy has a limited application in the management of tumors at this subsite with two exceptions: rhabdomyosarcoma, which is primarily treated with chemotherapy followed by radiation therapy with surgery reserved for the salvage setting, and SNUC, where triple modal-ity treatment is required given tumor aggressiveness. Chemo-therapy in this setting may help to reduce the tumor bulk and allow for orbital preservation.NasopharynxThe anatomic borders of the nasopharyx are superiorly the adenoid patch, superolaterally the fossa of Rosenmüller and the Eustachian tube orifices (torus tubarius), inferiorly the plane of the hard palate from the choana, anteriorly the posterior nasal cavity, and posteriorly the posterior pharyngeal wall. Malignant Subtotal temporalbone resectionTotal temporalbone resectionLateraltemporalbone resectionFigure 18-35.  Examples of resection specimens for lateral tem-poral bone resection, subtotal temporal bone resection, and total temporal bone resection.Brunicardi_Ch18_p0613-p0660.indd 64401/03/19 5:24 PM 645DISORDERS OF THE HEAD AND NECKCHAPTER 18tumors of the nasopharynx are typically well differentiated or lymphoepithelial SCC. However, other tumors can present in this region including lymphoma, chordoma, chondroma, nasopharyngeal cyst (Tornwaldt’s cyst), angiofibroma, minor salivary gland tumor, paraganglioma, rhabdomyosarcoma, extramedullary plasmacytoma, and, rarely, sarcoma.Unlike other head and neck cancers, the nasopharynx site has unique ethnic and geographic predilection, namely, a higher incidence in southern China, Africa, Alaska, and in Green-land Eskimos. EBV is also more commonly seen in patients with NPC, and EBV titers are helpful in following treatment response.As previously discussed, a posterior (level V) neck mass should be considered NPC until proven otherwise. Other signs and symptoms include nasal obstruction, epistaxis, unilateral serous otitis media in an adult, and otalgia. Advanced disease can present with cranial neuropathies, particularly of the cranial nerves, which run in the cavernous sinus (CN V1, V2, III, IV, VI). Bilateral regional disease spread is common, and the lym-phatic level involved include the posterior neck (level V), as well as the upper (level II) cervical nodes and retropharyngeal nodes. Distant metastatic disease is present in 5% of patients at diagnosis, highlighting the importance of a thorough staging workup.Staging includes a thorough physical examination using either a flexible or rigid endoscope to assess the mucosal extent of the disease. CT and MRI are complimentary as in the assess-ment of nasal cavity and paranasal sinus tumors with CT provid-ing better assessment of bony invasion and the MRI providing better soft tissue delineation, skull base invasion, and perineural spread with cranial nerve enhancement. Multimodality therapy with chemoradiotherapy is superior to radiotherapy alone in the management of nasopharyngeal carcinoma.169 Recurrent tumors are treated typically with reirradiation; however, there has been recent success with surgical salvage procedures, particular in those patients in which a negative margin can be achieved.170When resection is contemplated for recurrent nasopharyn-geal carcinoma or for low grade tumors such as some minor salivary gland tumors, a number of surgical approaches can be utilized for resection. These include endoscopic, transpalatal, transfacial via a maxillary swing procedure, and transcervical. In many cases, a combination of these techniques is required to achieve a negative margin. The transcervical approach pro-vides the added benefit of early access and control of the carotid artery. For benign and low-grade tumors, advances in EEA have made use of the open approaches less common.Ear and Temporal BoneTemporal bone and ear tumors are rare account for <0.5% of all head and neck cancers. Subsites in this head and neck site from lateral to medial include the pinna (external ear), external auditory canal, middle ear, mastoid, and petrous portion of the temporal bone. Although the typical pathology at this site is squamous cell carcinoma, minor salivary gland tumors such as adenocarcinoma and adenoid cystic carcinoma can also present here. Given that the ear is in the high-risk region for aggressive skin cancers due to its unique exposure to ultraviolet light, cuta-neous malignancies such as basal cell carcinoma and melanoma can also present here. In the pediatric population, soft tissue sar-comas, most commonly rhabdomyosarcoma, can present at this site. These tumors typically present with an advanced stage,171 and resection with clear margins and functional preservation is challenging because of the close proximity of vital structures, namely the facial nerve and the external auditory canal.172 Tumors involving the petrous apex or intracranial structures may present with headache and palsies of CN V and VI as well.Patients can present with ulceration, granulation, or bleed-ings from the external ear and auditory canal. This is often mistaken for an infectious or inflammatory process given the rarity of malignancy at this subsite; however, persistent granu-lation tissue in the ear should be biopsied and imaged to rule out malignancy. Patients can then present with otorrhea, otal-gia, hearing loss, vertigo, and facial nerve paralysis. Appropri-ate imaging with CT and MRI is often required to appropriately delineate the lesion and stage and assist with the appropriate management plan.Cutaneous malignancies of the pinna and tragus can usu-ally be locally excised. However, at this subsite, spread into the perichondrium and cartilage can lead to rapid spread long that tissue plane. The importance of negative margins cannot be overstated at this subsite. Mohs microsurgery has been advo-cated for select tumors at this subsite for this reason; however, some tumors are so extensive that a total auriculectomy provides the best oncologic and cosmetic result. When there is exten-sion of tumor to the bony cartilaginous EAC junction, spread to parotid, temporomandibular joint, and skull base is possible. Advanced tumors anterior to a vertical line along the EAC from a sagittal view benefit from a parotidectomy as well as a suprao-mohyoid neck dissection (levels I–III), whereas those behind this line benefit from a posterolateral neck dissection (levels II–V). As with other cutaneous malignancies, adjuvant radio-therapy is indicated for positive margins, perineural spread, or multiple involved lymph nodes.Tumors involving the EAC and middle ear require differ-ent management, including a sleeve resection of the external auditory canal, a lateral temporal bone resection, or a subtotal temporal bone resection (Fig. 18-36). A sleeve resection of the EAC skin and cartilage is rarely enough to achieve negative margins with the exception of some basal cell carcinomas of the skin overlying the cartilaginous EAC. For more extensive IIIIIIVIIVVFigure 18-36.  Levels of the neck denoting lymph node bearing regions.Brunicardi_Ch18_p0613-p0660.indd 64501/03/19 5:24 PM 646SPECIFIC CONSIDERATIONSPART IItumors and more aggressive pathology, a lateral temporal bone resection may be required removing the cartilaginous and bony external auditory canal as well as the middle ear en bloc.173 A subtotal temporal bone resection also removes the inner ear and facial nerve as part of the resection and is indicated when the tumor extends into the middle ear and a deeper resection margin is required. Both of these procedures are followed by postopera-tive radiotherapy, which provides improved locoregional con-trol.173 The neck is managed in a similar fashion to pinna and external auditory canal malignancies typically requiring a supra-omohyoid (levels I–III) neck dissection. Survival outcomes are poor with a 5-year overall survival of <40%.174 Important pre-dictors of disease free survival include margin status, perineu-ral invasion, and regional lymphatic spread; the most important of these on multivariate analysis being lymphatic spread of disease.171Lateral temporal bone resections often require reconstruc-tion to close the wound, provide bulk, and vascularize tissue. If dura is encountered and even resected, a watertight dural closure is required to prevent a CSF leak and meningitis. Vascularized tissue has the added benefit of preparing the surgical bed for postoperative radiotherapy. These defects can be reconstructed with regional pedicled flaps (e.g., submental flap) or free flaps. The most common free flaps used are the anterolateral thigh, although depending on body habitus and the depth of the defect, the radial forearm, lateral arm, and rectus abdominus may also be used.175 The deformity resulting from a total auriculectomy is often not reconstructed primarily, but an auricular prosthesis can be designed for further rehabilitation. Facial nerve reconstruc-tion when sacrifice is required is typically performed with cable grafts from the proximal facial nerve to select distal facial nerve branches. Because of the long distance between the proximal and distal branches, facial movement is typically delayed 6 to 12 months. However, if the masseteric nerve is connected through a cable graft to select distal facial nerve branches (typically the zygomatic branch), a shorter cable graft is required, and facial movement can be achieved earlier. A variety of other static and dynamic procedures can be provided secondarily. The most important of these procedures are related to preserving eye clo-sure to avoid corneal abrasions or desiccation, which can ulti-mately lead to blindness. In the immediate postoperative period, taping of the eyelids and generous application of eye lubrication is required to prevent exposure keratitis. Upper lid gold weight implants, lower lid shortening procedures, and tarsorrhaphy can be performed secondarily to assist with eye closure.NeckAn undiagnosed neck mass needs to be carefully evaluated and worked up so as to not interfere with the definitive management of the patient and future treatment options. The patient’s age, social history, including alcohol and smoking history, preced-ing illness history, and synchronous upper aerodigestive tract physical examination findings can significantly impact the dif-ferential diagnosis and the investigation to work up a neck mass. A thorough history and head and neck examination, including fiberoptic nasolaryngoscopy, are therefore paramount to com-plete evaluation. With regard to age, in children, a neck mass is far more likely to be congenital, inflammatory, or infectious, whereas in adults, neck masses >2 cm have a >80% probability of being malignant. Typically, the first investigation is an FNA biopsy, which can be performed with ultrasound or CT guid-ance when the mass is not easily palpable or largely cystic with a small solid component. Imaging is critical in characterizing the neck mass, particularly assessing the borders, consistency, and location which then impacts the differential diagnosis. For instance, a cystic neck mass can be a branchial cleft cyst or a regional metastasis from an oropharynx cancer or metastatic papillary thyroid cancer. Therefore, the imaging findings also significantly impact the differential diagnosis.When the imaging and FNA does not provide adequate information for a diagnosis, a core biopsy can be considered, particularly if the diagnosis of lymphoma is suspected and an open biopsy wants to be avoided. For a suspected carcinoma, an open biopsy may be required; however, in that case, the incision needs to be planned such that the procedure can be converted to a neck dissection, and a frozen section can be sent. If the diagnosis of squamous cell carcinoma is confirmed on frozen section, then a neck dissection should be performed to further prognosticate the disease. In the case of lymphoma, biopsy does not need to remove the entire lymphoma, particularly if there is an added risk of injuring normal anatomical structures.Patterns of Lymph Node Metastasis. The lymphatic drain-age into the neck is divided into seven levels with standardized reporting within and across specialties, particularly as radiolo-gists, pathologists, surgeons, radiation oncologists, and radiolo-gists share the findings176,177 (Fig. 18-37). The levels include• Level I—the submental and submandibular nodes• Level Ia—the submental nodes; medial to the anterior belly of the digastric muscle bilaterally, symphysis of mandible superiorly, and hyoid inferiorly; this level does not have any laterality as it includes both right and left sides• Level Ib—the submandibular nodes and gland; posterior to the anterior belly of digastric, anterior to the posterior belly of digastric, and inferior to the body of the mandibleFigure 18-37.  Shaded region indicates the region included in a supraomohyoid neck dissection.Brunicardi_Ch18_p0613-p0660.indd 64601/03/19 5:24 PM 647DISORDERS OF THE HEAD AND NECKCHAPTER 18• Level IIa—upper jugular chain nodes; anterior to the poste-rior border of the sternocleidomastoid (SCM) muscle, poste-rior to the posterior aspect of the posterior belly of digastric, superior to the level of the hyoid, inferior to spinal accessory nerve (CN XI)• Level IIb—submuscular recess; superior to spinal accessory nerve to the level of the skull base• Level III—middle jugular chain nodes; inferior to the hyoid, superior to the level of the cricoid, deep to SCM muscle from posterior border of the muscle to the strap muscles medially• Level IV—lower jugular chain nodes; inferior to the level of the cricoid, superior to the clavicle, deep to SCM muscle from posterior border of the muscle to the strap muscles medially• Level V—posterior triangle nodes• Level Va—lateral to the posterior aspect of the SCM muscle, inferior and medial to splenius capitis and trapezius, superior to the spinal accessory nerve• Level Vb—lateral to the posterior aspect of SCM muscle, medial to trapezius, inferior to the spinal accessory nerve, superior to the clavicle• Level VI—anterior compartment nodes; inferior to the hyoid, superior to suprasternal notch, medial to the lateral extent of the strap muscles bilaterally• Level VII—paratracheal nodes; inferior to the suprasternal notch in the upper mediastinumThere is a well-established pattern of regional spread from upper aerodigestive tract primary tumors.178 Lesions of the lip and oral cavity typically metastasize to levels I to III and skip metastases to the lower basin (levels III–IV) without involve-ment of the upper level (levels I–II). Oropharyngeal, laryngeal, and hypopharyngeal tumors most commonly spread to the lat-eral neck (levels II–IV). It is rare for any of these tumors to have isolated regional metastases to level V; however, naso-pharyngeal, thyroid, and head and neck malignant melanoma can metastasize to this level. Other sites for metastasis include the retropharyngeal nodes (oropharyngeal, nasopharyngeal, and hypopharyngeal tumors), paratracheal and level VII nodes (thyroid, hypopharynx, and cervical esophageal tumors), and pretracheal (Delphian) nodes (thyroid and advanced glottic tumors with subglottic extension).Historically, a radical neck dissection (RND) was per-formed for all upper aerodigestive tract malignancies with sac-rifice of the SCM, internal jugular vein (IJV), and accessory nerve (CN XI) and removal of all lymphatic level (levels I–V). This was because cervical metastasis decreased the 5-year over-all survival rate by approximately 50%. However, growing evi-dence demonstrated that this was not necessary, and now a neck dissection is only recommended for upper aerodigestive tract malignancies when the risk of occult disease is >20% in the clinically negative neck.179 When the neck is clinically positive, the level discussed in the previous paragraph for each site are excised with every attempt to preserve the SCM, IJV, and CN XI (selective neck dissection; SND). When there is direct exten-sion of the tumor or extralymphatic spread into these structures, sacrifice may be necessary in a modified radical neck dissection (MRND). The RND has been largely abandoned because the SND and MRND have been demonstrated to be equally effec-tive when it comes to oncologic outcomes with far improved functional outcomes.180,181SND has become the standard of care for most patients who are clinically node negative (cN0) and in those with limited cN1 disease. Patients with oral cavity cancer typically receive a supraomohyoid (Fig. 18-38) neck dissection (levels I–III). Many surgeons will include a portion of level IV just below the omohyoid muscle given the rate of skip metastases previously discussed. Approximately 80% of patients with oral cavity can-cer present cN0; however, the rate of occult metastatic disease is approximately 30% and differs by subsite.182 This rate is further impacted by tumor thickness at the tongue subsite, with tumors 4 mm or thicker having a higher rate of occult disease.183 A recent prospective, randomized trial demonstrated the oncologic benefit of an elective neck dissection in cN0 oral cavity patients regardless of tumor thickness over an observation followed by therapeutic neck dissection in those with regional failures.184 An additional role of SND is as a staging tool to determine the need for postoperative radiation therapy. The lateral (Fig. 18-39) neck dissection (levels II–IV) is typically used in laryngeal and hypo-pharyngeal cancers. The posterolateral (Fig. 18-40 neck dissec-tion (levels II–V) is typically recommended in thyroid cancers, although recent evidence has demonstrated that a partial level V dissection may be all that is necessary for equivalent outcomes to a full level II to V neck dissection.176,185,186Despite advances in the surgical management of neck dis-ease, in clinically advanced nodal disease (with the exception of uncomplicated N1 disease), an MRND remains the treatment of choice. When the neck disease is advanced with extrano-dal extension (ENE), perineural invasion (PNI), lymphovas-cular invasion (LVI), and the presence of multiple involved nodes, postoperative radiotherapy improves locoregional con-trol.103 If there is a positive margin or ENE, then the addition of adjuvant chemotherapy to radiotherapy provides a survival benefit.113,187,188In patients receiving primary radiotherapy with advanced N stage disease (N2a or greater) or only a partial response to Figure 18-38.  Shaded region indicates the region included in a lateral neck dissection.Brunicardi_Ch18_p0613-p0660.indd 64701/03/19 5:24 PM 648SPECIFIC CONSIDERATIONSPART IItreatment, a planned postradiotherapy neck dissection can be performed 6 to 8 weeks after completion of radiotherapy. This is to consolidate the treatment and provide prognostic information.Tumor factors that preclude surgery include prevertebral fascia invasion, skull base invasion, and >270o circumferential encasement of the internal carotid artery. These factors are asso-ciated with very poor 5-year survival (<20%). In such cases, sac-rifice of the carotid is not indicated given the risk of stroke and death. Surgical debulking is also not associated with improved survival. However, there is a role for neoadjuvant chemother-apy, and in those that respond and if the disease becomes resect-able, survival benefit has been demonstrated.189 Recurrent neck metastasis after radiotherapy to the neck or a comprehensive neck dissection is associated with very poor survival.190Parapharyngeal Space Masses. The parapharyngeal space is a potential inverted pyramidal space bordered superiorly at the skull base along the sphenoid and inferiorly at the greater cornu of the hyoid. Medially it is bordered by the buccopha-ryngeal fascia covering the superior constrictor, anteriorly the pterygomandibular raphe, posteriorly the prevertebral fascia, and laterally by the deep surface of the parotid gland and ramus of the mandible. The differential diagnosis for parapharyngeal masses is very much dependent on the anatomy and contents of this space which is divided into the preand poststyloid spaces by the tensor-styloid fascia. This fascia attaches the tensor veli palatini muscle to the styloid. The contents of the prestyloid parapharyngeal space include fat, the deep lobe of the parotid, and lymph nodes, and branches of V3 (lingual, inferior alveo-lus, and auriculotemporal nerves), whereas the contents of the poststyloid space including cranial nerves IX to XII, the inter-nal jugular vein, the internal carotid artery, and the sympathetic chain. Nearly half of all parapharyngeal masses are of parotid origin, while 20% to 25% are of neurogenic origin, such as paragangliomas (glomus vagale, carotid body tumor), schwan-nomas, and neurofibromas. Lymphatic origin masses such as lymphoma and lymph node metastases represent 15% of tumors at this subsite. Therefore, most prestyloid lesions are considered of salivary gland origin, whereas poststyloid lesions are typi-cally vascular or neurogenic.Tumors of the parapharyngeal space can displace the lat-eral pharyngeal wall medially into the oropharynx (Fig. 18-41) and can thus cause obstructive sleep apnea, voice change, and dysphagia in addition to cranial neuropathies, Horner’s syn-drome, or vascular compression. In addition to CT and MRI, poststyloid lesions should be investigated with a 24-hour uri-nary catecholamine collection because some paragangliomas are functional and this should be managed preoperatively.Surgical access to these tumors can be performed using a purely transcervical approach with the excision of the subman-dibular gland for access. A transfacial or transparotid approach can be used as an adjunct for certain tumors by removing the parotid gland. This ensures identification of the facial nerve Figure 18-39.  Shaded region indicates the region included in a posterolateral neck dissection.ParotidglandStylomandibularligamentFigure 18-40.  Parapharyngeal mass—prestyloid with prominent oropharyngeal presentation typical of a dumbbell tumor.Brunicardi_Ch18_p0613-p0660.indd 64801/03/19 5:24 PM 649DISORDERS OF THE HEAD AND NECKCHAPTER 18prior to removal of the mass, which is just deep to it. Rarely, a transmandibular approach is required by performing a midline or parasymphyseal mandibulotomy with a lateral swing. Tran-soral approaches have been described, but they are not recom-mended and are largely contraindicated due to poor exposure and control of the associated vasculature.Benign Neck Masses. Many benign neck masses require surgical intervention for diagnostic, cosmetic, and symptom-atic relief. This is particularly true for lesions that are prone to recurrent infections, especially in the pediatric population. Such masses include thyroglossal duct cyst, branchial cleft cyst, lymphangioma (cystic hygroma), hemangioma, and der-moid cyst. Lymphangioma and hemangioma were previously discussed and will not be discussed in this section.During fetal growth, the thyroid gland descends along a tract from the foramen cecum at the base of tongue into the ante-rior low neck. A vestigial remainder of this tract is called a thy-roglossal duct cyst, which typically presents as a subcutaneous swelling near the hyoid in the midline or slightly paramedian. Patients may complain of recurrent infections of this mass after an upper respiratory tract infection. Investigations include thy-roid function tests and a neck and thyroid ultrasound to confirm that the patient has thyroid tissue in the lower neck . Treatment involves removal of the cyst, the tract, and the central portion of the hyoid (Sistrunk procedure), often with a small portion of the base of tongue if the tract extends above the hyoid.During fetal growth, the branchial cleft apparatus may persist, forming a branchial cleft remnant (cyst, sinus, or tract), numbered to their corresponding embryologic branchial cleft. First branchial cleft anomalies parallel the EAC (Work Type I; preauricular) or go through the parotid gland ending at the bony-cartilaginous EAC junction (Work Type II; angle of the mandible). Second branchial anomalies (Fig. 18-42), the most common type, start at the anterior border of the SCM and head toward the tonsillar fossa traveling deep to second arch struc-tures (CN VII and external carotid artery) and superficial to third arch structures (stylopharyngeus, IX, and internal carotid artery). Third and fourth branchial anomalies are difficult to dis-tinguish clinically and frequently open into the pyriform sinus often presenting with recurrent thyroid infections.191 These anomalies ascend posterior the internal carotid artery and deep to CN IX but superficial to CN XI and XII. Dermoid cysts tend to present as midline masses and represent trapped epithelium originating from the embryonic closure of the midline. These can be reliably diagnosed and distinguished from thyroglossal duct cysts using an ultrasound predictive model.192Cervical Fascial Planes. The fascial planes often predict the pathway and extent of infectious spread in the neck and are there-fore clinically important. The deep fascial layers of the neck Figure 18-41. Computed tomography scan demonstrating a branchial cleft cyst with operative specimen.Facial n.Anterior facial v.Retromandibular v.Temporal branchFrontal branchPosterior bellyof digastric m.StylomastoidforamenCervicalbranchMasseter m.Zygomatic branchParotid ductBuccalbranchMandibularbranchFigure 18-42.  Example of a tumor in the parotid with the pattern of the facial nerve and associated anatomy. m. = muscle; n. = nerve; v. = vein.Brunicardi_Ch18_p0613-p0660.indd 64901/03/19 5:24 PM 650SPECIFIC CONSIDERATIONSPART IIinclude three separate layers: the superficial deep (investing) layer, the pretracheal (visceral) layer, and the prevertebral layer. The investing layer forms a cone around the neck and surrounds the SCM muscle and the anterior and posterior neck. It spans from the mandible to the clavicle and manubrium. The visceral layer surrounds the trachea, thyroid, and esophagus and blends laterally with the carotid sheath extending inferiorly to the upper mediastinum. Between this layer and the prevertebral fascia is the retropharyngeal space. The prevertebral fascia covers the pre-vertebral musculature and space and extends down to the tho-racic vertebra and diaphragm. Infections of the prevertebral space between this fascia and the prevertebral musculature are considered to be in the prevertebral space and can extend all the way down to the sacrum. Therefore, neck infections can extend to the mediasti-num or beyond and need to be treated aggressively.Salivary Gland TumorsPrimary malignant tumors of the salivary glands are relatively rare and account for <2% of all head and neck malignancies. As previously mentioned, minor salivary gland malignancies can present anywhere in the upper aerodigestive tract, particularly on the palate; however, the major salivary glands are the parotid, submandibular, and sublingual glands. The majority of tumors (80%) arise in the parotid gland (Fig. 18-44); however, 80% of these are benign, most commonly, pleomorphic adenomas (benign mixed tumors). As the salivary gland gets smaller, the proportion of tumors that are malignant increases; 50% of sub-mandibular/sublingual tumors and 80% of minor salivary gland tumors are malignant.Patients typically present with a mass because these tumors are well circumscribed and slow growing. However, certain signs and symptoms, such as pain, paresthesia, facial nerve weakness, or rapid growth, raise the concern for malig-nancy. If there is facial nerve weakness (10%–15% of cases), this usually represents tumor invading the facial nerve. Sub-mandibular and sublingual tumors present with a mass or swell-ing in the neck or floor of the mouth, respectively. Tumors in this region can invade the lingual nerve leading to tongue par-esthesia or the hypoglossal nerve invasion leading to paralysis. The close proximity to the mandible and tongue necessitates a thorough bimanual palpation to assess for fixation to these structures.The decision to dissect the neck in parotid cancers is fraught with uncertainty. However, parotid malignancies, par-ticularly carcinomas, have a propensity for regional lymphatic spread, first to the intraand periglandular nodes followed by the upper cervical chain (levels I–III). Occult nodal metastases are present in 30% of cases and are predicted by intraor peri-glandular nodes, high-risk histology (high histological grade), and extraparotid extension.193 Patients with advanced tumor stage (T3/T4a), perineural invasion, high risk histology, or clin-ically involved adenopathy should have their neck dissected. Submandibular gland cancers metastasize to the submental (Ia) and submandibular triangle lymph nodes followed by the upper cervical chain (levels II–III). Extraglandular extension and regional metastases are poor prognostic factors.Following a thorough history and physical examination, an FNA biopsy should be performed to provide an accurate preoperative diagnosis in 70% to 80% of cases when reviewed by an experienced cytopathologist. If the biopsy is nondiag-nostic, a repeat biopsy should be performed under image-guidance, typically with an ultrasound. An open or incisional biopsy should be avoided because of the risk of tumor spill-age and cutaneous spread. Also, this approach is fraught with risk to the facial nerve. Salivary gland tumors are worked up with appropriate imaging, typically with an MRI because of the increased soft tissue definition. FNA and imaging results are critical in guiding the surgeon to the extent of surgery. The minimal extent of surgery for salivary gland tumors is a superficial parotidectomy, removing all of the salivary gland tissue superficial to CN VII, which is meticulously dissected during this procedure.The final histopathologic diagnosis in salivary gland tumors can be challenging. Nonetheless, there is a well-outlined histological classification used by pathologists.194 Benign and malignant tumors of the salivary glands are divided into epi-thelial, nonepithelial, and metastatic neoplasms. Benign epithe-lial tumors are most commonly pleomorphic adenoma (85%), monomorphic adenoma, Warthin’s tumor (papillary cystad-enoma lymphomatosum), oncocytoma, or sebaceous neoplasm. Nonepithelial benign lesions include lipoma and hemangioma. Treatment of benign neoplasms is surgical excision for diag-nostic and therapeutic purposes. The parotid superficial lobe is usually dissected off of the facial nerve, which is preserved. For pleomorphic adenoma, an extracapsular dissection is favored over enucleation due to tumor pseudopods, incomplete excision, and a higher risk of tumor spillage, all of which are associated with higher recurrence rates.195 Recurrence is associated with a high degree of morbidity.Malignant epithelial tumors range in aggressiveness based on tumor histology, grade, perineural invasion, and regional metastases. Mucoepidermoid carcinoma is the most common primary malignancy of the salivary glands and can be high grade (more epidermoid) or low grade (more mucinous). High grade mucoepidermoid carcinoma can be hard to differentiated from squamous cell carcinoma, particularly on FNA. Adenoid cystic is the second most common primary salivary gland malignancy and has three histological subtypes: tubular, cribriform, and solid. Higher grade/risk tumors have a higher degree of solid differentiation.194 Adenoid cystic cancers are known for peri-neural invasion and late recurrences and distant metastases. Car-cinoma ex pleomorphic adenoma is an aggressive malignancy that arises from a preexisting benign mixed tumor highlighting the importance of removing these benign masses before malig-nant transformation.Surgical excision remains the standard of care, typi-cally with facial nerve preservation unless the nerve is directly invaded by tumor. For tumors that extend beyond the superficial lobe, nerve branches can be splayed, and a total parotid can be performed by removing parotid tissue deep to the nerve while preserving the integrity and function of the nerve. Whenever possible, the nerve is preserved even if microscopic disease is left on the nerve, so long as gross tumor is not left behind (i.e., the nerve is not encased). If this is not possible or if the nerve is not working preoperatively, nerve sacrifice is usually recommended.Elective neck dissection is warranted in high-grade muco-epidermoid carcinomas and other high-risk pathology and grade where the risk of occult disease is greater than 15% to 20%. Therapeutic neck dissection is recommended in patients with clinically or radiographically evident disease. Postoperative radiotherapy is indicated in patients with perineural invasion, advanced local disease (T4a), extraglandular disease including regional metastases, and high-grade histology.Brunicardi_Ch18_p0613-p0660.indd 65001/03/19 5:24 PM 651DISORDERS OF THE HEAD AND NECKCHAPTER 18RECONSTRUCTIONLocal Flaps and Skin GraftsLocal flaps are commonly used for cutaneous reconstruction in the head and neck. Local flaps are most commonly utilized for reconstruction after Mohs micrographic surgery for cutaneous malignancy, or for reconstruction of melanoma defects. Skin grafts are also commonly used for reconstruction of scalp defects after surgical resection of cutaneous malignancies. Skin grafts may also be utilized in the oral cavity for resurfacing of super-ficial defects of the tongue, floor of mouth, and buccal mucosa.Regional FlapsThree regional flaps deserve mention as potential flaps for head and neck reconstruction. The first is the pectoralis major myo-cutaneous flap, based upon the thoracoacromial artery.196 This flap may be used as a primary option for hypopharyngeal recon-struction after total laryngectomy. This flap may also be utilized to protect the great vessels from becoming exposed, or as a sal-vage reconstructive procedure should the great vessels become exposed. Another commonly utilized regional flap is the sub-mental flap, based upon the submental vessel branches of the facial artery. This flap may be utilized for intraoral reconstruc-tion and/or parotid and temporal bone reconstruction.197 Care must be taken during the neck dissection in order to preserve the submental vessels that supply this flap. Finally, the supraclavic-ular flap is based upon the supraclavicular artery, arising from the transverse cervical artery.198 This is a thin, fasciocutaneous flap that is commonly used for external neck and facial recon-struction in which thin tissue is desired.Free Tissue TransferThe majority of major defects of the head and neck require free tissue transfer for optimal reconstruction.199 A full discussion of head and neck reconstructive microsurgery is beyond the scope of this chapter; however, a brief overview of free tissue transfer is provided in this section. Free tissue transfer allows the sur-geon to transplant tissue from a wide array of donor sites, each of which have distinct advantages.200 For example, for floor of mouth reconstruction, where thin tissue is desired, the surgeon may select the radial forearm as the donor site. On the other hand, when presented with a total glossectomy defect, where thick tissue is desired for adequate volume reconstruction, the rectus may be the optimal donor site. Considering osseous defects, for reconstruction of a segmental mandible defect with minimal soft tissue deficit, the fibula osseocutaneous free tis-sue transfer may be the optimal choice.201 On the other hand, reconstruction of an osseous mandible defect with a large muco-sal and external soft tissue deficit may be best served by the scapula donor site, where vascularized bone can be combined with a large skin paddle, and an additional latissimus dorsi myocutaneous free tissue transfer, if needed.202 The ability to harvest tissue from multiple donor sites is critical to obtain-ing the optimal reconstructive result. Table 18-6 lists the com-monly utilized donor sites and their reconstructive advantages and disadvantages.Table 18-6Free tissue transfer donor sites for head and neck reconstructionFLAPBLOOD SUPPLYCHARACTERISTICSCOMMON DEFECTSRadial forearmRadial arteryThin, pliable, long pediclePartial and hemiglossectomy, floor of mouth, buccal defectsAnterolateral thighDescending branch of lateral femoral circumflex arteryThicker adipose than radial forearm, can have myocutaneous (most common) or septocutaneous perforatorsHypopharynx, external neck/facial skin, extended hemiglossectomy/total glossectomyLateral armPosterior radial collateral arteryOutstanding color match for facial skin, resists ptosis, diminutive pedicleParotid, temporal bone, external face and neck skinRectusDeep inferior epigastric arteryThick adipose tissue for large volume defects, long pedicle, poor external skin color matchTotal glossectomy, skull baseLatissimus dorsiThoracodorsal arteryLarge surface area of muscle, requires semi-lateral position, can be difficult for two-team harvestExtensive scalp and skull base defectsFibula osseocutaneousPeroneal arteryExcellent bone stock and length, long pedicle, thin skin paddleSegmental mandible and maxillaScapula osseocutaneousCircumflex scapular arteryLess bone length compared to fibula, large scapular or parascapular skin paddles ideal for large composite defectsSegmental mandible and maxilla defects with extensive soft tissue componentsRadial forearm osseocutaneousRadial arteryLong pedicle, diminutive bone stockPartial mandible defects, orbitIliac crestDeep circumflex iliac arteryUp to 16 cm of bone available, limited soft tissue, significant donor site morbiditySegmental mandible defects with small intraoral component and large external skin componentBrunicardi_Ch18_p0613-p0660.indd 65101/03/19 5:24 PM 652SPECIFIC CONSIDERATIONSPART IIFigure 18-43 shows a prototypical hemiglossectomy defect from a T2 N0 oral tongue cancer that was reconstructed with a rectangle template radial forearm free tissue transfer.203 The radial forearm free tissue transfer provides thin, pliable tis-sue, with a long pedicle, and is a staple for hemiglossectomy and partial glossectomy reconstruction.Figure 18-44 shows a composite mandible defect from a T4a N0 mandibular alveolus cancer, after segmental mandibu-lectomy, reconstructed with a fibula osseocutaneous free tissue transfer.204 The 2.5-mm titanium reconstruction plate was bent to a mandible model. A template of the osseous defect is made and transferred to the fibula, and wedge ostectomies are made in the bone so that it can be snug fit into the bone defect.Figure 18-45 shows a palate defect after an infrastructure maxillectomy for a T2 N0 maxillary alveolus cancer. The defect resulted in direct communication with the buccal space, nasal cavity, and maxillary sinus. A radial forearm free tissue transfer was utilized to achieve oronasal separation.TRACHEOTOMYIndications and TimingThe most common cause for tracheotomy is prolonged intuba-tion typically in critically ill intensive care unit patients. Pro-longed intubation increases the risk of laryngeal and subglottic injury, which may lead to stenosis. In the critically ill patient, it has been hypothesized that early tracheotomy may improve inpatient survival and decreased intensive care unit length of stay while increasing patient comfort. However, a large ran-domized clinical trial demonstrated no benefit from early tra-cheotomy on shortor long-term survival and other important secondary outcomes.205 Furthermore, clinicians are poor pre-dictors of which patients require extended ventilatory support. Another study demonstrated no evidence that early tracheos-tomy reduced mortality, duration of mechanical ventilation, intensive care unit stay, or ventilatory associated pneumonia.206 It did, however, provide a shorter duration of sedation. Beyond prolonged intubation, tracheotomy is also indicated in patients who require frequent pulmonary toilet, in patients with neu-rologic deficits that impair protective airway reflexes, and in head and neck upper aerodigestive tract surgery as a temporary airway in the perioperative period to bypass airway obstruction.Technique and ComplicationsThe procedure can be performed using an open or a percuta-neous technique. Complications of tracheostomy include pneu-mothorax, tracheal stenosis, wound infection/stomatitis with large-vessel erosion, and failure to close after decannulation. A meta-analysis of 15 randomized studies assessing nearly 1000 patients demonstrated no difference between the open and percutaneous techniques, although there was a trend toward fewer complications in the percutaneous approach.207 The per-cutaneous approach was also found to be cheaper and had the added benefit of being performed at the bedside outside of the operating room. A Cochrane review on the topic lower wound infection/stomatitis and unfavorable scarring rates with the per-cutaneous approach.208 Mortality and serious adverse events did not differ between the two techniques.The use of cricothyroidotomy, typically in the emergency setting, is inferior to a tracheotomy due to higher incidence of vocal cord dysfunction and subglottic stenosis. There-fore, soon after a cricothyroidotomy is performed, a formal Figure 18-43. A. Defect after left hemiglossectomy for T2 N0 oral tongue squamous cell carcinoma. B. Radial forearm free tissue transfer harvested for reconstruction. C. Inset of the radial forearm free tissue transfer.ABCBrunicardi_Ch18_p0613-p0660.indd 65201/03/19 5:25 PM 653DISORDERS OF THE HEAD AND NECKCHAPTER 18Figure 18-45. A. Palate defect after infrastructure maxillectomy for T2 N0 squamous cell carcinoma of the maxillary alveolus. B. Inset of radial forearm free tissue transfer. C. Six month postop-erative result, with complete oronasal separation and return to full, preoperative levels of speech and swallowing.tracheotomy should be used with decannulation of the crico-thyroidotomy site. Most tracheostomies are not permanent and can be reversed simply by removing the tube and applying a pressure dressing. The stoma usually spontaneously heals within 2 to 3 weeks.Speech with Tracheotomy and DecannulationWhen a large cuffed tracheostomy is initially placed, speech is not possible, particularly when the cuff is up. However, when the tube is downsized to a cuffless tracheostomy tube, ABCFigure 18-44. A. Segmental mandible defect after composite resec-tion for T4a N0 squamous cell carcinoma of the mandibular alveolus. B. Fibula free tissue transfer harvested for reconstruction and template for wedge ostectomy. C. Inset of fibula free tissue transfer.ABCBrunicardi_Ch18_p0613-p0660.indd 65301/03/19 5:25 PM 654SPECIFIC CONSIDERATIONSPART IIintermittent finger occlusion or placement of Passy-Muir valve can allow the patient to voice while still bypassing the upper airway obstruction in inspiration. Prior to decannulation, the patient has to tolerate capping for 24 to 48 hours, but this period can be extended in patients with concerns for pulmonary toilet and an inability to clear secretions.LONG TERM MANAGEMENT AND REHABILITATIONPalliative CareFor patients with unresectable disease (greater than 180o of encasement around the carotid artery, prevertebral fascia inva-sion, and skull base invasion) or distant metastases, palliative care options exist. The NCCN guidelines recommend clinical trials for patients in this category because there is not a single accepted regimen for patients with incurable disease but the goal of treatment is to control symptoms and maintain quality of life while minimizing the side effects of treatment.106 This may include a combination of radiotherapy, usually in a hypofrac-tionated pattern with high dose per fraction regimen, chemother-apy, or simply pain management. A recent trial demonstrated the utility of immunotherapy, specifically, Nivolumab, in the management of recurrent unresectable head and neck cancer, showing a higher response rate (13.3%) compared to standard therapy (5.8%) with lower treatment-related adverse events (13.1% vs. 35.1%, respectively).209 From a surgical perspective, some patients require tracheostomy or gastrostomy tube place-ment to manage airway compromise and dysphagia, respec-tively. Palliative care facilities and hospice care allow patients to retain dignity when they have a limited short-term outlook.Follow-Up CarePatients diagnosed and treated for a head and neck tumor require follow-up care aimed at monitoring for recurrence and the side effects of therapy. The NCCN guidelines recommend follow-up assessment every 3 months for the first year after treatment, every 4 months during the following year, and then every 6 months until year 4, with an annual follow-up at 5 years post treatment and thereafter.106 This regimen is not well followed in North America, and further investigation is required to assess why this might be and to improve adherence rates.210 Follow-up should consist of a thorough history to assess for any emerg-ing symptoms such as pain, otalgia, or dysphagia as these are often the first sign of a recurrence. Assessment by speech lan-guage pathology and a dietician is often beneficial to ascertain swallowing function and nutritional intake, respectively. Some patients require dilation or reinsertion of a gastrostomy tube if they develop pharyngeal strictures and are unable to maintain their weight. The history should be followed with a thorough head and neck examination, including fiberoptic nasolaryg-noscopy, because of the significant risk of developing a sec-ond primary in the upper aerodigestive tract.93 Patients should have their thyroid stimulating hormone (TSH) checked once a year, especially in those that have radiation as they may develop hypothyroidism at an earlier age than the general population. Shoulder dysfunction after neck dissection with extensive accessory nerve dissection or in patients who have had a scapu-lar system free flap should be managed with physiotherapy to minimize the long-term effects and improve function. Chronic pain can occur in head and neck cancer patients, and this is often assessed and managed by a pain specialist. Ongoing dental evaluation is needed in some patients to treat caries and prevent osteoradionecrosis.REFERENCESEntries highlighted in bright blue are key references. 1. Hajioff D, MacKeith S. Otitis externa. 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Head Neck. 2005;27(7):575-584. 167. Ganly I, Patel SG, Singh B, et al. Complications of cra-niofacial resection for malignant tumors of the skull base: report of an international collaborative study. Head Neck. 2005;27(6):445-451. 168. Fu TS, Monteiro E, Muhanna N, Goldstein DP, de Almeida JR. Comparison of outcomes for open versus endoscopic approaches for olfactory neuroblastoma: a systematic review and individual participant data meta-analysis. Head Neck. 2016;38 Suppl 1:E2306-E2316.Brunicardi_Ch18_p0613-p0660.indd 65801/03/19 5:25 PM 659DISORDERS OF THE HEAD AND NECKCHAPTER 18 169. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol. 1998;16(4):1310-1317. 170. Vlantis AC, Tsang RK, Yu BK, et al. Nasopharyngectomy and surgical margin status: a survival analysis. Arch Otolaryngol Head Neck Surg. 2007;133(12):1296-1301. 171. Sinha S, Dedmon MM, Naunheim MR, Fuller JC, Gray ST, Lin DT. Update on surgical outcomes of lateral temporal bone resection for ear and temporal bone malignancies. J Neurol Surg B Skull Base. 2017;78(1):37-42. 172. Beyea JA, Moberly AC. Squamous cell carcinoma of the temporal bone. Otolaryngol Clin North Am. 2015;48(2): 281-292. 173. Mazzoni A, Zanoletti E, Marioni G, Martini A. En bloc temporal bone resections in squamous cell carcinoma of the ear. technique, principles, and limits. Acta Otolaryngol. 2016;136(5):425-432. 174. Gurgel RK, Karnell LH, Hansen MR. Middle ear cancer: a population-based study. Laryngoscope. 2009;119(10): 1913-1917. 175. Rosenthal EL, King T, McGrew BM, Carroll W, Magnuson JS, Wax MK. Evolution of a paradigm for free tissue transfer reconstruction of lateral temporal bone defects. Head Neck. 2008;30(5):589-594. 176. Ferris R, Goldenberg D, Haymart MR, et al. American Thyroid Association consensus review of the anatomy, ter-minology and rationale for lateral neck dissection in dif-ferentiated thyroid cancer. Thyroid. 2012;22(5):501-508. 177. Robbins KT, Clayman G, Levine PA, et al. Neck dissection classification update:revisions proposed by the American Head and Neck Society and the American Academy of Otolar-yngology—Head and Neck Surgery. Arch Otolaryngol Head Neck Surg. 2002;128(7):751-758. 178. Wang Y, Ow TJ, Myers JN. Pathways for cervical metasta-sis in malignant neoplasms of the head and neck region. Clin Anat. 2012;25(1):54-71. 179. Weiss MH, Harrison LB, Isaacs RS. Use of decision analy-sis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg. 1994;120(7):699-702. 180. Bocca E, Pignataro O, Oldini C, Cappa C. Functional neck dissection: an evaluation and review of 843 cases. Laryngo-scope. 1984;94(7):942-945. 181. Medina JE, Byers RM. Supraomohyoid neck dissection: rationale, indications, and surgical technique. Head Neck. 1989;11(2):111-122. 182. Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990;160(4):405-409. 183. Huang SH, Hwang D, Lockwood G, Goldstein DP, O’Sullivan B. Predictive value of tumor thickness for cervi-cal lymph-node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies. Cancer. 2009;115(7):1489-1497. 184. D’Cruz AK, Vaish R, Kapre N, et al. Elective versus thera-peutic neck dissection in node-negative oral cancer. N Engl J Med. 2015;373(6):521-529. 185. Farrag T, Lin F, Brownlee N, Kim M, Sheth S, Tufano RP. Is routine dissection of level II-B and V-A necessary in patients with papillary thyroid cancer undergoing lateral neck dissec-tion for FNA-confirmed metastases in other levels. World J Surg. 2009;33(8):1680-1683. 186. Eskander A, Merdad M, Freeman JL, Witterick IJ. Pattern of spread to the lateral neck in metastatic well-differenti-ated thyroid cancer: a systematic review and meta-analy-sis. Thyroid. 2013;23(5):583-592. 187. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84(5):1198-1205. 188. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemo-therapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843-850. 189. Patil VM, Prabhash K, Noronha V, et al. Neoadjuvant che-motherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers. Oral Oncol. 2014;50(10):1000-1004. 190. Zafereo M. Surgical salvage of recurrent cancer of the head and neck. Curr Oncol Rep. 2014;16(5):386-014-0386-0. 191. James A, Stewart C, Warrick P, Tzifa C, Forte V. Branchial sinus of the piriform fossa: reappraisal of third and fourth bran-chial anomalies. Laryngoscope. 2007;117(11):1920-1924. 192. Oyewumi M, Inarejos E, Greer ML, et al. Ultrasound to differ-entiate thyroglossal duct cysts and dermoid cysts in children. Laryngoscope. 2015;125(4):998-1003. 193. Stodulski D, Mikaszewski B, Majewska H, Wisniewski P, Stankiewicz C. Probability and pattern of occult cervical lymph node metastases in primary parotid carcinoma. Eur Arch Otorhinolaryngol. 2017;274(3):1659-1664. 194. Seethala RR. An update on grading of salivary gland carcino-mas. Head Neck Pathol. 2009;3(1):69-77. 195. Colella G, Cannavale R, Chiodini P. Meta-analysis of sur-gical approaches to the treatment of parotid pleomorphic adenomas and recurrence rates. J Craniomaxillofac Surg. 2015;43(6):738-745. 196. Ariyan S. The functional pectoralis major musculocutaneous island flap for head and neck reconstruction. Plast Reconstr Surg. 1990;86(4):807-808. 197. Howard BE, Nagel TH, Barrs DM, Donald CB, Hayden RE. Reconstruction of lateral skull base defects: a comparison of the submental flap to free and regional flaps. Otolaryngol Head Neck Surg. 2016;154(6):1014-1018. 198. Herr MW, Emerick KS, Deschler DG. The supraclavicular artery flap for head and neck reconstruction. JAMA Facial Plast Surg. 2014;16(2):127-132. 199. Chepeha DB, Annich G, Pynnonen MA, et al. Pectoralis major myocutaneous flap vs revascularized free tissue trans-fer: complications, gastrostomy tube dependence, and hospi-talization. Arch Otolaryngol Head Neck Surg. 2004;130(2): 181-186. 200. Kang SY, Old MO, Teknos TN. Lateral arm free tissue transfer for parotid reconstruction: a pictorial essay. Head Neck. 2017. 201. Chepeha DB, Teknos TN, Fung K, et al. Lateral oroman-dibular defect: when is it appropriate to use a bridging reconstruction plate combined with a soft tissue revascu-larized flap? Head Neck. 2008;30(6):709-717. 202. Chepeha DB, Khariwala SS, Chanowski EJ, et al. Thoracodor-sal artery scapular tip autogenous transplant: vascularized bone with a long pedicle and flexible soft tissue. Arch Otolaryngol Head Neck Surg. 2010;136(10):958-964. 203. Chepeha DB, Teknos TN, Shargorodsky J, et al. Rectangle tongue template for reconstruction of the hemiglossectomy defect. Arch Otolaryngol Head Neck Surg. 2008;134(9):993-998. 204. Kang SY, Old MO, Teknos TN. Contour and osteotomy of free fibula transplant using a ruler template. Laryngoscope. 2016;126(10):2288-2290. 205. Young D, Harrison DA, Cuthbertson BH, Rowan K, Trac-Man Collaborators. Effect of early vs late tracheostomy placement on survival in patients receiving mechani-cal ventilation: the TracMan randomized trial. JAMA. 2013;309(20):2121-2129. 206. Szakmany T, Russell P, Wilkes AR, Hall JE. Effect of early tracheostomy on resource utilization and clinical outcomes in Brunicardi_Ch18_p0613-p0660.indd 65901/03/19 5:25 PM 660SPECIFIC CONSIDERATIONSPART IIcritically ill patients: meta-analysis of randomized controlled trials. Br J Anaesth. 2015;114(3):396-405. 207. Higgins KM, Punthakee X. Meta-analysis comparison of open versus percutaneous tracheostomy. Laryngoscope. 2007;117(3):447-454. 208. Brass P, Hellmich M, Ladra A, Ladra J, Wrzosek A. Percuta-neous techniques versus surgical techniques for tracheostomy. Cochrane Database Syst Rev. 2016;7:CD008045. 209. Ferris RL, Blumenschein G, Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016. 210. Eskander A, Monteiro E, Irish J, et al. Adherence to guideline-recommended process measures for squamous cell carcinoma of the head and neck in ontario: impact of surgeon and hospi-tal volume. 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Chest Wall, Lung, Mediastinum, and PleuraKatie S. Nason, Rose B. Ganim, and James D. Luketich 19chapterTRACHEAAnatomyThe trachea is composed of cartilaginous and membranous por-tions, beginning with the cricoid cartilage, the first complete cartilaginous ring of the airway. The cricoid cartilage consists of an anterior arch and a posterior broad-based plate. Articulat-ing with the posterior cricoid plate are the arytenoid cartilages. The vocal cords originate from the arytenoid cartilages and then attach to the thyroid cartilage. The subglottic space, the nar-rowest part of the trachea with an internal diameter of approxi-mately 2 cm, begins at the inferior surface of the vocal cords and extends to the first tracheal ring. The remainder of the distal trachea is 10.0 to 13.0 cm long, consists of 18 to 22 rings, and has an internal diameter of 2.3 cm (Fig. 19-1).1Bronchoscopically, the tracheal rings are visible as C-shaped hyaline cartilaginous structures that provide rigid-ity to the anterior and lateral tracheal walls. The open ends of the C-rings are connected by the trachealis smooth muscle and encased in a dense band of connective tissue called perichon-drium. The first tracheal ring is attached directly to the cricoid cartilage; there are approximately two rings for every 1 cm of tracheal length.The tracheal blood supply, which includes the inferior thy-roid, subclavian, supreme intercostal, internal thoracic, innomi-nate, and superior and middle bronchial arteries, enters the airway near the junction of the membranous and cartilaginous portions (Fig. 19-2). Each arterial branch supplies a segment of 1.0 to 2.0 cm, thereby limiting circumferential mobilization to that same distance. The vessels are interconnected along the lat-eral surface of the trachea by an important longitudinal vascular anastomosis that feeds transverse segmental vessels to the soft tissues between the cartilages.Tracheal InjuryTracheal injury can result from a variety of causes, includ-ing inhalation of smoke or toxic fumes, aspiration of liquids or solid objects, endotracheal intubation, blunt and penetrating trauma, and iatrogenic injury during operative procedures. Early diagnosis is critical to avoid subsequent complications, includ-ing respiratory infection and tracheal stenosis. Management of smoke or toxic fume inhalation and liquid aspiration is com-monly supportive; use of antibiotics, respiratory support, and airway clearance with flexible bronchoscopy is dictated by the patient’s condition. In rare circumstances, extracorporeal mem-brane oxygenation is required if there is associated injury to the more distal airways and lung parenchyma.Despite ubiquitous use of high-volume–low-pressure cuffs, overinflation of the endotracheal cuff is the most common cause of injury secondary to endotracheal intubation. High cuff pressures can cause ischemia of the contiguous airway wall in as short as 4 hours. Prolonged overinflation can lead to scarring Trachea661Anatomy / 661Tracheal Injury / 661Tracheal Fistulas / 664Tracheal Neoplasms / 665Lung667Anatomy / 667Normal Lung Histology / 668Preinvasive Lesions / 669Invasive or Malignant Lesions / 670Lung Cancer Epidemiology / 673Screening for Lung Cancer in High-Risk Populations / 675Solitary Pulmonary Nodule / 677Metastatic Lesions to the Lung / 678Primary Lung Cancer-Associated Signs and Symptoms / 680Lung Cancer Management / 683Lung Cancer Treatment / 693Options for Thoracic Surgical Approaches / 701Postoperative Care / 703Postoperative Complications / 705Spontaneous Pneumothorax / 705Pulmonary Infections / 706Massive Hemoptysis / 717End-Stage Lung Disease / 719Chest Wall720Chest Wall Mass / 720Benign Chest Wall Neoplasms / 722Primary Malignant Chest Wall Tumors / 723Other Tumors of the Chest Wall / 725Chest Wall Reconstruction / 726Mediastinum726Anatomy and Pathologic Entities / 726History and Physical Examination / 727Imaging and Serum Markers / 727Diagnostic Nonsurgical Biopsies of the Mediastinum / 729Surgical Biopsies and Resection of Mediastinal Masses / 730Mediastinal Neoplasms / 730Mediastinal Cysts / 735Mediastinitis / 735Pleura and Pleural Space736Anatomy / 736Pleural Effusion / 736Access and Drainage of Pleural Fluid Collections / 736Malignant Pleural Effusion / 739Empyema / 740Chylothorax / 741Tumors of the Pleura / 743Brunicardi_Ch19_p0661-p0750.indd 66101/03/19 7:00 PM 662Key Points1 Lung cancer continues to be a highly lethal and extremely common cancer, with 57% of patients presenting with dis-tant metastasis and 5-year survival of 18%. Lung cancer incidence is second only to the incidence of prostate cancer in men and breast cancer in women, with 222,500 esti-mated new cases in 2017. Squamous cell carcinoma and adenocarcinoma of the lung are the most common sub-types and are rarely found in the absence of a smoking history. Nonsmokers who live with smokers have a 24% increased risk of lung cancer compared to nonsmokers who do not live with smokers.2 A multidisciplinary approach to evaluation of NSCLC, with standardized criteria and terminology for diagnosis in cytologic and small biopsy specimens, and routine molec-ular testing for known mutations, such as EGFR mutations and EML4-ALK fusion oncogenes is now recommended for the evaluation and management of lung nodules due to major advances in targeted therapy. Adequate tissue acquisition at the time of diagnostic workup is critical and facilitates patient care while minimizing the number of procedures to which the patient is subjected.3 The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma have been eliminated from the classification of lung adenocarcinoma as a result of increased understanding of important clinical, radiologic, pathologic, and genetic differences between mucinous and nonmucinous adenocarcinomas. The classification system delineates a stepwise pathologic progression, from AAH to invasive adenocarcinoma based on the predominant histo-logic growth patterns.4 The U.S. Preventive Services Task Force now recommends annual screening for lung cancer with low-dose computed tomography screening in high risk patients. Annual screen-ing averted 14% of lung cancer deaths when applied to a population of asymptomatic adults age 55 to 80 years who have a 30 pack-year smoking history and are either currently smoking or have quit within the past 15 years. Patients should be healthy enough to tolerate curative treat-ment, specifically surgery per guidelines, and screening should be discontinued once the patient has not smoked for 15 years or develops a life-limiting health condition, becomes unable to tolerate lung surgery, or is unwilling to undergo curative lung resection. With this approach, it is expected that 50% of diagnosed cancers will be early stage. Screening of patients age 50 years or older with a 20 pack-year or greater history and additional risk factors (as determined by the Tammemagi lung cancer risk calculator or other validated risk scores) that increase the risk of lung cancer to 1.3% or greater should also be considered as part of lung cancer screening programs. In all cases, patient–physician shared decision-making should be undertaken, with a discussion of the risks and benefits of screening.5 Assessment of patient risk before thoracic resection is based on clinical judgment and systematic assessment of cardiopulmonary status using established algorithms.6 Maximum oxygen consumption (v. o2max) values provide important additional information in those patients with severely impaired Dlco and forced expiratory volume in 1 second. Values of <10 mL/kg per minute generally pro-hibit any major pulmonary resection because the mortality in patients with these levels is 26% compared with only 8.3% in patients whose v. o2max is ≥10 mL/kg per minute; values of >15 mL/kg per minute generally indicate the patient’s ability to tolerate pneumonectomy.7 Tumor ablative strategies are viable alternatives to surgical resection for early stage lung cancer in inoperable patients. While premature, ablative techniques may ultimately be shown to have efficacy equivalent to lobectomy for the pri-mary treatment of very small peripheral early-stage lung cancers and become primary therapy, even in operable patients, although limited resection with wedge (at least 2 cm margin and at least 1:1 tumor/margin ratio) and seg-mentectomy provide better margins of treatment and nodal sampling ensures occult nodal metastasis are identified. Multidisciplinary collaboration among thoracic surgery, interventional radiology/pulmonology, and radiation oncol-ogy is required to ensure that development of these ablative techniques occurs through properly designed and well-con-trolled prospective studies and will ensure that patients receive the best available therapy, regardless of whether it is surgical resection or ablative therapy.8 The term non–small cell lung carcinoma (NSCLC) includes many tumor cell types, including large cell, squa-mous cell, and adenocarcinoma. The approach to diagno-sis and management and the terminology used in describing these tumors are evolving rapidly. In particular, the evaluation and management of adenocarcinoma of the lung has shifted dramatically and firm establishment of NSCLC cell type prior to chemotherapy for advanced stage lung cancer is essential.9 Increasing evidence suggests a significant role for gastro-esophageal reflux disease in the pathogenesis of chronic lung diseases such as bronchiectasis and idiopathic pulmo-nary fibrosis, and it may also contribute to bronchiolitis obliterans syndrome in lung transplant patients.10 Treatment of pulmonary aspergillosis/aspergilloma is indi-vidualized. Following colonization of a lung cavity or area of bronchiectasis, fungal growth within the cavity appears as an irregular cavitary lining, progressing over time as a late finding in chronic pulmonary aspergillosis to a fungal ball called an aspergilloma. Asymptomatic patients can be observed without any additional therapy. Similarly, mild hemoptysis, which is not life-threatening, can be managed with medical therapy, including antifungals and cough suppressants. Oral triazole therapy is now considered the standard of care for chronic, cavitary pulmonary aspergil-losis. Massive hemoptysis had traditionally been an indi-cation for urgent or emergent operative intervention. However, with the advancement of endovascular tech-niques, bronchial artery embolization in select centers with experience in these techniques has been effective.11 In patients with malignant pleural effusion, poor expan-sion of the lung (because of entrapment by tumor or adhe-sions) generally predicts a poor result with pleurodesis and is the primary indication for placement of indwelling pleu-ral catheters. These catheters have dramatically changed the management of end-stage cancer treatment because they substantially shorten the amount of time patients spend in the hospital during their final weeks of life.Brunicardi_Ch19_p0661-p0750.indd 66201/03/19 7:00 PM

CHAPTER 19663CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAEpiglottisAryepiglottic m.Transverse, obliquearytenoid mm.Lateralcricoarytenoid m.Posteriorcricoarytenoid m.Thyroid cartilage facetRecurrentlaryngeal n.Internallaryngeal n.Thyroepiglottic m.Thyroarytenoid m.Cricothyroid m.(cut)Inferiorthyroid a.Branch from internal thoracic a. Superior bronchial a.Middle bronchial a.1Lateral longitudinalanastomosis32Figure 19-2. Arterial blood supply to the larynx and upper trachea. a. = artery.Figure 19-1. Anatomy of the larynx and upper trachea. m. = muscle; n. = nerve.and stenosis; full-thickness injury can result in fistulae between the innominate artery anteriorly and the esophagus posteriorly. Avoidance requires careful cuff management to keep pressures as low as possible; in circumstances of prolonged ventilatory support and high airway pressure, cuff pressure monitoring (to maintain pressures <20 mmHg) is advisable.Historically, clinically significant tracheal stenosis after tracheostomy occurred in 3% to 12% of cases, with severe stenosis in 1% to 2%.2 With the use of low-pressure cuffs, the estimated incidence has decreased to 4.9 cases per million patients per year. Intubation-related risk factors include pro-longed intubation; high tracheostomy through the first tracheal ring or cricothyroid membrane; transverse rather than vertical incision on the trachea; oversized tracheostomy tube; prior tra-cheostomy or intubation; and traumatic intubation. Stenosis is also more common in older patients, in women, after radiation, or after excessive corticosteroid therapy, and in the setting of concomitant diseases such as autoimmune disorders, severe reflux disease, or obstructive sleep apnea and the setting of severe respiratory failure. However, even a properly placed tra-cheostomy can lead to tracheal stenosis because of scarring and local injury. Mild ulceration and stenosis are frequently seen after tracheostomy removal. Use of the smallest tracheostomy tube possible, rapid downsizing, and a vertical tracheal incision minimize the risk for posttracheostomy stenosis.Stridor and dyspnea on exertion are the primary symp-toms of tracheal stenosis. In the setting of postintubation injury, a significant portion of the cartilaginous structural support to the airway is destroyed by regional ischemic necrosis; during healing, a weblike fibrous growth develops and narrows the airway (Fig. 19-3). In contrast, stenosis caused by tracheostomy is most commonly due to an excess of granulation tissue forma-tion around the tracheal stoma site. Time to onset of symptoms after extubation or tracheostomy decannulation usually ranges from 2 to 12 weeks, but symptoms can appear immediately or as long as 1 to 2 years later. Frequently, patients are misdiag-nosed as having asthma or bronchitis, and treatment for such illnesses can persist for some time before the correct diagnosis is discovered. Generally, symptom intensity is related to the degree of stenosis and to the patient’s underlying pulmonary disease.Brunicardi_Ch19_p0661-p0750.indd 66301/03/19 7:00 PM 664SPECIFIC CONSIDERATIONSPART IIFigure 19-3. Diagram of the principal postintubation lesions. A. A circumferential lesion at the cuff site after the use of an endotracheal tube. B. Potential lesions after the use of tracheostomy tubes. Anterolateral stenosis can be seen at the stomal level. Circumferential stenosis can be seen at the cuff level (lower than with an endotracheal tube). The segment in between is often inflamed and malacotic. C. Damage to the subglottic larynx. D. Tracheoesophageal fistula occurring at the level of the tracheostomy cuff; circumferential damage is usual at this level. E. Tracheoinnominate artery fistula. (Adapted with permission from Grillo H. Surgical treatment of postintubation tracheal injuries. J Thorac Cardiovasc Surg. 1979 Dec;78(6):860-875.)Acute Management. A comprehensive bronchoscopic evalua-tion is critical in the initial phase of evaluation. Stenosis length, location, distance between the vocal cords and proximal steno-sis, and distance from the distal aspect to the major carina must be documented. In patients with severe stenosis and respiratory compromise, rigid bronchoscopy can be used to dilate the steno-sis; this provides immediate relief of the airway obstruction and facilitates thorough evaluation of the stenosis. Rarely, if ever, is tracheostomy necessary.Most intubation injuries are located in the upper third of the trachea and can be accessed for resection through a col-lar incision. Resection typically involves 2 to 4 cm of trachea for benign stenosis. It is critical to fully resect all inflamed and scarred tissue. However, a primary anastomosis can still be per-formed without undue tension, even if up to one half of the tra-chea requires resection.2 Ideally, the patient is extubated in the operating room or shortly thereafter. For patients in whom tra-cheal resection is not possible, such as patients with significant comorbidities or with an excessively long stenosis, endotracheal stenting, typically silicone T-tubes, can provide palliation. Wire mesh stents should not be used, given their known propensity to erode through the wall of the airway. Balloon dilation, laser ablation, and tracheoplasty have also been described, although the efficacy is marginal.Tracheal replacement is evolving as an option for manage-ment of tracheal stenosis as bioengineering techniques for decel-lularizing donor trachea have been developed. This removes all antigens against which the recipient immune system might react and enables use of the donor trachea scaffolding without risk of rejection. Following decellularization, the donor tracheal scaf-folding is seeded with recipient chondrocytes, to restore tracheal rigidity, and with recipient epithelial cells, to recreate the inner epithelial lining. Several case reports of successful allogeneic tracheal transplantation have been published. The technique continues to be limited to a few highly specialized centers, due, in part, to the scarcity of donor trachea and the need for tissue bioengineering expertise as well as the lack of established effi-cacy for the approach. Current efforts are focused on creation of biosynthetic scaffolding that can be used instead of donor trachea. This would substantially increase the availability of the tracheal replacement material and enable widespread use of the technique, but early results have been contested, including three case reports called into question as containing multiple data fab-rications and omissions.Tracheal FistulasTracheoinnominate Artery Fistula. Tracheoinnominate artery fistula has two main causes: low placement of a trache-ostomy and hyperinflation of the tracheal cuff. Tracheostomy placement should be through the second to fourth tracheal rings without reference to the location of the sternal notch. When placed below the fourth tracheal ring, the inner curve of the tracheostomy cannula will be positioned to exert pressure on the posterior aspect of the innominate artery, leading to arterial ero-sion. Similarly, the tracheal cuff, when hyperinflated, will cause ischemic injury to the anterior airway and subsequent erosion into the artery. Most cuff-induced fistulas will develop within 2 weeks after placement of the tracheostomy.Clinically, tracheoinnominate artery fistulas present with bleeding. A premonitory hemorrhage often occurs and, although it is usually not massive, must not be ignored or simply attrib-uted to general airway irritation or wound bleeding. With sig-nificant bleeding, the tracheostomy cuff can be hyperinflated to temporarily occlude the arterial injury. If such an effort is unsuccessful, the tracheostomy incision should be immediately opened widely and a finger inserted to compress the artery Brunicardi_Ch19_p0661-p0750.indd 66401/03/19 7:00 PM

CHAPTER 19665CHEST WALL, LUNG, MEDIASTINUM, AND PLEURA1Cuffhyperinflation2Digital control3 BronchoscopiccompressionOrotracheal tubeready in place if neededOrotrachealtube replacingtracheostomytubeForward pressureapplied withbronchoscopeFigure 19-4. Steps in the emergency management of a tracheoinnominate artery fistula.against the manubrium (Fig. 19-4). The patient can then be orally intubated, and the airway suctioned free of blood. Emer-gent surgical resection of the involved segment of artery is per-formed, usually without reconstruction.Tracheoesophageal Fistula. Tracheoesophageal fistu-las (TEFs) occur primarily in patients receiving prolonged mechanical ventilator support concomitant with an indwelling nasogastric tube.4 Cuff compression of the membranous trachea against the nasogastric tube leads to airway and esophageal injury and fistula development. Clinically, airway suctioning reveals saliva, gastric contents, or tube feedings. Gastric insuf-flation, secondary to positive pressure ventilation, can occur. Bronchoscopy is diagnostic; with the bronchoscope inserted, the endotracheal tube is withdrawn, and the fistula at the cuff site is exposed. Alternatively, esophagoscopy demonstrates the cuff of the endotracheal tube in the esophagus.Treatment, first and foremost, requires removing tubes from the esophagus and weaning the patient from the ventila-tor. The cuff of the endotracheal tube should be placed below the fistula, avoiding overinflation. To minimize aspiration, a gastrostomy tube should be placed for gastric decompression (to prevent reflux) and a jejunostomy tube for feeding. If aspira-tion persists, esophageal diversion with cervical esophagostomy can be performed. Once weaned from the ventilator, tracheal resection and primary anastomosis, repair of the esophageal defect, and interposition of a muscle flap between the trachea and esophagus can be performed (Fig. 19-5).5Tracheal NeoplasmsAlthough extremely rare, the most common primary tracheal neoplasms are squamous cell carcinomas (related to smoking) and adenoid cystic carcinomas. Clinically, tracheal tumors pres-ent with cough, dyspnea, hemoptysis, stridor, or symptoms of invasion of contiguous structures (such as the recurrent laryn-geal nerve or the esophagus). The most common radiologic finding of tracheal malignancy is tracheal stenosis, but it is found in only 50% of cases. With tumors other than squamous cell carcinomas, symptoms may persist for months because of slow tumor growth rates. Stage of presentation is advanced, with approximately 50% of patients presenting with stage IV disease. Five-year survival for all tracheal neoplasms is 40% but falls to 15% for those with stage IV disease.6Squamous cell carcinomas often present with regional lymph node metastases and are frequently unresectable at pre-sentation. Their biologic behavior is similar to that of squamous cell carcinoma of the lung. Adenoid cystic carcinomas, a type of Brunicardi_Ch19_p0661-p0750.indd 66501/03/19 7:00 PM 666SPECIFIC CONSIDERATIONSPART IIACBDCricoidSternohyoid m.EsophagusFigure 19-5. Single-stage operation for clo-sure of a tracheoesophageal fistula and tra-cheal resection. A. The fistula is divided, and the trachea is transected below the level of damage. B. The fistula is closed on the tra-cheal side in a single layer and the esopha-geal side in a double layer. The damaged trachea segment is resected. C. A pedicled muscle flap, such as the sternohyoid muscle, is used to buttress the esophageal repair. D. View of completed tracheal anastomosis. m. = muscle.salivary gland tumor, are generally slow growing, spread sub-mucosally, and tend to infiltrate along nerve sheaths and within the tracheal wall. Although indolent in nature, adenoid cystic carcinomas are malignant and can spread to regional lymph nodes, lung, and bone. Squamous cell carcinoma and adenoid cystic carcinomas represent approximately 65% of all tracheal neoplasms. The remaining 35% is comprised of small cell car-cinomas, mucoepidermoid carcinomas, adenocarcinomas, lym-phomas, and others.7Therapy. Evaluation and treatment of patients with tracheal tumors should include neck and chest computed tomography (CT) and rigid bronchoscopy. Rigid bronchoscopy permits gen-eral assessment of the airway and tumor; it also allows debride-ment or laser ablation of the tumor to provide relief of dyspnea. If the tumor is judged to be completely resectable, primary resection and anastomosis is the treatment of choice for these tumors (Fig. 19-6). Up to 50% of the length of the trachea can be resected with primary anastomosis. In most tracheal resections, anterolateral tracheal mobilization and suturing of the chin to the sternum for 7 days are done routinely. Use of laryngeal and hilar release is determined at the time of surgery, based on the surgeon’s judgment of the degree of tension present. For longer resections, specialized maneuvers are necessary such as laryn-geal release and right hilar release to minimize tension on the anastomosis.Postoperative mortality, which occurs in up to 10% of patients, is associated with the length of tracheal resection, use of laryngeal release, the type of resection, and the histologic type of the cancer. Factors associated with improved long-term survival include complete resection and use of radiation as adjuvant therapy in the setting of incomplete resection.8 Due to their radiosensitivity, radiotherapy is frequently given postop-eratively after resection of both adenoid cystic carcinomas and squamous cell carcinomas.9 A dose of 50 Gy or greater is usual. Nodal positivity does not seem to be associated with worse sur-vival. Survival at 5 and 10 years is much better for adenoid Brunicardi_Ch19_p0661-p0750.indd 66601/03/19 7:00 PM

CHAPTER 19667CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAHigh-index of suspicion(cough, dyspnea, hemoptysis,stridor, and hoarseness)Complete staging: computedtomography/PETscan/mediastinoscopyFlexible/rigid bronchoscopyTumor resectablePerformance statusadequate for surgeryDebridement and/orlaser ablationPrinciples of tracheal resection• May resect up to 50% of tracheal length• Anterolateral mobilization only• Suture head in forward flexion for 7 days• Laryngeal and hilar release as needed for relief of tensionRadiotherapy 50 Gy (±chemotherapy)(primary treatment or postoperatively)Tumor unresectable1) Probable grossly positive tracheal resection margin2) Metastatic disease3) Length of resection precludes safe reconstruction4) Invasion of unresectable adjacent organsPoor performancestatuscystic (73% and 57%, respectively) than for tracheal cancers (47% and 36%, respectively; P <.05). For patients with unre-sectable tumors, radiation may be given as the primary therapy to improve local control, but it is rarely curative. For recurrent airway compromise, stenting or laser therapies should be con-sidered as part of the treatment algorithm.LUNGAnatomySegmental Anatomy. The segmental bronchial and vascular anatomy of the lungs allows subsegmental and segmental resec-tions, if the clinical situation requires or if lung tissue can be preserved10 (Fig. 19-7). Note the continuity of the pulmonary parenchyma between adjacent segments of each lobe.Lymphatic Drainage. Lymph nodes that drain the lungs are divided into two groups according to the tumor-node-metastasis (TNM) staging system for lung cancer: the pulmonary lymph nodes (N1) and the mediastinal nodes (N2) (Fig. 19-8).The N1 lymph nodes constitute the following: (a) intrapul-monary or segmental nodes that lie at points of division of seg-mental bronchi or in the bifurcations of the pulmonary artery; (b) lobar nodes that lie along the upper, middle, and lower lobe bronchi; (c) interlobar nodes located in the angles formed by the main bronchi bifurcating into the lobar bronchi; and (d) hilar nodes along the main bronchi. The interlobar lymph nodes lie in the depths of the interlobar fissure on each side and constitute a lymphatic sump for each lung, referred to as the lymphatic sump of Borrie; all of the pulmonary lobes of the corresponding lung drain into this group of nodes (Fig. 19-9). On the right, the nodes of the lymphatic sump lie around the bronchus inter-medius (bounded above by the right upper lobe bronchus and below by the middle lobe and superior segmental bronchi). On the left, the lymphatic sump is confined to the interlobar fis-sure, with the lymph nodes in the angle between the lingular and lower lobe bronchi. These nodes are always in close proximity to pulmonary arterial branches and typically must be carefully dissected to identify the pulmonary arterial segments for divi-sion during lung resection.The N2 lymph nodes consist of four main groups. (a) The anterior mediastinal nodes are located in association with the upper surface of the pericardium, the phrenic nerves, the liga-mentum arteriosum, and the left aspect of the innominate vein. (b) The posterior mediastinal group includes paraesophageal lymph nodes within the inferior pulmonary ligament and, more superiorly, between the esophagus and trachea near the arch of the azygos vein. (c) The tracheobronchial lymph nodes are made up of three subgroups that are located near the bifurcation of the trachea. These include the subcarinal nodes, which lie in the obtuse angle between the trachea and each main stem bronchus, and the nodes that lay anterior to the lower end of the trachea. (d) Paratracheal lymph nodes are located in proximity to the trachea in the superior mediastinum. Those on the right side form a chain with the tracheobronchial nodes inferiorly and with some of the deep cervical nodes above (scalene lymph nodes).Lymphatic drainage to the mediastinal lymph nodes from the right lung is ipsilateral, except for occasional bilateral drain-age to the superior mediastinum. In contrast, in the left lung, particularly the left lower lobe, lymphatic drainage occurs with equal frequency to ipsilateral and contralateral superior medi-astinal nodes.Figure 19-6. Algorithm for eval-uation and treatment of tracheal neoplasm. PET = positron emis-sion tomography.Brunicardi_Ch19_p0661-p0750.indd 66701/03/19 7:00 PM 668SPECIFIC CONSIDERATIONSPART IIRight lung and bronchiLeft lung and bronchi11112222333333444445555556666668888888999999101010101010107771+21+2Segments 1. Apical2. Posterior3. Anterior4. Lateral5. Medial6. Superior7. Medial Basal *8. Anterior Basal9. Lateral Basal10. Posterior Basal * Medial basal (7) not present in left lungFigure 19-7. Segmental anatomy of the lungs and bronchi.3p3a6AoPA512LBrachiocephalicartery2R4RAo4LAzygos vein10R711R12,13,14R8R9R9L8LPA11L10L12,13,14LFigure 19-8. The location of regional lymph node stations for lung cancer.Figure 19-9. The lymphatic sump of Borrie includes the groups of lymph nodes that receive lymphatic drainage from all pulmonary lobes of the corresponding lung.Normal Lung HistologyThe lung can be conveniently viewed as two linked compo-nents: the tracheobronchial tree (or conducting airways com-ponent) and the alveolar spaces (or gas exchange component). The tracheobronchial tree consists of approximately 23 airway divisions to the level of the alveoli. It includes the main bronchi, lobar bronchi, segmental bronchi (to designated bronchopulmo-nary segments), and terminal bronchioles (i.e., the smallest air-ways still lined by bronchial epithelium and without alveoli). The tracheobronchial tree is normally lined by pseudostratified ciliated columnar cells and mucous (or goblet) cells, which both derive from basal cells (Fig. 19-10). Ciliated cells predominate. Goblet cells, which release mucus, can significantly increase in number in acute bronchial injury, such as exposure to cigarette smoke. The normal bronchial epithelium also contains bron-chial submucosal glands, which are mixed salivary-type glands Brunicardi_Ch19_p0661-p0750.indd 66801/03/19 7:00 PM

CHAPTER 19669CHEST WALL, LUNG, MEDIASTINUM, AND PLEURABAFigure 19-10. Normal lung histology. A. Pseudostratified ciliated columnar cells and mucous cells normally line the tracheobronchial tree. B. A Kulchitsky cell is depicted (arrow).containing mucous cells, serous cells, and neuroendocrine cells called Kulchitsky cells, which are also found within the surface epithelium. The bronchial submucosal glands can give rise to salivary gland–type tumors, including mucoepidermoid carci-nomas and adenoid cystic carcinomas.Two cell types, called type I and type II pneumocytes, make up the alveolar epithelium. Type I pneumocytes com-prise 40% of the total number of alveolar epithelial cells, but cover 95% of the surface area of the alveolar wall. These cells are not capable of regeneration because they have no mitotic potential. Type II pneumocytes cover only 3% of the alveo-lar surface, but comprise 60% of the alveolar epithelial cells. In addition, clusters of neuroendocrine cells are seen in the alveolar spaces.Preinvasive LesionsThe term “precancerous” does not mean that an inevitable pro-gression to invasive carcinoma will occur, but such lesions, particularly those with high-grade dysplasia,11,12 do constitute a clear marker for potential development of invasive cancer. Three precancerous lesions of the respiratory tract are currently recognized.1. Squamous dysplasia and carcinoma in situ. Cigarette smoke can induce a transformation of the tracheobron-chial pseudostratified epithelium to metaplastic squamous mucosa, with subsequent evolution to dysplasia as cellu-lar abnormalities accumulate. Dysplastic changes include altered cellular polarity and increased cell size, number of cell layers, nuclear-to-cytoplasmic ratio, and number of mitoses. Gradations are considered mild, moderate, or severe. Carcinoma in situ represents carcinoma still con-fined by the basement membrane.2. Atypical adenomatous hyperplasia (AAH). AAH is a lesion smaller than 5.0 mm, comprising epithelial cells lining the alveoli that are similar to type II pneumocytes. Histologically, AAH is similar to adenocarcinoma in situ; it represents the beginning stage of a stepwise evolution to adenocarcinoma in situ and then to adenocarcinoma. With the availability of thin-section CT, it is possible to detect Brunicardi_Ch19_p0661-p0750.indd 66901/03/19 7:00 PM 670SPECIFIC CONSIDERATIONSPART IIpreinvasive adenocarcinoma lesions as early as AAH. These lesions can be multiple, are typically small (5 mm or less), and have a ground-glass appearance.3. Diffuse idiopathic pulmonary neuroendocrine cell hyper-plasia. This rare lesion represents a diffuse proliferation of neuroendocrine cells, but without invasion of the basement membrane. It can exist as a diffuse increase in the number of single neuroendocrine cells, or as small lesions less than 5.0 mm in diameter. Lesions over 5.0 mm in size or that breach the basement membrane are carcinoid tumors.Invasive or Malignant LesionsThe pathologic diagnosis of lung cancer is currently based on light microscopic criteria and is broadly divided into two main groups: non–small cell lung carcinoma and neuroendocrine tumors.13 Immunohistochemical staining and electron micros-copy are used as adjuncts in diagnosis, particularly in the assess-ment of potential neuroendocrine tumors.Non–Small Cell Lung Carcinoma. The term non–small cell lung carcinoma (NSCLC) includes many tumor cell types, including large cell, squamous cell, and adenocarcinoma. His-torically, these subtypes were considered to be a uniform group based on limited understanding of the distinct clinical behaviors of the subtypes as well as the fact that there were few treat-ment options available. With increasing understanding of the molecular biology underlying these tumor subtypes, however, the approach to diagnosis and management and the terminology used in describing these tumors are evolving rapidly.Adenocarcinoma The incidence of adenocarcinoma has increased over the last several decades, and it is now the most common lung cancer, accounting for 30% of lung cancers in Table 19-1Difference between invasive mucinous adenocarcinoma and nonmucinous adenocarcinoma in situ/minimally invasive adenocarcinoma/lepidic predominant adenocarcinoma INVASIVE MUCINOUS ADENOCARCINOMA (FORMERLY MUCINOUS BAC)NONMUCINOUS AIS/MIA/LPA (FORMERLY NONMUCINOUS BAC)Female49/84 (58%)52,120-123101/140 (72%)52,120-123Smoker39/87 (45%)52,120-122,12475/164 (46%)52,120-122,124Radiographic appearanceMajority consolidation; air bronchogram125Majority ground-glass attenuation23,56,58,103,129-134 Frequent multifocal and multilobar presentation56,125-128 Cell typeMucin-filled, columnar, and/or goblet50-52,125,135Type II pneumocyte and/or Clara cell50-52,125,135Phenotype   CK7Mostly positive (∼88%)a54,55,136-139Positive (∼98%)a54,55,136-139 CK20Positive (∼54%)a54,55,136-139Negative (∼5%)a54,55,136-139 TTF-1Mostly negative (∼17%)a54,55,120,137-139Positive (∼67%)a54,55,120,137-139Genotype   KRAS mutationFrequent (∼76%)a55,94,121,127,140-144Some (∼13%)a55,121,127,140-144 EGFR mutationAlmost none (∼3)a55,121,127,140-142Frequent (∼45%)a55,121,127,140-142Note: aNumbers represent the percentage of cases that are reported to be positive.Abbreviations: BAC = bronchioloalveolar carcinoma; AIS = adenocarcinoma in situ; MIA = minimally invasive adenocarcinoma; LPA = lepidic predominant adenocarcinoma; EGFR = epidermal growth factor receptor; TTF = thyroid transcription factor.Reproduced with permission from Travis WD, Brambilla E, Noguchi M, et al: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma, J Thorac Oncol. 2011 Feb;6(2):244-285.male smokers and 40% of lung cancers in female smokers. Adenocarcinoma is the histologic subtype for 80% and 60% of lung cancers in nonsmoking females and males, respectively. It occurs more frequently in females than in males. It is the most frequent histologic subtype in women, patients who are under 45 years of age, and Asian populations.14Histologic Subtyping of Adenocarcinoma. Increasing under-standing of lung adenocarcinoma, such as important clinical, radiologic, pathologic, and genetic differences between mucinous and nonmucinous adenocarcinomas, prompted multiple changes in the classification system in 2011.15 Based on consensus, the international working group proposed a multidisciplinary approach, with standardized criteria and terminology for diagno-sis in cytologic and small biopsy specimens, and routine molecu-lar testing for known mutations, such as EGFR and KRAS mutations (Table 19-1). The new classification system delineated a stepwise pathologic progression, from AAH to invasive adenocarcinoma based on the predominant histologic growth patterns; the terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma were eliminated in favor of more biologically driven classification (Table 19-2).1. Adenocarcinoma in situ (AIS). AISs are small (≤3 cm) sol-itary adenocarcinomas that have pure lepidic growth; lepidic growth is characterized by tumor growth within the alveolar spaces. These lesions are not invasive into the stroma, vas-cular system, or pleura and do not have papillary or micro-papillary patterns or intra-alveolar tumor cells. They are very rarely mucinous, consisting of type II pneumocytes or Clara cells. These patients are expected to have 100% dis-ease-specific survival with complete surgical resection. On CT scan, AIS can appear as a pure ground-glass neoplasm, 123Brunicardi_Ch19_p0661-p0750.indd 67001/03/19 7:00 PM

CHAPTER 19671CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-2New classification system for lung adenocarcinomaPreinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ (≤3 cm formerly BAC)  Nonmucinous  Mucinous  Mixed mucinous/nonmucinousMinimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm invasion) Nonmucinous Mucinous Mixed mucinous/nonmucinousInvasive adenocarcinoma Lepidic predominant (formerly nonmucinous BAC pattern, with >5 mm invasion) Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin productionVariants of invasive adenocarcinoma Invasive mucinous adenocarcinoma (formerly mucinous BAC) Colloid Fetal (low and high grade) EntericAbbreviations: BAC = bronchioloalveolar carcinoma; IASLC = International Association for the Study of Lung Cancer; ATS = American Thoracic Society; ERS = European Respiratory Society.Reproduced with permission from Travis WD, Brambilla E, Noguchi M, et al: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma, J Thorac Oncol. 2011 Feb;6(2):244-285.but occasionally it will present as part of a solid or part-solid nodule. Mucinous AIS is more likely to appear solid or to have the appearance of consolidation. As with AAH, the lesions can be single or multiple; the ground-glass changes in AIS, however, tend to have a higher attenuation com-pared to AAH. The 8th edition American Joint Committee on Cancer (AJCC) staging manual t-stage for AIS is tumor in situ (Tis).2. Minimally invasive adenocarcinoma (MIA). In the same size solitary lesion, if less than 5 mm of invasion are noted within a predominantly lepidic growth pattern, the lesion is termed minimally invasive adenocarcinoma (MIA) to indicate a patient group with near 100% survival when the lesion is completely resected. This differentiates patients with AIS, but recognizes the fact that the presence of invasion becomes prognostically significant when the size of the invasive com-ponent reaches 5 mm or greater in size.16 If multiple areas of microscopic invasion are found within the lepidic growth, the size of the largest invasive area, measured in the larg-est dimension, is used; this area must be ≤5 mm to be con-sidered MIA. As with AIS, MIA is very rarely mucinous. The invasive component histologically is acinar, papillary, micropapillary, and/or solid and shows tumor cells infil-trating into the surrounding myofibroblastic stroma. On CT scan, the appearance of MIA is often a part-solid nodule (≤5 mm) with a predominant ground-glass component, but can be highly variable. The 8th edition American Joint Committee on Cancer (AJCC) staging manual t-stage for MIA is T1mi.3. Lepidic predominant adenocarcinoma (LPA). If lympho-vascular invasion, pleural invasion, tumor necrosis, or more than 5 mm of invasion are noted in a lesion that has lepidic growth as its predominant component, MIA is excluded, the lesion is called lepidic predominant adenocarcinoma (LPA), and the size of the invasive component is recorded for the T stage.4. Invasive adenocarcinoma. The new classification system now recommends classifying invasive adenocarcinoma by the most predominant subtype after histologic evaluation of the resection specimen. To determine the predominant subtype, histologic sections are evaluated, and the patterns are determined, in 5% increments, throughout the speci-men. This semiquantitative method encourages the viewer to identify and quantify all patterns present, rather than focus-ing on a single pattern. In the pathology report, the tumor is classified by the predominant pattern, with percentages of the subtypes also reported (Fig. 19-11).Subtypes include:a. Lepidic predominantb. Acinar predominantc. Papillary predominantd. Micropapillary predominante. Solid predominantAdenocarcinoma is often peripherally located and frequently discovered incidentally on routine chest radiographs, unlike squamous cell cancers. When symptoms occur, they are due to pleural or chest wall invasion (pleuritic or chest wall pain) or pleural seeding with malignant pleural effusion. Invasive adenocarcinoma is usually solid by CT scan, but can also be part-solid and even a ground-glass nodule. Occasionally, a lobar ground-glass opacification may be present, which is often associated with significant respiratory compromise and can be mistaken for lobar pneumonia. Bubble-like or cystic lucency on CT scan in small (≤2 cm) adenocarcinomas or extensive associated ground-glass components correlate with slow growth and well-differentiated tumors and a more favor-able prognosis. Intratumoral air bronchograms are usually indicative of well-differentiated tumor, whereas spiculations that are coarse and thick (≥2 mm) portend vascular invasion and nodal metastasis and are associated with decreased sur-vival following complete surgical resection. Pleural retraction is also a poor prognostic indicator.5. Additional histologic variants include colloid adenocarci-noma (formerly mucinous cystadenocarcinoma), fetal ade-nocarcinoma, and enteric adenocarcinoma. Clear cell and signet ring cell types are no longer considered to be distinct subtypes as they are found in association with most of the five dominant histologic patterns (lepidic, acinar, papillary, micropapillary, and solid). However, they are still notable, as they can signal clinically relevant molecular changes, such as the presence of the EML4-ALK fusion gene in solid tumors with signet ring features.Squamous Cell Carcinoma Representing 30% to 40% of lung cancers, squamous cell carcinoma is the most frequent cancer in men and highly correlated with cigarette smoking. They arise primarily in the main, lobar, or first segmental bronchi, which are collectively referred to as the central airways. Symptoms of airway irritation or obstruction are common, and include cough, Brunicardi_Ch19_p0661-p0750.indd 67101/03/19 7:00 PM 672SPECIFIC CONSIDERATIONSPART IIFigure 19-11. Major histologic patterns of invasive adenocarcinoma. A. Lepidic predominant pattern with mostly lepidic growth (right) and a smaller area of invasive acinar adenocarcinoma (left). B. Lepidic pattern consists of a proliferation type II pneumo-cytes and Clara cells along the surface alveolar walls. C. Area of invasive acinar adenocarcinoma (same tumor as in A and B). D. Acinar adenocarcinoma con-sists of round to oval-shaped malignant glands invad-ing a fibrous stroma. E. Papillary adenocarcinoma consists of malignant cuboidal to columnar tumor cells growing on the surface of fibrovascular cores. F. Micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, most of which do not show fibrovascular cores. G. Solid adenocarcinoma with mucin consist-ing of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli. No acinar, papillary, or lepidic patterns are seen, but multiple cells have intracytoplasmic baso-philic globules that suggest intracytoplasmic mucin. H. Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this diastase-periodic acid Schiff stain. (Repro-duced with permission from Travis WD, Brambilla E, Noguchi M, et al: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisci-plinary classification of lung adenocarcinoma, J Thorac Oncol. 2011 Feb;6(2):244-285.)hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postob-structive atelectasis), and pneumonia (caused by airway obstruc-tion with secretion retention and atelectasis).Occasionally a more peripherally based squamous cell carcinoma will develop in a tuberculosis scar or in the wall of a bronchiectatic cavity. Histologically, cells develop a pattern of clusters with intracellular bridges and keratin pearls. Central necrosis is frequent and may lead to the radiographic findings of a cavity (possibly with an air-fluid level). Such cavities may become infected, with resultant abscess formation.Large Cell Carcinoma Large cell carcinoma accounts for 10% to 20% of lung cancers and may be located centrally or periph-erally. These tumors have cell diameters of 30 to 50 µm, which are often admixed with various other malignant cell types. Large cell carcinoma can be confused with a large cell variant of neu-roendocrine carcinoma, but can be differentiated by special immunohistochemical stains.Salivary Gland–Type Neoplasms. Salivary-type submucosal bronchial glands throughout the tracheobronchial tree can give rise to tumors that are histologically identical to those seen in the salivary glands. The two most common are adenoid cystic carcinoma and mucoepidermoid carcinoma. Both occur cen-trally due to their site of origin. Adenoid cystic carcinoma is a slow-growing tumor that is locally and systemically invasive, growing submucosally and infiltrating along perineural sheaths. Mucoepidermoid carcinoma consists of squamous and mucous cells and is graded as low or high grade, depending on mitotic rate and degree of necrosis.Neuroendocrine Neoplasms. Neuroendocrine lung tumors are classified into neuroendocrine hyperplasia and three grades of neuroendocrine carcinoma (NEC). Immunohistochemical staining for neuroendocrine markers (including chromogranins, synaptophysin, CD57, and neuron-specific enolase) is essential to accurate diagnosis.17Grade I NEC (classic or typical carcinoid) is a low-grade NEC; 80% arise in the central airway epithelium and occur primarily in younger patients. Because it is a central lesion, hemoptysis, with or without airway obstruction and pneumonia is the most common presentation. Histologically, tumor cells Brunicardi_Ch19_p0661-p0750.indd 67201/03/19 7:00 PM

CHAPTER 19673CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAare arranged in cords and clusters with a rich vascular stroma, which can lead to life-threatening hemorrhage with even simple bronchoscopic biopsy maneuvers. Regional lymph node metas-tases are seen in 15% of patients, but systemic spread and death from Grade I NEC is rare.Grade II NECs (atypical carcinoid) have a much higher malignant potential and, unlike grade I NEC, are etiologically linked to cigarette smoking and more likely to be peripherally located. Histologic findings may include areas of necrosis, nuclear pleomorphism, and higher mitotic rates. Lymph node metastases are found in 30% to 50% of patients. At diagnosis, 25% of patients already have remote metastases.Grade III NEC large cell–type tumors occur primarily in heavy smokers and in the mid to peripheral lung fields. Often large with central necrosis and a high mitotic rate, their neuro-endocrine nature is revealed by positive immunohistochemical staining for at least one neuroendocrine marker.Grade IV NEC (small cell lung carcinoma [SCLC]) is the most malignant NEC and accounts for 25% of all lung cancers; these NECs often have early, widespread metastases. These cancers also arise primarily in the central airways. As with squamous cell cancers, symptoms include cough, hemoptysis, wheezing (due to high-grade airway obstruction), dyspnea (due to bronchial obstruction with or without postobstructive atel-ectasis), and pneumonia (caused by airway obstruction with secretion retention and atelectasis). Evaluation includes expert pathology review and comprehensive evaluation for metastatic disease. Three groups of grade IV NEC are recognized: pure small cell carcinoma (previously referred to as oat cell carci-noma), small cell carcinoma with a large cell component, and combined (mixed) tumors.Grade IV NECs consist of smaller cells (diameter 10 to 20 µm) with little cytoplasm and very dark nuclei; they can be difficult to distinguish from lymphoproliferative lesions and atypical carcinoid tumors. Histologically, a high mitotic rate with easily visualized multiple mitoses and areas of extensive necrosis are characteristic. Importantly, very small bronchoscopic biopsies can distinguish NSCLC from SCLC, but crush artifact may make NSCLC appear similar to SCLC. If uncertainty exists, special immunohistochemical stains or rebiopsy (or both) will be necessary. These tumors are the leading producer of paraneoplastic syndromes.Lung Cancer EpidemiologyLung cancer is the leading cancer killer and second most frequently diagnosed cancer in the United States, account-ing for 26% of all cancer deaths in 2017—more than cancers of the breast, prostate, ovary, and colon and rectum com-bined (Fig. 19-12).18 Lung cancer incidence continues to decline, though at twice the rate for men compared to women (Fig. 19-13A, B). It is encouraging, however, that the average annual death rate declined by 3.5% per year for men and 2% per year for women from 2010 to 2014, representing a 43% decline in mortality for men and a 17% decline for women from 1990 MalesFemalesBreastLung & bronchusColon & rectumUterine corpusNon-Hodgkin lymphomaThyroidMelanoma of the skinPancreasLeukemiaKidney & renal pelvisAll Sites252,710105,51064,01061,38042,47034,94032,16025,84025,70023,380852,63030%12%8%7%5%4%4%3%3%3%100%MalesFemalesLung & bronchusProstateColon & rectumPancreasLiver & intrahepatic bile ductLeukemiaEsophagusUrinary bladderNon-Hodgkin lymphomaBrain & other nervous systemAll SitesLung & bronchusBreastColon & rectumPancreasOvaryLeukemiaNon-Hodgkin lymphomaUterine corpusLiver & intrahepatic bile ductBrain & other nervous systemAll Sites71,28040,61023,11020,79014,08010,92010,2009,3108,6907,080282,50025%14%8%7%5%4%4%3%3%3%100%84,59027,15026,73022,30019,61014,30012,72012,24011,4509,620318,42027%9%8%7%6%4%4%4%4%3%100%ProstateLung & bronchusColon & rectumUrinary bladderMelanoma of the skinNon-Hodgkin lymphomaKidney & renal pelvisOral cavity & pharynxLeukemiaLiver & intrahepatic bile ductAll Sites161,360116,99071,42060,49052,17040,61040,08036,29035,72029,200836,15019%14%9%7%6%5%5%4%4%3%100%Estimated new casesEstimated deathsFigure 19-12. Leading new cancer cases and deaths: 2017 estimates. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. (Reproduced with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)Brunicardi_Ch19_p0661-p0750.indd 67301/03/19 7:00 PM 674SPECIFIC CONSIDERATIONSPART IIFigure 19-13. Trends in death rates by sex for select cancers, United States, 1930 to 2014. A. Males. B. Female rates are age-adjusted to the 2000 U.S. standard population. Due to improvements in International Classification of Diseases (ICD) coding over time, numerator data for cancers of the lung and bronchus, colon and rectum, liver, and uterus differ from the contemporary time period. For example, rates for lung and bronchus include pleura, trachea, mediastinum, and other respiratory organs. (Adapted with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)0102030405060708090100Pancreas†StomachLung and BronchusColon and RectumProstateLiver†LeukemiaTrends in Age-Adjusted Cancer Death Rates* by Site, Males, US, 1930-2014*Per 100,000, age adjusted to the 2000 US standard population.†Mortality rates for pancreatic and liver cancers are increasing.1930193419381942194619501954195819621966197019741978198219861990199419982002200620102014Trends in Age-Adjusted Cancer Death Rates* by Site, Females, US, 1930-2014*Per 100,000, age adjusted to the 2000 US standard population.†Uterus refers to uterine cervix and uterine corpus combined.‡Mortality rates for liver cancer are increasing.010203040505152535451930193419381942194619501954195819621966197019741978198219861990199419982002200620102014StomachColon and RectumPancreas‡Lung and BronchusBreastUterus†Liver‡Brunicardi_Ch19_p0661-p0750.indd 67401/03/19 7:00 PM

CHAPTER 19675CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-3Relative risk of lung cancer in smokersSMOKING CATEGORYRELATIVE RISKNever smoked1.0Currently smoke15.8–16.3Formerly smoked  Years of abstinence  1–95.9–19.5 10–192.0–6.1 >201.9–3.7Data from Samet JM. Health benefits of smoking cessation, Clin Chest Med. 1991;12(4):669-679.to 2014.18 Unfortunately, most patients are still diagnosed at an advanced stage of disease (22% with regional metastasis and 57% with distant metastasis), so therapy is rarely curative.18Prognostic markers for lung cancer survival include female sex (5-year survival of 18.3% for women vs. 13.8% for men), younger age (5-year survival of 22.8% for those <45 years vs. 13.7% for those >65 years), and white race (5-year survival of 16.1% for whites vs. 12.2% for blacks). When access to advanced medical care is unrestricted, as for the military pop-ulation, the racial difference in survival disappears, suggesting that, at least in part, differences in survival may be explained by less access to advanced medical care and later diagnosis.19Risk Factors for Lung Cancer. Cigarette smoking is the leading preventable cause of cancer death, accounting for 29% of the popu-lation attributable fraction in 2010, and is implicated as a causal factor in approximately 90% of lung cancers in men and nearly 80% in women. Two lung cancer types—squamous cell and small cell carcinoma—are extraordinarily rare in the absence of cigarette smoking. The risk of developing lung cancer escalates with the number of cigarettes smoked, the number of years of smoking, and the use of unfiltered cigarettes. Conversely, the risk of lung cancer declines with smoking cessation, but never drops to that of never smokers, regardless of the length of abstinence (Table 19-3).20 Radon exposure accounts for the vast majority of the remaining cancers. Approximately 25% of all lung cancers worldwide and 53% of cancers in women are not related to smoking, and most of them (62%) are adenocarcinomas. Table 19-4 summarizes the existing data regarding the etiology of lung cancer in nonsmokers.21Nearly 3500 deaths from lung cancer each year are attrib-utable to secondhand (environmental) smoke exposure, which confers an excess risk for lung cancer of 24% when a non-smoker lives with a smoker.22 Risk is conferred by exposure to any burning tobacco, including cigars. The amount of second-hand exposure from one large cigar is equivalent to the exposure from 21 cigarettes. As with active smoking, risk of developing lung cancer increases with longer duration and higher level of exposure to environmental tobacco.Over 7000 chemicals have been identified in tobacco smoke, and more than 70 of the compounds are known to be carcinogens. The main chemical carcinogens are polycyclic aromatic hydrocarbons, which are actively or passively inhaled in the tobacco smoke and absorbed; these compounds are acti-vated by specific enzymes and become mutagenic, bind to mac-romolecules such as deoxyribonucleic acid (DNA), and induce genetic mutations. In treating any patient with a previous smok-ing history, it is important to remember that there has been field cancerization of the entire aerodigestive tract. The patient’s risk is increased for cancers of the oral cavity, pharynx, larynx, tra-cheobronchial tree and lung, and esophagus. In examining such patients, a detailed history and physical examination of these organ systems must be performed.Other causes of lung cancer include exposure to a num-ber of industrial compounds, including asbestos, arsenic, and chromium compounds. In fact, the combination of asbestos and cigarette smoke exposure has a multiplicative effect on risk. Pre-existing lung disease confers an increased risk of lung cancer—up to 13%—for individuals who have never smoked. Patients with chronic obstructive pulmonary disease are at higher risk for lung cancer than would be predicted based on smoking risk alone. Patients with secondary scar formation related to a his-tory of tuberculosis or other lung infections also have a higher risk of primary lung carcinoma. This increase is thought to be related to poor clearance of inhaled carcinogens and/or to the effects of chronic inflammation.Screening for Lung Cancer in High-Risk PopulationsIn 2002, the National Lung Screening Trial (NLST) was launched to determine whether screening with CT in high-risk populations would reduce mortality from lung cancer. The study randomized 53,353 eligible patients age 55 to 74 years to either three annual low-dose helical CT scans (LDCT; aka spiral CT) or posteroante-rior view chest radiograph. Patients were eligible for the trial if they had a greater than 30 pack-year history of cigarette smoking; had smoked within the past 15 years if a former smoker; had no prior history of lung cancer; had no history of other life-threatening cancers in the prior 5 years; did not have symptoms suggestive of an undiagnosed lung cancer (such as hemoptysis or weight loss); and had not had a chest CT scan in the prior 18 months. Accrual to the study was excellent, and the primary endpoint of a 20% rela-tive reduction in mortality was achieved in 2010. An absolute risk reduction of lung cancer death of four per 1000 individuals screened by LDCT was realized. Interestingly, all-cause mortality was also reduced by nearly 7% in the LDCT group, further empha-sizing the impact of lung cancer on the mortality of smokers and former smokers.23 The U.S. Preventive Services Task Force (USPSTF) now recommends annual screening for lung cancer with low-dose computed tomography screening in high risk patients. Annual screening averted 14% of lung cancer deaths when applied to a population of asymptomatic adults age 55 to 80 years who have a 30 pack-year smoking history and are either currently smoking or have quit within the past 15 years. Patients should be healthy enough to tolerate curative treatment, specifically surgery per guidelines, and screening should be dis-continued once the patient has not smoked for 15 years or develops a life-limiting health condition, becomes unable to tolerate lung surgery or is unwilling to undergo curative lung resection. Require-ments for coverage differ between Medicare and private insurers, with private insurers following the USPSTF guidelines, while Medicare uses age 55 to 77 years with the same smoking history but does not define comorbid conditions. Use of standardized reporting with criteria for lung nodule identification and classifica-tion is required by the Center for Medicaid & Medicare Services (CMS) but is only recommended by private insurers. Shared deci-sion-making is also required by Medicare, but it is only recom-mended by private insurers. Medicare also differs from private 4Brunicardi_Ch19_p0661-p0750.indd 67501/03/19 7:00 PM 676SPECIFIC CONSIDERATIONSPART IITable 19-4Summary of selected studies of risk factors for lung cancer in individuals who never smokedRISK FACTORRISK ESTIMATE (95% CI)COMMENTSREFERENCEEnvironmental tobacco smoke1.19 (90% CI: 1.04–1.35)Meta-analysis of 11 U.S. studies of spousal exposure (females only)2251.21 (1.13–1.30)Meta-analysis of 44 case-control studies worldwide of spousal exposure2261.22 (1.13–1.33)Meta-analysis of 25 studies worldwide of workplace exposure2261.24 (1.18–1.29)Meta-analysis of 22 studies worldwide of workplace exposure227Residential radon8.4% (3.0%–15.8%) per 100 Bq m3 increase in measured radonMeta-analysis of 13 European studies22811% (0%–28%) per 100 Bq m3Meta-analysis of 7 North American studies229Cooking oil vapors2.12 (1.81–2.47)Meta-analysis of 7 studies from China and Taiwan (females who never smoked)230Indoor coal and wood burning2.66 (1.39–5.07)Meta-analysis of 7 studies from China and Taiwan (both sexes)2301.22 (1.04–1.44)Large case-control study (2861 cases and 3118 controls) from Eastern and Central Europe (both sexes)2312.5 (1.5–3.6)Large case-control study (1205 cases and 1541 controls) from Canada (significant for women only)232Genetic factors: family history, CYP1A1 Ile462Val polymorphism, XRCC1 variants1.51 (1.11–2.06)Meta-analysis of 28 case-control, 17 cohort, and 7 twin studies2332.99 (1.51–5.91)Meta-analysis of 14 case-control studies of Caucasian never smokers2342.04 (1.17–3.54)Meta-analysis of 21 case-control studies of Caucasian and Asian never smokers (significant for Caucasians only)235No associationMeta-analysis of 13 case-control studies236No association overall; reduced risk 0.65 (0.46–0.83) with Arg194Trp polymorphism and 0.56 (0.36–0.86) with Arg280His for heavy smokersLarge case-control study from Europe (2188 cases and 2198 controls)237Increased risk for never smokers 1.3 (1.0–1.8) and decreased risk for heavy smokers 0.5 (0.3–1.0) with Arg299GlnLarge case-control study from the United States (1091 cases and 1240 controls)238Viral factors: HPV 16 and 1810.12 (3.88–26.4) for never smoking women >60 yCase-control study (141 cases, 60 controls) from Taiwan of never smoking women239Abbreviations: Bq = becquerels; CI = confidence interval; CYP1A1 = cytochrome P450 enzyme 1A1; HPV = human papilloma virus.Reproduced with permission from Sun S, Schiller JH, Gazdar AF: Lung cancer in never smokers—a different disease, Nat Rev Cancer. 2007 Oct; 7(10):778-790.insurers in that it requires accreditation of the imaging center and submission of all low-dose CT data to a CMS-approved national registry, among other specifications. With this approach, it is expected that 50% of diagnosed cancers will be early stage. Screening of patients age 50 years or older with a 20 pack-year or greater history and additional risk factors (as determined by the Tammemagi lung cancer risk calculator or other validated risk scores) that increase the risk of lung cancer to 1.3% or greater should also be considered as part of lung cancer screening pro-grams. In all cases, patient–physician shared decision-making should be undertaken, with a discussion of the risks and benefits of screening. It is important to note that there was a 7% false-positive rate in NLST trial, which can lead to patient anxiety, invasive testing, and potentially morbid procedures to further evaluate the finding. The impact of these issues on patient quality of life and cost-effectiveness requires further study, particularly as screening programs are implemented outside of the controlled set-ting of a clinical trial. It is also critical that regulatory guidelines for patient eligibility, frequency of screening, interpretation of the scans, processes for further evaluation and management of posi-tive findings, and dose of radiation are well established and well accepted to ensure the generalizability of the results for patients who will be screened in the general medical community rather than in the specialized centers that performed the trial.Brunicardi_Ch19_p0661-p0750.indd 67601/03/19 7:00 PM

CHAPTER 19677CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAABCDFigure 19-14. Spiral computed tomography scan showing normal transverse chest anatomy at four levels. A. At the level of the tracheal bifurcation, the aorticopulmonary window can be seen. B. The origin of the left pulmonary artery can be seen at a level 1 cm inferior to A. C. The origin and course of the right pulmonary artery can be seen at this next most cephalad level. The left upper lobe bronchus can be seen at its origin from the left main bronchus. D. Cardiac chambers and pulmonary veins are seen in the lower thorax. AA = ascending aorta; APW = aorticopulmonary window; DA = descending aorta; LA = left ventricle; LMB = left main bronchus; LPA = left pulmonary artery; MPA = main pulmonary artery; RA = right atrium; RPA = right pulmonary artery; RV = right ventricle; SVC = superior vena cava; T = trachea.Solitary Pulmonary NoduleA solitary pulmonary nodule is typically described as a single, well-circumscribed, spherical lesion that is 3 cm or less cm in diameter and completely surrounded by normal aerated lung parenchyma.24 Lung atelectasis, hilar enlargement, and pleural effusion are absent. The majority are detected incidentally on chest radiographs (CXRs) or CT scans obtained for some other purpose. About 150,000 solitary nodules are found inciden-tally each year, with increasing numbers as low-dose computed tomography screening in high-risk populations is adopted. The clinical significance of such a lesion depends on whether or not it represents a malignancy.The differential diagnosis of a solitary pulmonary nodule should include a broad variety of congenital, neoplastic, inflam-matory, vascular, and traumatic disorders. The probability of cancer in a solitary pulmonary nodule increases if the patient has a history of smoking (50% or higher for smokers compared to 20% to 40% in never smokers). It is also more likely to be malignant if it is symptomatic or the patient is older, male, or has had occupational exposures.Solitary pulmonary nodules were defined by findings on CXR, but with the increased sensitivity of low-dose screening CT, up to 50% of solitary lesions are found to be associated with multiple (one to six) other, usually subcentimeter, nodules. In the Early Lung Cancer Action project, almost 7% of healthy volunteers were found to have between one and three nodules, and 25% had up to six nodules. CT scanning is necessary to characterize nodule number, location, size, margin morphol-ogy, calcification pattern, and growth rate.25 Spiral (helical) CT allows continuous scanning as the patient is moved through a scanning gantry, allowing the entire thorax to be imaged during a single breath hold (Fig. 19-14). Compared to conventional CT, this provides a superior image quality, because motion artifacts are eliminated, and improves detection of pulmonary nodules and central airway abnormalities.26 The shorter acquisition time of spiral CT also allows for consistent contrast filling of the great vessels, resulting in markedly improved visualization of pathologic states and anatomic variation contiguous to vascular structures. In addition, three-dimensional spiral CT images can be reconstructed for enhanced visualization of spatial anatomic relationships.27 Thin sections (1 to 2 mm collimation) at 1-cm intervals should be used to evaluate pulmonary parenchyma and peripheral bronchi. If the goal is to find any pulmonary metas-tases, thin sections at intervals of 5 to 7 mm collimation are recommended. For assessing the trachea and central bronchi, collimation of 3 to 5 mm is recommended. Providing accurate clinical history and data is of paramount importance to obtaining appropriate imaging.CT findings characteristic of benign lesions include small size, calcification within the nodule, and stability over time. Brunicardi_Ch19_p0661-p0750.indd 67701/03/19 7:00 PM 678SPECIFIC CONSIDERATIONSPART IIABCFigure 19-15. Computed tomography scan images of solitary pulmonary nodules. A. The corona radiata sign demonstrated by a solitary nodule. Multiple fine striations extend perpendicularly from the surface of the nodule like the spokes of a wheel. B. A biopsy-proven adenocarcinoma demonstrating spiculation. C. A lesion with a scalloped border, an indeterminate finding suggesting an intermediate probability for malignancy.Table 19-5Actuarial survival data from the International Registry of Lung MetastasesSURVIVALCOMPLETE RESECTION (%)INCOMPLETE RESECTION (%)5 years361310 years26715 years22—Four patterns of benign calcification are common: diffuse, solid, central, and laminated or “popcorn.” Granulomatous infections such as tuberculosis can demonstrate the first three patterns, whereas the popcorn pattern is most common in hamartomas. In areas of endemic granulomatous disease, differentiating benign versus malignant can be challenging. Infectious granulomas arising from a variety of organisms account for 70% to 80% of this type of benign solitary nodules; hamartomas are the next most common single cause, accounting for about 10%.CT findings characteristic of malignancy include growth over time; increasing density on CT scan (40% to 50% of partial solid lesions are malignant compared to only 15% of subcenti-meter solid or nonsolid nodules); size >3 cm; irregular, lobu-lated, or spiculated edges; and the finding of the corona radiata sign (consisting of fine linear strands extending 4 to 5 mm out-ward and appearing spiculated on radiographs) (Fig. 19-15). Calcification that is stippled, amorphous, or eccentric is usually associated with cancer.Growth over time is an important characteristic for differentiating benign and malignant lesions. Lung cancers have volume-doubling times from 20 to 400 days; lesions with shorter doubling times are likely due to infection, and longer doubling times suggest benign tumors, but can represent slower-growing lung cancer. Positron emission tomography (PET) scan-ning can differentiate benign from malignant nodules28; most lung tumors have increased signatures of glucose uptake, as compared with healthy tissues, and thus glucose metabolism can be measured using radio-labeled 18F-fluorodeoxyglucose (FDG). Meta-analysis estimates 97% sensitivity and 78% spec-ificity for predicting malignancy in a nodule. False-negative results can occur (especially in patients who have AIS, MIA, or LPA, carcinoids, and tumors <1 cm in diameter), as well as false-positive results (because of confusion with other infectious or inflammatory processes).Metastatic Lesions to the LungThe cause of a new pulmonary nodule(s) in a patient with a previous malignancy can be difficult to discern.29 Features sug-gestive of metastatic disease are multiplicity; smooth, round borders on CT scan; and temporal proximity to the original pri-mary lesion. One must always entertain the possibility that a single new lesion is a primary lung cancer. The probability of a new primary cancer vs. metastasis in patients presenting with solitary lesions depends on the type of initial neoplasm. The highest likelihood of a new primary lung cancer is in patients with a history of uterine (74%), bladder (89%), lung (92%), and head and neck (94%) carcinomas.Surgical resection of pulmonary metastases has a role in properly selected patients.30 The best data regarding outcomes of resection of pulmonary metastases come from the Interna-tional Registry of Lung Metastases (IRLM). The registry was established in 1991 by 18 thoracic surgery departments in Europe, the United States, and Canada and included data on 5206 patients. About 88% of patients underwent complete resection. Survival analysis at 5, 10, and 15 years (grouping all primary tumor types) was performed (Table 19-5). Multivariate analysis showed a better prognosis for patients with germ cell tumors, osteosarcomas, a disease-free interval over 36 months, and a single metastasis.31 Depicted in Fig. 19-16, survival after metastasectomy in a variety of cancers is optimal when meta-static disease is resectable, solitary, and identified 36 or more months after initial treatment. When any or all of these optimal characteristics are absent, survival progressively declines.Brunicardi_Ch19_p0661-p0750.indd 67801/03/19 7:00 PM

CHAPTER 19679CHEST WALL, LUNG, MEDIASTINUM, AND PLEURA10080604020002448All Sites7296120Soft Tissue Sarcomas100806040200024487296120Breast Cancer100806040200024487296120Osteosarcoma1001234806040200024487296120Colon Cancer100806040200024487296120Melanoma100806040200024487296120ABCDEFFigure 19-16. The actuarial survival after metastasectomy is depicted for patients with various tumor types (A-F) further categorized into four groups according to resectabil-ity, solitary or multiple, the inter-val between primary resection and metastesectomy, and a combination of factors known in our work and in others, as follows: (1) resectable, soli-tary, and disease-free interval (DFI) greater than or equal to 36 months; (2) resectable, solitary, and DFI 36+ months; (3) resectable, multiple metastases, and DFI <36 months; and (4) unresectable. (Reproduced with permission from Pastorino U: The development of an international registry, J Thorac Oncol. 2010 Jun; 5(6 Suppl 2):S196-S197.)The general principles of patient selection for metasta-sectomy are listed in Table 19-6. The technical aim of pulmo-nary metastasectomy is complete resection of all macroscopic tumors. In addition, any involved adjacent structures should be resected en bloc (i.e., chest wall, diaphragm, and pericardium). Multiple lesions and/or hilar lesions may require lobectomy. Pneumonectomy is rarely justified or employed.Pulmonary metastasectomy can be approached through a thoracotomy or via video-assisted thoracic surgery (VATS) techniques. McCormack and colleagues reported their expe-rience at Memorial Sloan-Kettering in a prospective study of 18 patients who presented with no more than two pulmonary metastatic lesions and underwent VATS resection.32 A thora-cotomy was performed during the same operation; if palpation Brunicardi_Ch19_p0661-p0750.indd 67901/03/19 7:00 PM 680SPECIFIC CONSIDERATIONSPART IITable 19-7Clinical presentation of lung cancerCATEGORYSYMPTOMCAUSEPulmonary symptomsCoughBronchus irritation or compressionDyspneaAirway obstruction or compressionWheezing>50% airway obstructionHemoptysisTumor erosion or irritationPneumoniaAirway obstructionNonpulmonary thoracic symptoms Pleuritic painParietal pleural irritation or invasionLocal chest wall painRib and/or muscle involvementRadicular chest painIntercostal nerve involvementPancoast’s syndromeStellate ganglion, chest wall, brachial plexus involvementHoarsenessRecurrent laryngeal nerve involvementSwelling of head and armsBulky involved mediastinal lymph nodes Medially based right upper lobe tumorTable 19-6General principles governing appropriate selection of patients for pulmonary metastasectomy1. Primary tumor must already be controlled.2. Patient must be able to tolerate general anesthesia, potential single-lung ventilation, and the planned pulmonary resection.3. Metastases must be completely resectable based on computed tomographic imaging.4. There is no evidence of extrapulmonary tumor burden.5. Alternative superior therapy must not be available.identified any additional lesions, they were resected. The study concluded that the probability that a metastatic lesion will be missed by VATS excision is 56%. Patients in the Memorial study were evaluated before the advent of spiral CT scanning, however, and it remains controversial whether metastasis resec-tion should be performed via VATS. Proponents of VATS argue that the resolution of spiral CT scanning is so superior that prior studies using standard CT scanners are no longer relevant. Indeed, a recent study suggested that only 18% of malignant nodules would be missed using a VATS approach in the current era while another study from the United Kingdom found equiv-alent outcomes with regard to missed lesions and pulmonary progression comparing open and VATS approaches. To date, no prospective study using spiral CT scan has been performed to resolve this clinical dilemma.Primary Lung Cancer-Associated Signs and SymptomsLung cancer displays one of the most diverse presentation pat-terns of all human maladies (Table 19-7). The wide range of symptoms and signs is related to (a) histologic features, which often help determine the anatomic site of origin in the lung; (b) the specific tumor location in the lung and its relationship to surrounding structures; (c) biologic features and the pro-duction of a variety of paraneoplastic syndromes; and (d) the presence or absence of metastatic disease. Symptoms related to the local intrathoracic effect of the primary tumor can be conveniently divided into two groups: pulmonary and nonpul-monary thoracic.Pulmonary Symptoms. Pulmonary symptoms result from the direct effect of the tumor on the bronchus or lung tissue. Symptoms (in order of frequency) include cough (secondary to irritation or compression of a bronchus), dyspnea (usually due to central airway obstruction or compression, with or without atelectasis), wheezing (with narrowing of a central airway of >50%), hemoptysis (typically, blood streaking of mucus that is rarely massive; indicates a central airway location), pneu-monia (usually due to airway obstruction by the tumor), and lung abscess (due to necrosis and cavitation, with subsequent infection).Nonpulmonary Thoracic Symptoms. Nonpulmonary tho-racic symptoms result from invasion of the primary tumor directly into a contiguous structure (e.g., chest wall, diaphragm, pericardium, phrenic nerve, recurrent laryngeal nerve, superior vena cava, and esophagus), or from mechanical compression of a structure (e.g., esophagus or superior vena cava) by enlarged tumor-bearing lymph nodes.Peripherally located tumors (often adenocarcinomas) extending through the visceral pleura lead to irritation or growth into the parietal pleura and potentially to continued growth into the chest wall structures. Three types of symptoms, depend-ing on the extent of chest wall involvement, are possible: (a) pleuritic pain, from noninvasive contact of the parietal pleura with inflammatory irritation or direct parietal pleural invasion; (b) localized chest wall pain, from deeper invasion and involvement of the rib and/or intercostal muscles; and (c) radicular pain, from involvement of the intercostal nerve(s). Radicular pain may be mistaken for renal colic in the case of tumors invading the inferoposterior chest wall.Other specific nonpulmonary thoracic symptoms include:1. Pancoast’s syndrome. Tumors originating in the supe-rior sulcus (posterior apex) elicit: apical chest wall and/or shoulder pain (from involvement of the first rib and chest wall); Horner’s syndrome (unilateral enophthal-mos, ptosis, miosis, and facial anhidrosis from invasion of the stellate sympathetic ganglion); and radicular arm pain (from invasion of T1, and occasionally C8, brachial plexus nerve roots).2. Phrenic nerve palsy. The phrenic nerve traverses the hemi-thorax along the mediastinum, parallel and posterior to the superior vena cava and anterior to the pulmonary hilum. Tumors at the medial lung surface or anterior hilum can directly invade the nerve; symptoms include shoulder pain (referred), hiccups, and dyspnea with exertion because of Brunicardi_Ch19_p0661-p0750.indd 68001/03/19 7:00 PM

CHAPTER 19681CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAdiaphragm paralysis. Radiographically, unilateral diaphragm elevation on chest radiograph is present; the diagnosis is confirmed by fluoroscopic examination of the diaphragm with paradoxical motion with breathing and sniffing (the “sniff” test).3. Recurrent laryngeal nerve palsy. Recurrent laryngeal nerve (RLN) involvement most commonly occurs on the left side, given the hilar location of the left RLN as it passes under the aortic arch. Paralysis results from: (a) invasion of the vagus nerve above the aortic arch by a medially based left upper lobe tumor; or (b) direct invasion of the RLN by hilar tumor and/or hilar or aortopulmonary lymph node metastases. Symptoms include voice change, often referred to as hoarseness, but more typically a loss of tone associ-ated with a breathy quality, and coughing, particularly when drinking liquids.4. Superior vena cava (SVC) syndrome. As a result of bulky enlargement of involved mediastinal lymph nodes com-pressing or a medially based right upper lobe tumor invad-ing the SVC, SVC syndrome symptoms include variable degrees of swelling of the head, neck, and arms; headache; and conjunctival edema. It is seen most commonly with NEC grade IV (small cell) lung cancer.5. Pericardial tamponade. Pericardial effusions (benign or malignant), associated with increasing levels of dyspnea and/or arrhythmias, and pericardial tamponade occur with direct pericardial invasion. Diagnosis requires a high index of suspicion in the setting of a medially based tumor with symptoms of dyspnea and is confirmed by CT scan or echocardiography.6. Back pain. Results from direct invasion of a vertebral body and is often localized and severe. If the neural foramina are involved, radicular pain may also be present.7. Other local symptoms. Dysphagia is usually secondary to external esophageal compression by enlarged lymph nodes involved with metastatic disease, usually with lower lobe tumors. Finally, dyspnea, pleural effusion, or referred shoulder pain can result from invasion of the diaphragm by a tumor at the base of a lower lobe.Associated Paraneoplastic Syndromes. All lung cancer his-tologies are capable of producing a variety of paraneoplastic syndromes, most often from systemic release of tumor-derived biologically active materials (Table 19-8). Paraneoplastic syn-dromes may produce symptoms even before any local symp-toms are produced by the primary tumor, thereby aiding in early diagnosis. Their presence does not influence resectabil-ity or treatment options. Symptoms often abate with success-ful treatment; paraneoplastic symptom recurrence may herald tumor recurrence. The majority of such syndromes are associ-ated with grade IV NEC (small cell carcinoma), including many endocrinopathies.1. Hypertrophic pulmonary osteoarthropathy (HPO). Often severely debilitating, symptoms of HPO may antedate the diagnosis of cancer by months. Clinically, ankle, feet, fore-arm, and hand tenderness and swelling are characteristic, resulting from periostitis of the fibula, tibia, radius, meta-carpals, and metatarsals. Clubbing of the digits may occur in up to 30% of patients with grade IV NEC (Fig. 19-17). Plain radiographs show periosteal inflammation and elevation, while bone scans demonstrate intense but Table 19-8Paraneoplastic syndromes in patients with lung cancerEndocrineHypercalcemia (ectopic parathyroid hormone)Cushing’s syndromeSyndrome of inappropriate secretion of antidiuretic hormoneCarcinoid syndromeGynecomastiaHypercalcitoninemiaElevated growth hormone levelElevated levels of prolactin, follicle-stimulating hormone, luteinizing hormoneHypoglycemiaHyperthyroidismNeurologicEncephalopathySubacute cerebellar degenerationProgressive multifocal leukoencephalopathyPeripheral neuropathyPolymyositisAutonomic neuropathyEaton-Lambert syndromeOptic neuritisSkeletalClubbingPulmonary hypertrophic osteoarthropathyHematologicAnemiaLeukemoid reactionsThrombocytosisThrombocytopeniaEosinophiliaPure red cell aplasiaLeukoerythroblastosisDisseminated intravascular coagulationCutaneousHyperkeratosisDermatomyositisAcanthosis nigricansHyperpigmentationErythema gyratum repensHypertrichosis lanuginosa acquistaOtherNephrotic syndromeHypouricemiaSecretion of vasoactive intestinal peptide with diarrheaHyperamylasemiaAnorexia or cachexiasymmetric uptake in the long bones. Aspirin or nonsteroidal anti-inflammatory agents provide temporary relief; treat-ment requires successful tumor eradication.2. Hypercalcemia. Up to 10% of patients with lung cancer will have hypercalcemia, most often due to metastatic disease. Ectopic parathyroid hormone secretion by the tumor, most often squamous cell carcinoma, is causative in up to 15%, however, and should be suspected if metastatic bone disease is not present. Symptoms of hypercalcemia include leth-argy, depressed level of consciousness, nausea, vomiting, Brunicardi_Ch19_p0661-p0750.indd 68101/03/19 7:00 PM 682SPECIFIC CONSIDERATIONSPART IIABCFigure 19-17. Hypertrophic pulmonary osteoarthropathy associated with small cell carcinoma. A. Painful clubbing of the fingers. B. Painful clubbing of the toes (close-up). C. The arrows point to new bone formation on the femur.and dehydration. Following complete tumor eradication, the calcium level will normalize. Unfortunately, tumor recur-rence is extremely common and may manifest as recurrent hypercalcemia.3. Hyponatremia. Characterized by confusion, lethargy, and possible seizures, hyponatremia can result from the inappro-priate secretion of antidiuretic hormone from the tumor into the systemic circulation (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) in 10% to 45% of patients with grade IV NEC (small cell). It is diagnosed by the pres-ence of hyponatremia, low serum osmolality, and high urinary sodium and osmolality. Another cause of hyponatremia can be the ectopic secretion of atrial natriuretic peptide (ANP).4. Cushing’s syndrome. Autonomous tumor production of an adrenocorticotropic hormone (ACTH)-like molecule leads to rapid serum elevation of ACTH and subsequent severe hypokalemia, metabolic alkalosis, and hyperglycemia. Symptoms are primarily related to the metabolic changes while the physical signs of Cushing’s syndrome (e.g., trun-cal obesity, buffalo hump, striae) are unusual due to the rapidity of ACTH elevation. Diagnosis is made by dem-onstrating hypokalemia (<3.0 mmol/L); nonsuppressible elevated plasma cortisol levels that lack the normal diurnal variation; elevated blood ACTH levels; or elevated urinary 17-hydroxycorticosteroids, all of which are not suppressible by administration of exogenous dexamethasone. Immuno-reactive ACTH is present in nearly all extracts of SCLC, and a high percentage of patients with SCLC have elevated ACTH levels by radioimmunoassay, yet fewer than 5% have symptoms of Cushing’s syndrome.5. Peripheral and central neuropathies. Unlike other para-neoplastic syndromes, which are usually due to ectopic secretion of an active substance, these syndromes are felt to be immune mediated. Cancer cells are thought to secrete antigens normally expressed only by the nervous system, generating antibodies leading either to interference with neurologic function or to immune neurologic destruction. Up to 16% of lung cancer patients have neuromuscular dis-ability, and, of these, half have grade IV NEC (small cell) and 25% have squamous cell carcinomas. In patients with neurologic or muscular symptoms, central nervous system (CNS) metastases must be ruled out with CT or magnetic resonance imaging (MRI) of the head. Other metastatic dis-ease leading to disability must also be excluded.6. Lambert-Eaton syndrome. This myasthenia-like syndrome is caused by tumor secretion of immunoglobulin G (IgG) antibodies targeting voltage-gated calcium channels, which causes a neuromuscular conduction defect by decreasing the amount of acetylcholine released from presynaptic sites at the motor end plate. Symptoms, including gait abnormali-ties from proximal muscle weakness and impaired coordi-nation, may actually precede radiographic evidence of the tumor. Therapy is directed at the primary tumor with resec-tion, radiation, and/or chemotherapy. Many patients have dramatic improvement after successful therapy. For patients with refractory symptoms, treatment consists of guanidine Brunicardi_Ch19_p0661-p0750.indd 68201/03/19 7:00 PM

CHAPTER 19683CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAhydrochloride, immunosuppressive agents such as predni-sone and azathioprine, and occasionally plasma exchange. Unlike with myasthenia gravis patients, neostigmine is usu-ally ineffective.Symptoms Associated with Metastatic Lung Cancer. Lung cancer metastasizes most commonly to the CNS, vertebral bod-ies, bone, liver, adrenal glands, lungs, skin, and soft tissues. CNS metastases are present at diagnosis in 10% of patients; another 10% to 15% will develop CNS metastases following diagnosis. Focal symptoms, including headache, nausea, vom-iting, seizures, hemiplegia, and dysarthria, are common. Lung cancer is the most common cause of spinal cord compression, either by primary tumor invasion of an intervertebral foramen or direct extension of vertebral metastases. Bony metastases are identified in 25% of lung cancer patients. They are primar-ily lytic and produce pain locally; thus, any new and localized skeletal symptoms must be evaluated radiographically. Liver metastases and adrenal metastases are typically asymptomatic and usually discovered by routine CT scan. Adrenal metastasis may lead to adrenal hypofunction. Skin and soft tissue metas-tases occur in 8% of patients dying of lung cancer and gener-ally present as painless subcutaneous or intramuscular masses. Occasionally, tumor erodes through overlying skin; excision may then be necessary for both mental and physical palliation.Nonspecific Cancer-Related Symptoms. Lung cancer often produces a variety of nonspecific symptoms such as anorexia, weight loss, fatigue, and malaise and their presence raises con-cern for metastatic disease.Lung Cancer ManagementRole of Histologic Diagnosis and Molecular Testing.  Establishing a clear histologic diagnosis early in the evaluation and management of lung cancer is critical to effective treat-ment. Molecular signatures are also key determinants of treat-ment algorithms for adenocarcinoma and will likely become important for squamous cell carcinoma as well. Currently, differentiation between adenocarcinoma and squamous cell carcinoma in cytologic specimens or small biopsy specimens is imperative in patients with advanced stage disease, as treat-ment with pemetrexed or bevacizumab-based chemotherapy is associated with improved progression-free survival in patients with adenocarcinoma but not squamous cell cancer. Further-more, life-threatening hemorrhage has occurred in patients with squamous cell carcinoma who were treated with bevacizumab. Finally, EGFR mutation predicts response to EGFR tumor kinase inhibitors and is now recommended as first-line therapy in advanced adenocarcinoma. Because adequate tissue is required for histologic assessment and molecular testing, each institution should have a clear, multidisciplinary approach to patient evalu-ation, tissue acquisition, tissue handling/processing, and tissue analysis (Fig. 19-18). In many cases, tumor morphology differ-entiates adenocarcinoma from the other histologic subtypes. If no clear morphology can be identified, then additional testing for one immunohistochemistry marker for adenocarcinoma and one for squamous cell carcinoma will usually enable differentiation. Immunohistochemistry for neuroendocrine markers is reserved for lesions exhibiting neuroendocrine morphology. Additional molecular testing should be performed on all adenocarcinoma specimens for known predictive and prognostic tumor mark-ers (e.g., EGFR, KRAS, and EML4-ALK fusion gene). Ideally, use of tissue sections and cell block material is limited to the minimum necessary at each decision point. This emphasizes the importance of a multidisciplinary approach; surgeons and radiologists must work in direct cooperation with the cytopa-thologist to ensure that tissue samples are adequate for morpho-logic diagnosis as well as providing sufficient cellular material to enable molecular testing. With adoption of endobronchial and endoscopic ultrasound, electromagnetic navigational bronchos-copy, VATS, and even transthoracic image-guided fine-needle and core-needle biopsy, surgeons are increasingly involved in the acquisition of diagnostic tissue for primary, metastatic, and recurrent intrathoracic disease, and a thorough understanding of key issues is necessary to ensure optimal treatment and patient outcomes.Patient Evaluation. Pretreatment evaluation encompasses three areas: diagnosis and assessment of the primary tumor, assessment for metastatic disease, and determination of func-tional status (the patient’s ability to tolerate the prescribed treatment regimen). A discrete approach to each area allows the surgeon to systematically evaluate the patient, perform accurate clinical staging, and determine the patient’s functional suitabil-ity for therapy (Table 19-9).Assessment of the Primary Tumor Primary tumor assessment begins with directed history questions regarding the presence or absence of pulmonary, nonpulmonary, thoracic, and paraneo-plastic symptoms. Because patients often present to the surgeon with a CXR or CT scan demonstrating the lesion, tumor location can guide the history and physical examination.A routine chest CT scan should be performed; this should include intravenous contrast to enable assessment of the pri-mary tumor, delineation of mediastinal lymph nodes relative to normal mediastinal structures, and the tumor’s relationship to surrounding and contiguous structures. Recommendations for treatment and options for obtaining tissue diagnosis require a thorough understanding and assessment of CT findings.Concern for contiguous invasion of adjacent structures is often raised in response to a combination of symptom history, location of the primary tumor, and CT imaging. It is common to see the primary tumor abutting the chest wall without clear radiographic evidence of rib destruction. In this circumstance, localized pain can indicate parietal pleural, rib, or intercostal nerve involvement. Similar observations apply to tumors abut-ting the recurrent laryngeal nerve, phrenic nerve, diaphragm, vertebral bodies, and chest apex. Thoracotomy should not be denied because of presumptive evidence of invasion of the chest wall, vertebral body, or mediastinal structures; proof of invasion may require thoracoscopy or even thoracotomy.MRI of pulmonary lesions and mediastinal nodes, over-all, offers no real advantages over CT scanning. It is an excel-lent modality, however, for defining a tumor’s relationship to a major vessel, given its excellent imaging of vascular structures. This is especially true if the use of iodine contrast material is contraindicated. Thus, use of MRI in lung cancer patients is reserved for those with contrast allergies or suspected mediasti-nal, vascular, or vertebral body invasion.Options for Tissue Acquisition The surgeon must have an evidence-based algorithm for diagnosis and treatment of a pul-monary nodule and masses (Fig. 19-19).24 Depending on nodule size, bronchial tree proximity, and the population prevalence of lung cancer, bronchoscopy has a 20% to 80% sensitivity for detecting neoplastic processes within a pulmonary lesion. Brunicardi_Ch19_p0661-p0750.indd 68301/03/19 7:00 PM 684SPECIFIC CONSIDERATIONSPART IISTEP 1STEP 2POSITIVE BIOPSY (FOB,TBBx, Core, SLBx)POSITIVE CYTOLOGY(effusion, aspirate, washings,brushings)Histology: Lepidic, papillary, and/oracinar architecture(s)Cytology: 3-D arrangements, delicatefoamy/vacuolated (translucent)cytoplasm,Fine nuclear chromatin and oftenprominent nucleoliNuclei are often eccentrically situatedClassic morphology:ADCADC markerand/orMucin +ve;SQCCmarker –ve(or weak insame cells)NSCLC, favor ADCNE morphology, large cells,NE IHC+No clear ADC orSQCC morphology:NSCLC-NOSNSCLC, favor SQCCSQCC marker +veADC marker –ve/orMucin –veApply ancillary panel ofOne SQCC and one ADC marker+/OR MucinIHC –ve andMucin –veNSCLC NOSADC marker or Mucin +ve;as well as SQCC marker +vein different cellsMolecular analysis:e.g., EGFR mutation†NSCLC, NOS,possibleadenosquamous caIf tumor tissue inadequate for molecular testing,discuss need for further sampling — back to Step 1NE morphology, small cells, nonucleoli, NE IHC+, TTF-1 +/–,CK+Keratinization, pearlsand/or intercellular bridgesNSCLC,LCNECClassic Morphology:SQCCSCLCSTEP 3Figure 19-18. Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology. Step 1: When positive biopsies (fiberoptic bronchos-copy [FOB], transbronchial [TBBx], core, or surgical lung biopsy [SLBx]) or cytology (effusion, aspirate, washings, and brushings) show clear adenocarcinoma (ADC) or squamous cell carcinoma (SQCC) morphology, the diagnosis can be firmly established. If there is neuroendocrine (NE) morphology, the tumor may be classified as small cell carcinoma (SCLC) or non–small cell lung carcinoma (NSCLC), probably large cell neuroendocrine carcinoma (LCNEC) according to standard criteria (+ = positive, – = negative, and ± = positive or negative). If there is no clear ADC or SQCC morphology, the tumor is regarded as NSCLC—not otherwise specified (NOS). Step 2: NSCLC-NOS can be further classified based on (a) immunohistochemical stains, (b) mucin (DPAS or mucicarmine) stains, or (c) molecular data. If the stains all favor ADC-positive ADC marker(s) (i.e., TTF-1 and/or mucin positive) with negative SQCC markers, then the tumor is classified as NSCLC, favor ADC. If SQCC markers (i.e., p63 and/or CK5/6) are positive with negative ADC markers, the tumor is classified as NSCLC, favor SQCC. If the ADC and SQCC markers are both strongly positive in different populations of tumor cells, the tumor is classified as NSCLC-NOS, with a comment it may represent adenosquamous carcinoma. If all markers are negative, the tumor is classified as NSCLC-NOS. †EGFR mutation testing should be performed in (1) classic ADC, (2) NSCLC, favor ADC, (3) NSCLC-NOS, and (4) NSCLC-NOS, possible adenosquamous carcinoma. In NSCLC-NOS, if EGFR mutation is positive, the tumor is more likely to be ADC than SQCC. Step 3: If clinical management requires a more specific diagnosis than NSCLC-NOS, additional biopsies may be indicated. CD = cluster designation; CK = cytokeratin; DPAS = diastase-periodic acid Schiff; DPAS +ve = periodic-acid Schiff with diastase; EGFR = epidermal growth factor receptor; IHC = immunohistochemistry; NB = of note; TTF-1 = thyroid transcription factor-1; –ve = negative; +ve = positive. (Reproduced with permission from Travis WD, Brambilla E, Noguchi M, et al: Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, Arch Pathol Lab Med. 2013 May;137(5):668-684.)Brunicardi_Ch19_p0661-p0750.indd 68401/03/19 7:00 PM

CHAPTER 19685CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-9Evaluation of patients with lung cancer PRIMARY TUMORMETASTATIC DISEASEFUNCTIONAL ASSESSMENTHistoryPulmonaryWeight lossAbility to walk up two flights of stairsNonpulmonary thoracicMalaiseAbility to walk on a flat surface indefinitelyParaneoplastic  New bone painNeurologic signs or symptomsSkin lesionsPhysical examination  VoiceSupraclavicular node palpationAccessory muscle usage Skin examinationAir flow by auscultation Neurologic examinationForce of coughRadiographic examinationChest CTChest CT, PETChest CT: tumor anatomy, atelectasisTissue analysisBronchoscopyBone scan, head MRI, abdominal CTQuantitative perfusion scanTransthoracic needle aspiration and biopsy Bronchoscopic lymph node FNAEndoscopic ultrasoundMediastinoscopyBiopsy of suspected metastasisOtherThoracoscopy—Pulmonary function tests (FEV1, Dlco, O2 consumption)Abbreviations: CT = computed tomography; Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second; FNA = fine-needle aspiration; MRI = magnetic resonance imaging; O2 = oxygen; PET = positron emission tomography.Diagnostic tissue from bronchoscopy can be obtained by one of four methods:1. Brushings and washings for cytology2. Direct forceps biopsy of a visualized lesion3. Endobronchial ultrasound-guided fine-needle aspiration (FNA) of an externally compressing lesion without visual-ized endobronchial tumor4. Transbronchial biopsy with fluoroscopy to guide forceps to the lesion or electromagnetic navigational bronchoscopyElectromagnetic navigation bronchoscopy is a recent addi-tion to the surgeon’s armamentarium for transbronchial biopsy of peripheral lung lesions. Using electromagnetic markers that create a three-dimensional image and align the recorded CT images to the patient’s true anatomy, a transbronchial catheter is advanced, and brushings, FNA, cup biopsy, and washings can be performed. Diagnostic yield using electromagnetic naviga-tion bronchoscopy as an adjunct to standard bronchoscopy is reported as high as 80%. The approach can also be used for placement of fiducial markers for subsequent stereotactic body radiation therapy and for tattooing the perilesional region to guide subsequent video-assisted thoracoscopic resection.Pneumothorax rates are approximately 1% to 3.5%.For peripheral lesions (roughly the outer half of the lung), transbronchial biopsy is performed first, followed by brushings and washings. This improves diagnostic yield by disrupting the lesion with the biopsy forceps and mobilizing additional cells. For central lesions, direct forceps biopsy is often possible. For central lesions with external airway compression but no visible endobronchial lesions, endobronchial ultrasound (EBUS) is highly accurate and safe for transbronchial biopsies of both the primary tumor (when it abuts the central airways) as well as the mediastinal lymph nodes.33Image-guided transthoracic FNA (ultrasound or CT FNA) biopsy can accurately diagnose appropriately selected peripheral pulmonary lesions in up to 95% of patients. Three biopsy results are possible after image-guided biopsy procedures: malignant, a specific benign process, or indeterminate. Because falsenegative rates range from 3% to 29%, further diagnostic efforts are warranted in the absence of a specific benign diagnosis (such as granulomatous inflammation or hamartoma) because malig-nancy is not ruled out.34 The primary complication is pneumo-thorax in as many as 30% of cases. Intrapulmonary bleeding occurs, but it rarely causes clinically significant hemoptysis or respiratory compromise.Some groups advocate use of video-assisted thoracoscopic biopsy as the first option for diagnosis, citing superior diagnostic accuracy and low surgical risk. With VATS, the nodule can be excised with a wedge or segmental resection, if less than 3 cm, or a core-needle biopsy can be performed under direct vision for larger lesions. VATS can also provide valuable staging informa-tion, including sampling/dissection of mediastinal lymph nodes and assessing whether the primary tumor has invaded a contigu-ous structure (such as the chest wall or mediastinum).Lesions most suitable for VATS are those that are located in the outer one-third of the lung. The surgeon should avoid direct manipulation of the nodule or violation of the visceral pleura overlying the nodule. In addition, the excised nodule must be extracted from the chest within a bag to prevent seeding of the chest wall. If the patient’s pulmonary reserve is adequate, the surgeon can proceed to lobectomy (either VATS or open) after frozen section diagnosis.Brunicardi_Ch19_p0661-p0750.indd 68501/03/19 7:00 PM 686SPECIFIC CONSIDERATIONSPART IIA thoracotomy is occasionally necessary to diagnose and stage a primary tumor. Although this occurs rarely, two circum-stances may require such an approach: (a) a deep-seated lesion that yielded an indeterminate needle biopsy result or that could not be biopsied for technical reasons; or (b) inability to determine inva-sion of a mediastinal structure by any method short of palpation. In the circumstance of a deep-seated lesion without a diagnosis, tissue can be obtained via thoracotomy using FNA, core-needle biopsy, or excisional biopsy. Intraoperative frozen-section analysis is required; if the open biopsy frozen-section result is indetermi-nate, a lobectomy may be necessary in extremely rare situations. If a pneumonectomy is required to remove the lesion, a tissue diag-nosis of cancer must be made before proceeding.Assessment for Metastatic Disease Approximately 40% of patients with newly diagnosed lung cancer present with distant metastasis. The presence of lymph node or systemic metastases may imply inoperability. As with the primary tumor, assess-ment for the presence of metastatic disease should begin with the history and physical examination, focusing on new bone pain, neurologic symptoms, and new skin lesions. In addition, constitutional symptoms (e.g., anorexia, malaise, and unin-tentional weight loss of >5% of body weight) suggest either a large tumor burden or the presence of metastases. Physical examination focuses on overall appearance, noting any evi-dence of weight loss such as redundant skin or muscle wasting, and a complete examination of the head and neck, including NegativetestsPositivetestsNoNoNew SPN (8 mm to 30 mm)identified on CXR orCT scanBenign calcificationpresent or 2-year stabilitydemonstrated?Surgical risk acceptable?Assess clinicalprobability of cancer Low probabilityof cancer(<5%)Intermediateprobability of cancer(>5%–60%)High probabilityof cancer(>60%)Establish diagnosis bybiopsy when possible.Consider XRT or monitorfor symptoms andpalliate as necessarySerial high-resolutionCT at 3, 6, 12 and24 monthsAdditional testing• PET imaging, if available• Contrast-enhanced CT, depending on institutional expertise• Transthoracic fine-needle aspiration biopsy, if nodule is peripherally located• Bronchoscopy, if airbronchogram present or if operator has expertise with newer guided techniques Video-assistedthoracoscopic surgery:examination of a frozensection, followed byresection if nodule ismalignantYesYesNo further interventionrequired except forpatients with pure groundglass opacities, in whomlonger annual follow-upshould be consideredFigure 19-19. Recommended management algorithm for patients with solitary pulmonary nodules (SPNs) measuring 8 mm to 30 mm in diameter. CT = computed tomography; CXR = chest radiograph; PET = positron emission tomography; XRT = radiotherapy. (Adapted with permission from Gould MK, Fletcher J, Iannettoni MD, et al: Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition), Chest. 2007 Sep;132(3 Suppl):108S-130S.24)Brunicardi_Ch19_p0661-p0750.indd 68601/03/19 7:01 PM

CHAPTER 19687CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAevaluation of cervical and supraclavicular lymph nodes and the oropharynx. This is particularly true for patients with a sig-nificant tobacco history. The skin should be thoroughly exam-ined. Routine laboratory studies include serum levels of hepatic enzymes (e.g., serum glutamic oxaloacetic transaminase and alkaline phosphatase), and serum calcium (to detect bone metas-tases or the ectopic parathyroid syndrome). Elevation of either hepatic enzymes or serum calcium levels typically occurs with extensive metastases.Mediastinal Lymph Nodes. Chest CT scanning facilitates assessment of mediastinal and hilar nodes for enlargement. How-ever, a positive CT result (i.e., nodal diameter >1.0 cm) predicts actual metastatic involvement in only about 70% of lung cancer patients. Thus, up to 30% of such nodes are enlarged from non-cancerous reactive causes (e.g., inflammation due to atelectasis or pneumonia secondary to the tumor). Patients should not be denied an attempt at curative resection just because of a posi-tive CT result for mediastinal lymph node enlargement; any CT finding of metastatic nodal involvement must be confirmed his-tologically. The negative predictive value of normal-appearing lymph nodes by CT (lymph nodes <1.0 cm) is better than the positive predictive value of a suspicious-appearing lymph node, particularly with small squamous cell tumors. With normal-size lymph nodes and a T1 tumor, the false-negative rate is less than 10%, leading many surgeons to omit mediastinoscopy. How-ever, the false-negative rate increases to nearly 30% with cen-trally located and T3 tumors. It has also been demonstrated that T1 adenocarcinomas or large cell carcinomas have a higher rate of early micrometastasis. Therefore, all such patients should undergo mediastinoscopy.Mediastinal lymph node staging by PET scanning appears to have greater accuracy than CT scanning. PET staging of mediastinal lymph nodes has been evaluated in two meta-analyses. The overall sensitivity for mediastinal lymph node metastasis was 79% (95% confidence interval [CI] 76%–82%), with a specificity of 91% (95% CI 89%–93%) and an accuracy of 92% (95% CI 90%–94%).35In comparing PET with CT scans in patients who also underwent lymph node biopsies, PET had a sensitivity of 88% and a specificity of 91%, whereas CT scanning had a sensitivity of 63% and a specificity of 76%. Combining CT and PET scan-ning may lead to even greater accuracy.36 In one study of CT, PET, and mediastinoscopy in 68 patients with potentially opera-ble NSCLC, CT correctly identified the nodal stage in 40 patients (59%). It understaged the tumor in 12 patients and overstaged it in 16 patients. PET correctly identified the nodal stage in 59 patients (87%). It understaged the tumor in five patients and overstaged it in four. For detecting N2 and N3 disease, the combination of PET and CT scanning yielded a sensitivity, specificity, and accuracy of 93%, 95%, and 94%, respectively. CT scan alone yielded 75%, 63%, and 68%, respectively. Studies examining combined PET-CT consistently show improved accuracy compared to PET or CT alone; accuracy for PET-CT nodal positivity confirmed by medi-astinoscopy is approximately 75%, with a negative predictive value of approximately 90%. Right upper lobe lesions were more likely to have occult N2 disease than other lobes of the lung.37-40 PET-positive mediastinal lymph nodes require histologic verifica-tion of node positivity, either by EBUS-guided FNA or mediasti-noscopy, to minimize the risk of undertreatment, assuming node positivity without histologic confirmation relegates the patient to, at a minimum, induction chemotherapy. If there is a suggestion of TABLE 19-10Techniques for invasive mediastinal stagingEndoscopicEndobronchial ultrasound with transbronchial needle aspirationEndoscopic ultrasound with needle aspirationTransbronchial needle aspirationComputed tomography–guided transthoracic needle aspirationSurgicalVideo-assisted mediastinoscopyTranscervical extended mediastinal lymphadenectomy (TEMLA)Video-assisted mediastinal lymphadenectomy (VAMLA)Thoracoscopic transthoracic lymphadenectomyIndications for invasive mediastinal staging in lung cancer1. Radiographically enlarged mediastinal lymph nodes2. Centrally located tumors3. N1 nodal enlargement4. Tumor size >3 cm5. Peripheral clinical stage I tumor with nonenlarged but FDG-avid mediastinal lymph nodesIndications for prethoracotomy/thoracoscopy biopsy of stations 5 and 6 lymph nodes1. Criteria for invasive staging met and other mediastinal lymph node stations are negative (assuming patient would have induction therapy if any nodal station positive)2. Enrollment criteria for induction therapy protocol require pathologic confirmation of N2 disease3. Computed tomography scan shows evidence of bulky nodal metastasis or extracapsular spread that could prevent complete resection4. Tissue diagnosis of a hilar mass or of lymph nodes causing recurrent laryngeal nerve paralysis is neededN3 disease, the patient would be incorrectly staged as having IIIB disease and would not be considered a candidate for potentially curative surgical resection.It is important for surgeons who are managing patients with lung cancer to have a clear algorithm for invasive medias-tinal staging. In general, invasive staging is underutilized, plac-ing many patients at risk for overor understaging and, thus, inappropriate treatment. An absolute indication for obtaining a tissue diagnosis is mediastinal lymph node enlargement greater than 1.0 cm by CT scan. There are several options for invasive mediastinal staging (Table 19-10):1. Endobronchial Ultrasound (EBUS)-guided transbron-chial needle aspiration. Less invasive than mediasti-noscopy, EBUS enables image-guided transtracheal and transbronchial FNA cytologic samples from hilar masses and lymph nodes from level 4R and 4L, level 7, level 10, and level 11. Rapid onsite pathologic evaluation with expert cytopathology evaluation greatly increases the diagnostic accuracy of the procedure; importantly, the intraoperative evaluation will confirm whether the target lesion is being sampled and greatly facilitates acquisition of satisfactory samples for determining the morphologic diagnosis as well as sufficient material for cell block for immunohistochemistry Brunicardi_Ch19_p0661-p0750.indd 68701/03/19 7:01 PM 688SPECIFIC CONSIDERATIONSPART IIFigure 19-20. Cervical mediastinoscopy. Paratracheal and sub-carinal lymph node tissues (within the pretracheal space) can be sampled using a mediastinoscope introduced through a suprasternal skin incision.and molecular testing. EBUS does not allow assessment of level 3, 5, or 6 nodal stations.2. Endoscopic ultrasound (EUS). EUS can accurately visual-ize mediastinal paratracheal lymph nodes (stations 4R, 7, and 4L), paraesophageal (station 8) and inferior pulmonary ligament (station 9) lymph nodes and visualize primary lung lesions contiguous with or near the esophagus (see Fig. 19-8). Using FNA or core-needle biopsy, samples of lymph nodes or primary lesions can be obtained. Diagnos-tic yield is improved with intraoperative cytologic evalua-tion, which can be performed with the cytopathologist in the operating room. Limitations of EUS include the inability to visualize the anterior (pretracheal) mediastinum; thus, EUS does not replace mediastinoscopy/EBUS for complete medi-astinal nodal staging. However, it may not be necessary to perform mediastinoscopy if findings on EUS are positive for N2 nodal disease, particularly if more than one station is found to harbor metastases.3. Cervical video-assisted mediastinoscopy. Mediastinos-copy provides tissue sampling of all paratracheal and sub-carinal lymph nodes and permits visual determination of the presence of extracapsular extension of nodal metastasis (Fig. 19-20). With complex hilar or right paratracheal primary tumors, it allows direct biopsies and assessment of invasion into the mediastinum. Mediastinoscopy is recommended for centrally located tumors, T2 and T3 primary tumors, and occasionally for T1 adenocarcinomas or large cell carcinomas (due to their higher rate of metastatic spread). Some surgeons perform mediastinoscopy in all lung cancer patients because of the poor survival associated with surgi-cal resection of N2 disease.4. It is important to note that EBUS or EUS can be used for initial diagnosis in enlarged lymph nodes, but the predictive value of a negative EBUS in a patient with radiographically suspicious mediastinal disease is not sufficient to accurately guide treatment. At the authors’ institutions, it is standard to begin mediastinal lymph node staging with EBUS-guided FNA of clinically suspicious mediastinal lymphadenopathy. If intraoperative rapid onsite cytologic evaluation is nega-tive, mediastinoscopy is performed in the same operative setting to ensure accurate mediastinal staging. However, if the FNA is positive, mediastinoscopy is not performed, and the patient is referred to medical oncology for induc-tion therapy; avoiding a pretreatment mediastinoscopy in this manner facilitates the safe performance of a postinduc-tion mediastinoscopy for restaging of the mediastinum in patients who respond favorably to induction therapy.5. Left video-assisted thoracoscopic lymph node sampling may be needed for patients with left upper lobe tumors who have localized regional spread to stations 5 and 6 lymph nodes, without mediastinal paratracheal involvement (see Fig. 19-8). If there is a low index of suspicion for nodal metastasis, the patient can be schedule for VATS biopsy and lobectomy under the same anesthesia; the procedure begins by sampling the level 5 and 6 nodes for frozen section, and if the nodes are negative, the anatomic lung resection is performed. If the index of suspicion is high, the VATS biopsy is performed as a separate procedure. Cervical mediastinoscopy should precede VATS biopsy, even if patients have normal para-tracheal lymph nodes. Additional diagnostic evaluation of the lymph nodes in stations 5 and 6 may be unnecessary if the mediastinal lymph nodes are proven to be benign with biopsy during cervical mediastinoscopy and the preoperative CT scan suggests complete respectability of the tumor. There are, however, several indications for prethoracotomy biopsy of stations 5 and 6 lymph nodes, which are listed in Table 19-10. It is particularly important to prove that mediastinal lymph nodes are pathologically involved and not just radio-graphically suspicious for nodal metastasis prior to deciding that the patient is not a candidate for resection.Pleural Effusion. The presence of pleural effusion on radio-graphic imaging should not be assumed to be malignant. Pleural effusion may be secondary to atelectasis or consolidation (seen with central tumors), cardiac dysfunction, or may be a reac-tive effusion. When associated with a peripherally based tumor abutting the visceral or parietal pleural surface, probability of being malignant is higher. If this is the only site concerning for metastatic disease, pathologic confirmation is mandatory. It is reasonable to start with thoracentesis, but cytology reveals malignant cells in only 50% of malignant effusions on initial thoracentesis; negative cytology 5 times is needed to have 95% certainty of a benign process. Thoracoscopy may be needed to rule out pleural metastases in select patients and is usually per-formed as a separate staging procedure, often with subsequent mediastinoscopy if thoracoscopy is negative for metastasis.Distant Metastases. Currently, chest CT and PET are rou-tine in the evaluation of patients with lung cancer. Integrated PET-CT scanners have become standard and have substan-tially improved accuracy of detection and localization of lymph node and distant metastases, as compared with independently performed PET and CT scans (Fig. 19-21). This technology overcomes the imprecise information on the exact location of focal abnormalities seen on PET and has become the standard imaging modality for lung cancer. Compared to routine chest or abdominal CT and bone scans, PET scanning detects 10% to 15% more distant metastases, but should be confirmed with MRI and/or biopsies if the patient otherwise has early-stage dis-ease. Brain MRI should be performed when the suspicion or risk of brain metastases is increased, such as in patients with Brunicardi_Ch19_p0661-p0750.indd 68801/03/19 7:01 PM

CHAPTER 19689CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAABCFigure 19-21. Imaging of non–small cell lung cancer by integrated positron emission tomography (PET)-computed tomography (CT) scan. A. CT of the chest showing a tumor in the left upper lobe. B. PET scan of the chest at the identical cross-sectional level. C. Coregistered PET-CT scan clearly showing tumor invasion (con-firmed intraoperatively). (Adapted with permission from Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung can-cer with integrated positron-emission tomography and computed tomography, N Engl J Med. 2003 Jun 19;348(25):2500-2507.)clinical stage III disease. In the absence of neurologic symp-toms or signs, the probability of a negative head CT scan is 95%. Liver abnormalities that are not clearly simple cysts or hemangiomas and adrenal enlargement, nodules, or masses are further evaluated by MRI scanning and, occasionally, by needle biopsy. Adrenal adenomas have a high lipid content (secondary to steroid production), but metastases and most primary adrenal malignancies contain little if any lipid; thus, MRI is usually able to distinguish the two.Tumor, Node, and Metastasis: Lung Cancer Staging The staging of any tumor is an attempt to estimate the extent of dis-ease and determine the patient’s prognosis; in a given patient, tumors are typically classified into a clinical stage and a patho-logic stage. Clinical staging includes history and physical examination, radiographic test results, and diagnostic biopsy information. Therapeutic plans are generated based on clinical stage. After surgical resection of tumor and lymph nodes, post-operative pathologic stage (pTNM) is determined, providing further prognostic information.The staging of solid epithelial tumors is based on the TNM staging system. The primary tumor “T” status provides infor-mation about tumor size and relationship to surrounding struc-tures; the “N” status provides information about regional lymph nodes; and the “M” status provides information about the pres-ence or absence of metastatic disease. The designation of lymph nodes as N1, N2, or N3 requires familiarity with the lymph node mapping system41 (see Fig. 19-8). Based on clearly delineated anatomic boundaries, accurate and reproducible localization of thoracic lymph nodes is possible, facilitating detailed nodal staging for individual patients and standardization of nodal assessment between surgeons.Pathologic staging criteria are based on the predicted sur-vival relative to each combination of tumor, node, and metas-tasis status. In 2018, the AJCC eighth edition incorporated multiple changes into the staging system for NSCLC based on analysis of survival predictors from 77,156 lung cancer patients worldwide. Table 19-11a shows the clinical and pathologic cri-teria changes implemented and each of the TNM descriptors currently used in staging NSCLC (Table 19-11b) and the over-all stage classifications (Table 19-11c). T-staging is markedly changed, including T category designation for each centimeter in size up to 5 cm, as well as size of the invasive component in lepidic growth tumors. Visceral pleural invasion increases T-stage to T2 for patients with tumors ≤3 cm in size, and syn-chronous primary tumors have an added T suffix (m) in tumor staging. Metastatic disease has also been subdivided into intra-thoracic, single-site extrathoracic, and multiple extrathoracic metastasis. In addition to the TNM stage, it is recommended that histologic grade, lymphovascular invasion, adequacy of resec-tion margins and mediastinal dissection, tumor mutation status, treatment, and residual tumor after treatment also be recorded into cancer registries to facilitate evaluation of these potential predictors in future analysis of staging criteria.Staging for small cell lung cancer (SCLC) is typically based on the extent of disease. SCLC presenting with bulky locoregional disease confined to the ipsilateral hemithorax, with no evidence for distant metastatic disease, is termed “limited” SCLC. Limited disease must be treatable within a tolerable field of radiation. Using AJCC descriptors, this includes any T stage, any N stage, without metastatic disease (M0). The only excep-tion is when multiple lung nodules are widely spread throughout the ipsilateral lung in the same hemithorax; in these patients, the size of the involved area would preclude a “safe” radiation field. In contrast, in “disseminated” disease, tumor is beyond the ipsi-lateral hemithorax or widely spread within the ipsilateral lung and to distant sites. Metastases to the pleura and pericardium, with resultant effusions, are considered disseminated disease. Brunicardi_Ch19_p0661-p0750.indd 68901/03/19 7:01 PM 690SPECIFIC CONSIDERATIONSPART IITable 19-11aChanges in Descriptors for non-small cell lung cancer comparing the 7th and 8th editions of the American Joint Committee on Cancer Staging ManualDESCRIPTORSEVENTH EDITIONEIGHTH EDITIONT component0 cm (pure lepidic adenocarcinoma ≤3 cm total size)T1a if ≤2 cm; T1b if >2–3 cmTis (AIS)≤0.5 cm invasive size (lepidic predominant adenocarcinoma ≤3 cm total size)T1a if ≤2 cm; T1b if >2–3 cmT1mi≤1 cmT1aT1a>1–2 cmT1aT1b>2–3 cmT1bT1c>3–4 cmT2aT2a>4–5 cmT2aT2b>5–7 cmT2bT3>7 cmT3T4Bronchus <2 cm from carinaT3T2Total atelectasis/pneumonitisT3T2Invasion of diaphragmT3T4Invasion of mediastinal pleuraT3-N componentNo assessment, no involvement, or involvement of regional lymph nodesNX, N0, N1, N2, N3No changeM componentMetastases within the thoracic cavityM1aM1aSingle extrathoracic metastasisM1bM1bMultiple extrathoracic metastasesM1bM1cAbbreviations: AIS, adenocarcinoma in situ; mi, minimally invasive adenocarcinoma; Tis, tumor in situ.Modified with permission from Rami-Porta R, Asamura H, Travis WD, et al: Lung cancer — major changes in the American Joint Committee on Cancer eighth edition cancer staging manual, A Cancer J Clin. 2017 Mar;67(2):138-155.(Continued)Table 19-11bAmerican Joint Committee on Cancer Lung Cancer Staging Eight EditionTPRIMARY TUMORTXPrimary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopyT0No evidence of primary tumorTisCarcinoma in situSquamous cell carcinoma in situ (SCIS)Adenocarcinoma in situ (AIS); adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimensionT1Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus) T1miMinimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension T1aTumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon. T1bTumor >1 cm but ≤2 cm in greatest dimension T1cTumor >2 cm but ≤3 cm in greatest dimensionT2Tumor >3 cm but ≤5 cm or having any of the following features:• Involves the main bronchus regardless of distance to the carina, but without involvement of the carina• Invades visceral pleura (PL1 or PL2)• Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lungT2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.Brunicardi_Ch19_p0661-p0750.indd 69001/03/19 7:01 PM

CHAPTER 19691CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-11cStage Group in the 8th AJCC Tumor, Node, Metastasis staging systemN0N1N2N3T1/M0T1aIA1IIBIIIAIIIBT1bIA2IIBIIIAIIIBT1cIA3IIBIIIAIIIBT2/M0T2aIBIIBIIIAIIIBT2bIIAIIBIIIAIIIBT3/M0IIBIIIAIIIBIIICT4/M0IIIAIIIAIIIBIIICTX/M1M1aIVAIVAIVAIVAM1bIVAIVAIVAIVAM1cIVBIVBIVBIVBUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Table 19-11bAmerican Joint Committee on Cancer Lung Cancer Staging Eight Edition T2aTumor >3 cm but ≤4 cm in greatest dimension T2bTumor >4 cm but ≤5 cm in greatest dimensionT3Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primaryT4Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primaryNREGIONAL LYMPH NODENXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extensionN2Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)N3Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)MDISTANT METASTASISM0No distant metastasisM1Distant metastasis M1aSeparate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor. M1bSingle extrathoracic metastasis in a single organ (including involvement of a single nonregional node) M1cMultiple extrathoracic metastases in a single organ or in multiple organsUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Metastases to brain, bone, bone marrow, and the pleural and pericardial spaces are common.Assessment of Functional Status Patients with potentially resectable tumors require careful assessment of their functional status and ability to tolerate either lobectomy or pneumonectomy. The surgeon should first estimate the likelihood of pneumonec-tomy, lobectomy, or possibly sleeve resection, based on the CT images. A sequential process of evaluation then unfolds.5A patient’s history is the most important tool for gauging risk. Specific questions regarding performance status should be routinely asked. If the patient can walk on a flat surface indefi-nitely, without oxygen and without having to stop and rest sec-ondary to dyspnea, he will be very likely to tolerate lobectomy. If the patient can walk up two flights of stairs (up two stan-dard levels), without having to stop and rest secondary to dys-pnea, she will likely tolerate pneumonectomy. Finally, nearly (Continued)Brunicardi_Ch19_p0661-p0750.indd 69101/03/19 7:01 PM 692SPECIFIC CONSIDERATIONSPART IIPercent mortalityppoDLCO%504030201002030405060708090100Figure 19-22. Operative mortality after major pulmonary resec-tion for non–small cell lung cancer (334 patients) as a function of percent predicted postoperative carbon monoxide diffusion capacity (ppoDlco%). Solid line indicates logistic regression model; dashed lines indicate 95% confidence limits. (Reproduced with permission from Wang J, Olak J, Ferguson MK: Diffusing capacity predicts operative mortality but not long-term survival after resection for lung cancer, J Thorac Cardiovasc Surg. 1999 Mar;117(3):581-586.)all patients, except those with carbon dioxide (CO2) retention on arterial blood gas analysis, will be able to tolerate periods of single-lung ventilation and wedge resection. Formal assess-ment of cardiac fitness is mandatory; use of risk scores such as the Thoracic Revised Cardiac Risk Index developed by Dr. Brunelli and colleagues provides useful prognostic infor-mation for postresection survival from early-stage lung cancer.Current smoking status and sputum production are also pertinent. Current smokers and patients with a greater than 60 pack-year history of smoking have a significantly increased risk of postoperative pulmonary complications; heavy smokers are 2.5 times more likely to develop pulmonary complications and three times more likely to develop pneumonia compared to patients with a ≤60 pack-year history (odds ratio [OR] 2.54; 95% CI 1.28–5.04; P = .0008). Impaired exchange of CO2 is also pre-dictive of increased risk, independent of the smoking history. For every 10% decline in percent carbon monoxide diffusion capac-ity (%Dlco), the risk of any pulmonary complication increased by 42% (OR 1.42; 95% CI 1.16–1.75; P = .008).42 Risk reduc-tion requires smoking cessation at least 8 weeks preoperatively, a requirement that is often not feasible in a cancer patient. Nev-ertheless, abstinence for at least 2 weeks before surgery should be encouraged. Smoking cessation on the day of surgery leads to increased sputum production and potential secretion reten-tion postoperatively, and some authors have reported increased rates of pulmonary complications in this group.43 Patients with chronic daily sputum production will have more problems post-operatively with retention and atelectasis; they are also at higher risk for pneumonia. Sputum culture, antibiotic administration, and bronchodilators may be warranted preoperatively.Pulmonary function studies are routinely performed when any resection greater than a wedge resection will be performed. Of all the measurements available, the two most valuable are forced expiratory volume in 1 second (FEV1) and carbon mon-oxide diffusion capacity (Dlco). General guidelines for the use of FEV1 in assessing the patient’s ability to tolerate pulmonary resection are as follows: greater than 2.0 L can tolerate pneumo-nectomy, and greater than 1.5 L can tolerate lobectomy. It must be emphasized that these are guidelines only. It is also important to note that the raw value is often imprecise because normal values are reported as “percent predicted” based on corrections made for age, height, and gender. For example, a raw FEV1 value of 1.3 L in a 62-year-old, 75-inch (190-cm) male has a percent predicted value of 30% (because the normal expected value is 4.31 L); in a 62-year-old, 62-inch female, the predicted value is 59% (normal expected value 2.21 L). The male patient is at high risk for lobectomy, while the female could potentially tolerate pneumonectomy.To calculate the predicted postoperative value for FEV1 or Dlco, the percent predicted value of FEV1 or Dlco is mul-tiplied by the fraction of remaining lung after the proposed sur-gery. For example, with a planned right upper lobectomy, a total of three segments will be removed. Therefore, three of a total 20 segments will leave the patient with (20 – 3/20) × 100 = 85% of their original lung capacity. In the two patients mentioned ear-lier, the man will have a predicted postoperative FEV1 of 30% × 0.85 = 25%, whereas the woman will have a predicted postop-erative FEV1 of 50%. Percent predicted value of less than 50% for either FEV1 or Dlco correlates with risk for postoperative complications, particularly pulmonary complications; the risk of complications increases in a stepwise fashion for each 10% decline. Figure 19-22 shows the relationship between predicted postoperative Dlco and estimated operative mortality.Quantitative perfusion scanning is used in select circum-stances to help estimate the functional contribution of a lobe or whole lung. Such perfusion scanning is most useful when the impact of a tumor on pulmonary physiology is difficult to discern. With complete collapse of a lobe or whole lung, the impact is apparent, and perfusion scanning is usually unneces-sary. Figure 19-23 shows a tumor with significant right main stem airway obstruction with associated atelectasis and volume loss of the right lung. At presentation, the patient was dyspneic with ambulation, and the FEV1 was 1.38 L. Six months prior, this patient could walk up two flights of stairs without dyspnea. The surgeon can anticipate that the patient will tolerate pneumo-nectomy because the lung is already not functioning due to main stem airway obstruction, and may, in fact, be contributing to a shunt. However, with centrally located tumors associated with partial obstruction of a lobar or main bronchus or of the pulmo-nary artery, perfusion scanning may be valuable in predicting the postoperative result of resection. For example, if the quan-titative perfusion to the right lung is measured to be 21% (nor-mal is 55%) and the patient’s percent predicted FEV1 is 60%, the predicted postoperative FEV1 after a right pneumonectomy would be 60% × 0.79 = 47%, indicating the ability to tolerate pneumonectomy. If the perfusion value is 55%, the predicted postoperative value would be 27%, and pneumonectomy would pose a significantly higher risk.It is not uncommon to encounter patients with significant reductions in their percent predicted FEV1 and Dlco whose his-tory shows a functional status that is inconsistent with the pul-monary function tests. In these circumstances, exercise testing that yields maximal oxygen consumption (v. o2max ) has emerged as a valuable decision-making technique to help patients with abnormal FEV1 and Dlco (Table 19-12). Values <10 mL/kg/min are associated with a 26% mortality after major pulmonary Brunicardi_Ch19_p0661-p0750.indd 69201/03/19 7:01 PM

CHAPTER 19693CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAFigure 19-23. Chest computed tomography scan of an obstructing right main stem lung tumor. Arrow indicates location of right main bron-chus. The right lung volume is much less than the left lung volume.Table 19-12Relation between maximum oxygen consumption (v. o2max) as determined by preoperative exercise testing and perioperative mortalitySTUDYDEATHS/TOTALv. o2max 10–15 mL/kg per minute Smith et al1961/6 (33%) Bechard and Wetstein1970/15 (0%) Olsen et al1981/14 (7.1%) Walsh et al1991/5 (20%) Bolliger et al2002/17 (11.7%) Markos et al2011/11 (9.1%) Wang et al2020/12 (0%) Win et al2032/16 (12.5%)  Total8/96 (8.3%)v. o2max <10 mL/kg per minute Bechard and Wetstein1972/7 (29%) Olsen et al1983/11 (27%) Holden et al2042/4 (50%) Markos et al2010/5 (0%)  Total7/27 (26%)Reproduced with permission from Colice GL, Shafazand S, Griffin JP: Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition), Chest. 2007 Sep;132(3 Suppl):161S-177S.resection compared to only 8.3% with v. o2max ≥10 mL/kg/min. Values >15 mL/kg/min generally indicate the patient’s ability to tolerate pneumonectomy.The risk assessment of a patient is an amalgam of clinical judgment and data that must be integrated with the experienced clinician’s sense of the patient and with the patient’s attitude 6toward the disease and toward life. Figure 19-24 provides a useful algorithm for determining suitability for lung resection.44Lung Cancer TreatmentGrade IV NEC (Small Cell) Lung Carcinoma. In rare cir-cumstances where SCLC presents as an isolated lung lesion, lobectomy followed by chemotherapy is warranted after sur-gical mediastinal staging has confirmed the absence of N2 disease. Often, ultrasound-guided FNA provides a definitive positive diagnosis and more invasive approaches are not needed. However, less than 5% are stage I, and there is no benefit from surgical resection for more advanced-stage disease; treatment is chemotherapy with or without radiation therapy depending on the extent of disease and the patient performance status.Early-Stage Non–Small Cell Lung Cancer. Early-stage disease includes T1 and T2 tumors (with or without N1 nodal involvement) and T3 tumors (without N1 nodal involvement). This group represents a small but increasing proportion of the total number of patients diagnosed with lung cancer each year (approximately 16% of an estimated 222,500 patients in 2017).18 Surgical resection is the current standard, ideally accomplished by video-assisted lobectomy or pneumonectomy, depending on the tumor location.Despite the term “early-stage,” the overall 5-year sur-vival rate for all localized lung cancer is 55% and only 26% when regional metastasis was present between 2004 and 2009.45 Median survival for untreated patients with stage IA NSCLC is 14 months, and 5-year survival rate is 22%.46 After surgical resection of postoperative pathologic stage IA disease, 5-year survival is better than with no treatment, but still only 67%.41 Survival declines with higher stages. Advanced age at diagno-sis, male sex, low socioeconomic status, nonsurgical treatment, and poor histologic grade are associated with increased mortal-ity risk on multivariate analysis.45Depending on tumor size and location, lobectomy, sleeve lobectomy, and occasionally pneumonectomy, with mediastinal lymph node dissection or sampling, are appropriate for patients with clinical early-stage disease. Sleeve resection is performed for tumors located at airway bifurcations when an adequate bronchial Brunicardi_Ch19_p0661-p0750.indd 69301/03/19 7:01 PM 694SPECIFIC CONSIDERATIONSPART IIVO2max > 15 ml/kg/minPerform spirometryUnexplained dyspneaor diffuse parenchymaldisease on CXR/CT?Perform CPETEstimate %ppoFEV1 and %ppoDLCOIncreased riskVO2max>15 mL/kg/minVO2max10 to 15 mL/kg/minVO2max<10 mL/kg/minFEV1 >1.5 L lobectomyFEV1 >2 L pneumonectomyFEV1 >80% predictedFEV1 <1.5 L lobectomyFEV1 <2 L pneumonectomyFEV1 <80% predictedYesNoDLCO >80%predictedDLCO <80%predicted%ppo FEV1 and%ppo DLCO >40%ppo FEV1 or%ppo DLCO <40%ppo FEV1 <30 or%ppo FEV1 x%ppo DLCO <1650Measure DLCOAverage riskIncreased riskFigure 19-24. Algorithm for preoperative evaluation of pulmonary function and reserve prior to resectional lung surgery. CPET = cardiopulmonary exercise test; CT = computed tomographic scan; CXR = chest radiograph; Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second; %ppo = percent predicted postoperative lung function; V.o2max = maximum oxygen consumption. (Modified with permission from Colice GL, Shafazand S, Griffin JP: Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition), Chest. 2007 Sep;132(3 Suppl):161S-177S.44)Brunicardi_Ch19_p0661-p0750.indd 69401/03/19 7:01 PM

CHAPTER 19695CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAmargin cannot be obtained by standard lobectomy. Pneumonec-tomy is rarely performed; primary indications for pneumonec-tomy in early-stage disease include large central tumors involving the distal main stem bronchus and inability to completely resect involved N1 lymph nodes. The latter circumstance occurs with bulky adenopathy or with extracapsular nodal spread.Management of Early-Stage Lung Cancer in the High-Risk Patient Lobectomy may not be an option for some patients with early-stage disease, due to poor cardiopulmonary function or other comorbid illnesses. The ultimate decision that a patient is inoperable, both with regard to the patient’s ability to tolerate surgery and the likelihood of successful resection, should be accepted only after evaluation by an expert surgeon. Surgeons with limited expertise, when faced with a complicated patient, should refer the patient to a high-volume center for further eval-uation if they are unable to offer the patient surgical resection in their own center.Rationale for Limited Resection in Early-Stage Lung Cancer.  Limited resection, defined as segmentectomy or wedge resec-tion, is a viable option for achieving local control in high-risk patients. Historically, limited resection with wedge or segmen-tectomy has been considered a compromise operation due to unacceptably high rates of local recurrence and concerns for worse survival.47,48 Subsequent meta-analysis of the literature shows that the difference in death rate is likely negligible49 (Table 19-13). The high rates of local recurrence demonstrated by Ginsberg and others, however, remain a significant concern and continue to restrict the use of limited resection for early-stage lung cancer to the high-risk patient.With the recent publication of a 20% reduction in lung cancer mortality with screening CT scans in high-risk popula-tions, the topic of limited resection is again the subject of inten-sive review. Studies investigating anatomic segmentectomy (or extended wedge resection) with hilar and mediastinal lymph node dissection suggest that close attention to the ratio of surgi-cal margin to tumor diameter and a careful assessment of the lymph nodes substantially reduce local recurrence.50-52 Recur-rence rates were 6.2%, comparable to rates associated with lobectomy, when the margin-to-tumor diameter ratio exceeded 1, compared to 25% if the margin-to-tumor diameter ratio was less than 1.50 In most centers, this requires use of a thora-cotomy, although increasing experience with VATS in highvolume centers shows that limited resection is safe and feasi-ble, with perioperative adverse outcomes that are comparable to lobectomy.52-55Rationale for Tumor Ablation in the Management of Primary Lung Cancer. Limited resection, by definition, requires that the patient has sufficient cardiopulmonary reserve to undergo a general anesthesia and loss of at least one pulmonary seg-ment. For the high-risk or nonoperable patient, as determined by experience pulmonary surgeons, tumor ablation techniques have been developed for treatment of early-stage lung cancers.Current limitations of this approach include the absence of nodal staging, lack of tissue for molecular profiling, chemo-resistance, or sensitivity testing, concerns about definitions of locoregional recurrence, and a lack of uniformity across cen-ters. Surgeons typically define locoregional recurrence as tumor growth within the operative field, including resectable lymph nodes, whereas local recurrence after ablation is most com-monly defined as tumor growth within the field of treatment. Despite the fact that in-transit or lymph node metastases are present in up to 27% of clinically stage I NSCLCs at resection, any tumor growth outside the field of ablative treatment is not be considered treatment failure.56Despite these limitations, tumor ablative strategies are increasingly proposed as viable alternatives to surgical resec-tion, even in potentially operable patients.57-62 While prema-ture, ablative techniques may ultimately be shown to have efficacy equivalent to lobectomy for the primary treatment of very small peripheral early-stage lung cancers. Multidisci-plinary collaboration between thoracic surgery, interventional radiology/pulmonology, and radiation oncology is required to ensure that development of these ablative techniques occurs through properly designed and well-controlled prospective studies and will ensure that patients receive the best available therapy, regardless of whether it is surgical resection or ablative therapy.The two most commonly applied ablation techniques are radiofrequency ablation and stereotactic body radiotherapy.1. Radiofrequency ablation. Radiofrequency ablation is per-formed using either monopolar or bipolar delivery of elec-trical current to electrodes placed within the tumor tissue. In lung tumors, the electrodes are typically inserted into the tumor mass under CT guidance. An electrical current is delivered; the current is converted by means of friction into heat, which quickly leads to immediate and irreparable tissue destruction in the tissue surrounding the electrode. The efficacy of radiofrequency ablation for controlling the primary tumor and improving survival in poor operative candidates (either due to significant comorbid diseases precluding general anesthesia or poor pulmonary function excluding lung resection) is safe and feasible for peripheral lung nodules. In tumors <3.5 cm, the rate of radiographic resolution of tumor is up to 80%, and cancer-specific sur-vival at 2 years was approximately 90%, indicating excel-lent local control of the primary site.57-59,63 It has become the preferred modality for small peripheral tumors over standard external-beam radiation in centers where the tech-nique is available. Radiofrequency ablation is an excellent modality for the patient at risk for adverse outcomes with pulmonary resec-tion or for patients who refuse surgery, and surgeons should have an algorithm for determining which patients are optimal for this modality64-69 (see Fig. 19-24). Target lesions larger than 5 cm, tumor abutting the hilum, associated malignant pleural or pericardial effusion, greater than three lesions in one lung, and the presence of pulmonary hypertension are all contraindications to radiofrequency ablation.64 Proximity to a large vessel is a contraindication not only due to the risk of massive bleeding, but also because large blood vessels act as a heat sink and lethal cellular temperatures are less likely to be achieved. For these patients, stereotactic body radiotherapy may provide local tumor control with less risk of major complications. Combination therapy with either external-beam radiation or stereotactic body radiotherapy is also under investigation.2. Stereotactic body radiotherapy. Stereotactic body radiotherapy applies highly focused, high-intensity, three-dimensional conformal radiation to the target lesion over a few sessions. Tumor motion quantification and image guidance technologies have significantly improved the delivery of radiation with high levels of precision 7Brunicardi_Ch19_p0661-p0750.indd 69501/03/19 7:01 PM 696SPECIFIC CONSIDERATIONSPART IITable 19-13New classification system for lung adenocarcinomaSTUDY OR SUBGROUPlog [HAZARD RATIO]SESEGMENTECTOMY TOTALLOBECTOMY TOTALWEIGHTHAZARD RATIO IV, RANDOM, 95% CIHAZARD RATIO IV, RANDOM, 95% CIBando 2002–0,3150,3495741323,3%0,73 [0,37,1,45]Favours Segmentectomy0.005200100.11Favours LobectomyCheng 2012–0,210,2908132324,8%0,81 [0,46, 1,43]Dai 20160,3320,21044240115209,2%1,39 [0,92, 2,11]Ginsberg 19950,3680,21571221258,7%1,44 [0,95, 2,21]Hamatake 20120,19890,280632775,1%1,22 [0,70, 2,11]Iwasaki 2007–0,083380,5076531551,6%0,92 [0,34, 2,49]Keenan 20040,1310,4158541472,3%1,14 [0,50, 2,58]Kilic 2009–0,23570,21683106788,6%0,79 [0,52, 1,21]Kodama 19970,10110,573246771,2%1,11 [0,36, 3,40]Koike 20030,07730,4385741592,1%1,08 [0,46, 2,55]Landreneau 20140,460,24821021176,6%1,58 [0,97, 2,58]Martin–Ucar 2005–1,04350,707117170,8%0,35 [0,09, 1,41]Nakamura 20110,2391382890,4%1,27 [0,18, 9,02]Okada 2001–0,11650,7168681040,8%0,89 [0,22, 3,63]Okumura 2007–0,16320,3595672733,1%0,85 [0,42, 1,72]Razi 2016–0,020,256911910516,1%0,98 [0,59, 1,62]Read 19900,31480,41841131312,3%1,37 [0,60, 3,11]Sienel 20071,04020,91581491500,5%2,83 [0,47,17,03]Soukiasian 20120,28521,6735561780,1%1,33 [0,05, 35,35]Sugi 2010–0,02020,2543956,5%0,98 [0,60, 1,60]Tsutani 2014–0,71330,3087983834,3%0,49 [0,27, 0,90]Warren 19940,54810,5661031,6%1,73 [0,65, 4,61]Watanabe 2005–0,61620,8979620570,5%0,54 [0,09, 3,14]Yamashita 20120,198860,73469901240,8%1,22 [0,29, 5,15]Yamato 20080,30010,40561532772,5%1,35 [0,61 , 2,99]Yendamuri 20110,2390,2756216225995,3%1,27 [0,74, 2,18]Zhong 2012–0,16250,19388398110,8%0,85 [0,58, 1,24]Total (95% CI)611118431100,0%1,04 [0,92, 1,18]Heterogeneity: Tau2 = 0,00; Chi2 = 25,04, df = 26 (P = 0,52); I2 = 0%Test for overall effect: Z = 0,68 (P = 0,50)Forest plot of HR for overall survival impact of operative approach (segmentectomy versus lobectomy) of stage I NSCLC patients. The pooled HR displayed in this figure when compared with segmentectomy suggested that there was not a significant benefit of lobectomy on HR of stage I patients (7-21) (HR 1.04; 95% CI, 0.92–1.18, P = 0.50) (22–33).Abbreviations: HR = hazard ratio; NSCLC = non–small cell lung cancer; CI = confidence interval; df = degree of freedom; SE = standard error.Reproduced with permission from Bedetti B, Bertolaccini L, Rocco R, et al: Segmentectomy versus lobectomy for stage I non-small cell lung cancer: a systematic review and meta-analysis, J Thorac Dis. 2017 Jun; 9(6):1615-1623.Brunicardi_Ch19_p0661-p0750.indd 69601/03/19 7:01 PM

CHAPTER 19697CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAto the target lesion. This accuracy is important because the lung is extremely sensitive to radiation injury and the majority of patients with early-stage lung cancer who are currently considered candidates for ablative therapy have marginal lung function; excessive injury to normal surrounding lung tissue is not desirable. Importantly, these techniques allow the safe delivery of up to 66 Gy of radiation to the target tumors without exceeding the maximum-tolerated dose.62-70 A phase II North American multicenter study recently demonstrated the safety and efficacy of this approach in 59 nonoperable patients.62 Patients with biopsy-proven, node-negative peripheral NSCLCs less than 5 cm in diameter (T1 or T2) were treated with stereotactic body radiotherapy after they were deemed inoperable, based on coexisting medical conditions, by a thoracic surgeon and/or pulmonolo-gist. Primary tumor control was excellent; at 3 years, 97.6% were deemed to have primary tumor control by the authors, and 90.6% had local control. However, it is important to note that primary tumor failure was defined specifically as at least a 20% increase in the longest diam-eter of the gross tumor volume by CT scan and evidence of tumor viability either by biopsy confirming carcinoma or by demonstration of FDG avidity on PET scan. For viability to be confirmed with PET scan, the uptake was required to be of similar intensity to the pretreatment staging PET scan. Failure beyond a 1.5to 2-cm margin around the primary tumor volume was considered local failure. Failure in regional node basins was seen in two patients. When compared to locoregional control rates of approximately 6.5% with limited resection, the 3-year locoregional recurrence was higher at 12.8%.3. Patient selection for stereotactic body radiotherapy, as with limited resection and radiofrequency ablation, is impor-tant. Because the radiation field is so precise, patients with severe emphysema and chronic obstructive pulmonary dis-ease can be safely treated without significant concern for worsening lung function. However, patients with central tumors near the mediastinum and hilum have increased incidence of significant hypoxia, hemoptysis, atelecta-sis, pneumonitis, and reduced pulmonary function.70 In the multicenter trial detailed earlier, treated tumors were required to be greater than 2 cm from the proximal bron-chial tree in all directions (which they defined as the distal 2 cm of the trachea, carina, and named major lobar bronchi up to their first bifurcation).62Rationale for Chemotherapy in the Management of Early-Stage NSCLC. The role of chemotherapy in early-stage (stages I and II) NSCLC is evolving, with several pro-spective phase 2 studies having shown a potential benefit.71,72 Initial concerns that induction chemotherapy may result in increased perioperative morbidity or mortality appear to be unwarranted, as the incidence of perioperative morbidity and mortality is not different between the two groups, except in patients undergoing right-sided pneumonectomy after induc-tion chemotherapy.73 As shown in Table 19-14, an absolute survival benefit of 4% to 7% can be realized using induction for all stages of lung cancer, and in situations where use of adjuvant chemotherapy is anticipated, induction chemother-apy is an acceptable alternative.Table 19-14Five-year stage-specific survival after induction chemotherapy followed by surgerySTAGE5-YEAR SURVIVAL (%)ABSOLUTE BENEFIT (%)NEW 5-YEAR SURVIVAL (%)IA75479IB55661IIA50757IIB40747IIIA15–356–721–42IIIB5–103–58–15Reproduced with permission from Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer, Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006157.National Comprehensive Cancer Network guidelines cur-rently recommend observation for T1a (≤1 cm), T1b (>1–2 cm), and T1c (>2–3 cm), node-negative, completely resected NSCLCs (T1abcN0M0). For patients with larger tumors (T2a tumor >3–4 cm; T2b tumor >4–5 cm) that are node-negative, it is recommended that chemotherapy be considered in high-risk patients, ideally in the setting of a clinical trial. High-risk tumor characteristics include poorly differentiated tumors, moderately to poorly differentiated lung neuroendocrine tumors, vascular invasion, resection limited to wedge resection only, tumors >4 cm in size, visceral pleural involvement, and when lymph node sampling at the time of resection was incomplete (Nx).Evaluation and Management of Locally Advanced NSCLC. Five-year relative survival in patients with locore-gional disease is 28%, but there is significant heterogeneity within the group. Stage III disease includes patients with small tumors that have metastasized to the mediastinal lymph nodes as well as large tumors (>7 cm), and tumor invading unresectable structures or the major carina with no nodal metastasis at all. Patients with clinically evident N2 disease (i.e., bulky adenopa-thy present on CT scan or mediastinoscopy, with lymph nodes often replaced by tumor) have a 5-year survival rate of 5% to 10% with surgery alone. In contrast, patients with microscopic N2 disease discovered incidentally in one lymph node station after surgical resection have a 5-year survival rate that may be as high as 30%. As a result, many surgeons and oncologists dif-ferentiate between microscopic and bulky N2 lymphadenopathy and the number of involved N2 nodal stations in determining whether to proceed with resection following induction therapy. It is generally accepted that surgical resection is appropriate for patients with a single-station metastasis with a single lymph node smaller than 3 cm, although randomized trials specifically investigating resection following induction therapy for patients with single-station microscopic disease have not yet been performed.Histologic confirmation of N2 nodal metastases is impera-tive; false-positive findings on PET scan are unacceptably high, and reliance on this modality will lead to significant undertreat-ment of patients with earlier stage cancers. This is particularly true in regions with high incidence of granulomatous diseases. Brunicardi_Ch19_p0661-p0750.indd 69701/03/19 7:01 PM 698SPECIFIC CONSIDERATIONSPART IIWhen N2 nodes are found, incidentally, to harbor metastasis at the time of planned anatomic lung resection, the decision to proceed with resection varies depending on surgeon preference; it is acceptable to either proceed with anatomic resection and mediastinal lymph node sampling/dissection or to stop the pro-cedure, refer the patient for induction therapy, and reevaluate for resection after induction therapy is completed.When histologically confirmed metastases are found dur-ing preoperative staging evaluation, patients should be referred for induction chemotherapy; patients in whom the mediastinal nodes are sterilized by induction therapy have a better prognosis, and surgical resection is generally warranted as part of a mul-timodal approach. As with preinduction evaluation, histologic confirmation of persistent N2 disease after induction therapy is imperative; patients should not be denied surgical resection fol-lowing induction chemotherapy based on radiographic evidence for N2 disease because the survival for resected NSCLC is sig-nificantly better than with definitive chemotherapy.Surgery in T4 and Stage IV Disease Surgery is occasion-ally appropriate for highly selected patients with tumors invad-ing the SVC, carinal or vertebral body involvement, or satellite nodules in the same lobe (T3, N0-1, M0) or in T4, N0-1 tumors with limited invasion into the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, diaphragm or carina through direct extension. Surgery gener-ally does not have a role in the care of patients with any tumor with N3 disease or T4 tumors with N2 disease. Survival rates remain extremely low for these patients. Similarly, the treat-ment of patients with stage IV disease is chemotherapy. How-ever, on occasion, patients with a single site of metastasis are encountered, particularly with adenocarcinomas presenting with a solitary brain metastasis. In this highly select group, 5-year survival rates of 10% to 15% can be achieved with surgical exci-sion of the brain metastasis and the primary tumor, assuming it is early stage.Surgery for Management of Pancoast’s Tumor Carcinoma arising in the extreme apex of the chest with associated arm and shoulder pain, atrophy of the muscles of the hand, and Horner’s syndrome presents a unique challenge to the surgeon. Any tumor of the superior sulcus, including tumors without evi-dence for involvement of the neurovascular bundle, is now com-monly known as Pancoast’s tumors, after Henry Pancoast who described the syndrome in 1932. The designation is reserved for tumors involving the parietal pleura or deeper structures overly-ing the first rib. Chest wall involvement at or below the second rib is not a Pancoast’s tumor.74 Treatment is multidisciplinary; due to the location of the tumor and involvement of the neu-rovascular bundle that supplies the ipsilateral extremity, pre-serving postoperative function of the extremity is critical. For this reason, resection should only be performed in patients who are proven negative for mediastinal lymph node involvement. Survival with N2 positive nodes is poor, and the morbidity and mortality associated with surgical resection are high. If bulky lymphadenopathy is present, EBUSor EUS-guided FNA may prove nodal involvement. However, a negative FNA is not suf-ficient for proving the absence of mediastinal involvement and should be followed by mediastinoscopy to ensure accurate and complete evaluation of the mediastinum.Because Pancoast’s tumors have high rates of local recur-rence and incomplete resection, induction chemoradiotherapy fol-lowed by surgery is recommended. This treatment regimen was well tolerated in a study performed by the Southwest Oncology Group, with 95% of patients completing induction treatment. Com-plete resection was achieved in 76%. Five-year survival was 44% overall and 54% when complete resection was achieved. Disease progression with this regimen was predominantly at distant sites, with the brain being the most common.75 The current treatment algorithm for Pancoast’s tumors is presented in Fig. 19-25.Surgical excision is performed via thoracotomy with en bloc resection of the chest wall and vascular structures and ana-tomic lobectomy. A portion of the lower trunk of the brachial plexus and the stellate ganglion are also typically resected. With chest wall involvement, en bloc chest wall resection, along with lobectomy, is performed, with or without chest wall reconstruction.For small rib resections or those posterior to the scapula, chest wall reconstruction is usually unnecessary. Larger defects (two rib segments or more) are usually reconstructed with Gore-Tex to provide chest wall contour and stability. En bloc resection is also used for other locally advanced tumors (T3) with direct invasion of the adjacent chest wall, diaphragm, or pericardium. If a large portion of the pericardium is removed, reconstruction with thin Gore-Tex membrane will be required to prevent cardiac herniation and venous obstruction.Preoperative (Induction) Chemotherapy for NSCLC The use of chemotherapy before anatomic surgical resection has a number of potential advantages:1. The tumor’s blood supply is still intact, allowing better chemotherapy delivery and avoiding tumor cell hypoxia (in any residual microscopic tumor remaining postoperatively), which would increase radioresistance.2. The primary tumor may be downstaged, enhancing resectability.3. Patients are better able to tolerate chemotherapy before sur-gery and are more likely to complete the prescribed regimen than after surgery.4. It functions as an in vivo test of the primary tumor’s sensi-tivity to chemotherapy.5. Response to chemotherapy can be monitored and used to guide decisions about additional therapy.6. Systemic micrometastases are treated.7. It identifies patients with progressive disease/nonresponders and spares them a pulmonary resection.Potential disadvantages include:1. There is a possible increase in the perioperative complica-tion rate in patients requiring right pneumonectomy after induction chemotherapy.2. While the patient is receiving chemotherapy, potentially curative resection is delayed; if the patient does not respond, this delay could result in tumor spread.In stage IIIA N2 disease, the response rates to induction chemotherapy are high, in the range of 70%. The treatment is generally safe, as it does not cause a significant increase in peri-operative morbidity. Two randomized trials have now compared surgery alone for patients with N2 disease to preoperative che-motherapy followed by surgery. Both trials were stopped before complete accrual because of a significant increase in survival for the chemotherapy arm.The initially observed survival differences have been maintained for up to 3 years and beyond (5-year data not shown). Given these results, induction chemotherapy with Brunicardi_Ch19_p0661-p0750.indd 69801/03/19 7:01 PM

CHAPTER 19699CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAConfirm T3–4, N0-1 M0 NSCLCNo evidence for metastatic or N2 nodal diseaseTumor progression orpoor performance statusDefinitivechemoradiotherapyMetastatic disease or N2nodal diseaseConcurrent induction chemotherapy (Cisplatin/Etoposide)And radiotherapy: 45 Gy over 5 weeksCT chest/upper abdomenMRI/MRA of vessels/brachialplexusMediastinoscopyBrain CT or MRI andPET scanReassessment performance score, physiologic reserve,tumor responseRadiographic evaluation: CT scans of thechest, upper abdomen, and brain. PET scan for metastasesAdditional chemotherapyas toleratedAssess performance status:performance score, cardiopulmonary reserve,renal function and neurologic functionInitial evaluation, biopsy and stagingThoracotomy, en bloc chest wall resection, lobectomy, chest wall with reconstructionTumor stable/regression; good toexcellent performance statusPoor performance statusGood to excellent performance statusFigure 19-25. Treatment algo-rithm for Pancoast’s tumors. CT = computed tomography; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; NSCLC = non–small cell lung cancer; PET = positron emission tomography.cisplatin-based regimen (two to three cycles) has become stan-dard for patients with N2 disease. Table 19-15 summarizes the findings of a systematic review and meta-analysis reporting response rates, progression-free survival, and overall survival after induction chemotherapy followed by surgical resection.Postoperative (Adjuvant) Chemotherapy for NSCLC Post-operative adjuvant chemotherapy was previously thought to confer no benefit based on multiple prospective randomized tri-als, in part because patients who had undergone thoracotomy and lung resection had difficulty tolerating the adjuvant regi-mens. More recently, however, newer, more effective agents have shown promise, and adjuvant therapy is better tolerated after minimally invasive lung resection (i.e., VATS or robotic anatomic resection). Targeted therapies, which have been shown to be beneficial in advanced-stage lung cancer, are of particular interest.Any patient with nodal metastasis (N1 or N2) or with T3 tumors (defined as tumors >5 to ≤7 cm or separate tumor in same lobe or direct invasion of chest wall [includes parietal pleura and superior sulcus]/parietal pericardium/phrenic nerve) should receive adjuvant chemotherapy if they are able to toler-ate the regimen. In the situation where the margins of resec-tion are positive, re-resection is recommended. If not possible, concurrent chemoradiation is recommended for macroscopic residual tumor and sequential chemoradiation for microscopic residual tumor.Definitive Nonsurgical Treatment for NSCLC. Recent advances in targeted therapies have changed the management of advanced NSCLC from a generalized, platinum-based approach to one in which molecular analysis and targeted, personalized therapies are now standard of care. It is now mandatory that the pathologist clearly differentiate between squamous cell carcinoma and adenocarcinoma because the therapeutic options are different and use of bevacizumab, while beneficial in patients with adenocarcinoma, has been found to cause exces-sive pulmonary hemorrhage in patients with squamous histol-ogy. For the surgeon, this requirement translates into a much more aggressive approach to tissue diagnosis. At our institution, the cytopathologist provides onsite rapid assessment of the fine-needle aspirate to determine whether tumor cells are present and confirm that sufficient tumor cells are present to enable molecu-lar testing. This has increased the number of passes performed during an EBUS-guided FNA or during CT-guided aspiration of a pulmonary or intrathoracic lesion; typically, an additional two to three passes are made for cell block material after confirming the presence of tumor cells in the target area. When insufficient cells are obtained for molecular testing, despite having a diag-nosis, additional sampling is warranted; this is mandatory in patients with adenocarcinoma and likely to become necessary for other non–small cell histologic types as advances in targeted therapies become available for clinical use. Acquiring adequate tissue for diagnosis may require mediastinoscopy or VATS; close communication between the oncologist, surgeon, patholo-gist, and patient is needed to ensure that the benefits to the patient clearly outweigh the risks and that results obtained through more aggressive diagnostic measures are needed to direct subsequent care.8Brunicardi_Ch19_p0661-p0750.indd 69901/03/19 7:01 PM 700SPECIFIC CONSIDERATIONSPART IITable 19-15Selected randomized trials of neoadjuvant chemotherapy for stage III non–small cell lung cancerTRIAL (REFERENCE)NO. OF PATIENTS (STAGE III)CHEMOTHERAPYRESPONSE RATE (%)PCR (%)COMPLETE RESECTIONPFSOS5-YEAR SURVIVALRosell et al8560 (60)MitomycinIfosfamideCisplatin60485%12 vs. 5 mo (DFS; P = .006)22 vs. 10 mo (P = .005)16% vs. 0%Roth et al9060 (60)Cyclophosphamide EtoposideCisplatin35NR39% vs. 31%Not reached vs. 9 mo (P = .006)64 vs. 11 mo (P = .008)56% vs. 15%aPass et al9127 (27)EtoposideCisplatin62885% vs. 86%12.7 vs. 5.8 mo (P = .083)28.7 vs. 15.6 mo (P = .095)NRNagai et al9262 (62)CisplatinVindesine28065% vs. 77%NR17 vs. 16 mo (P = .5274)10% vs. 22%Gilligan et al93519 (80)Platinum basedb49482% vs. 80%NR54 vs. 55 mo (P = .86)44% vs. 45%Depierre et al94355 (167)MitomycinIfosfamideCisplatin641192% vs. 86%26.7 vs. 12.9 mo (P = .033)37 vs. 26 mo (P = .15)43.9% vs. 35.3%cPisters et al95354 (113)dCarboplatinPaclitaxel41NR94% vs. 89%33 vs. 21 mo (P = .07)75 vs. 46 mo (P = .19)50% vs. 43%Sorensen et al9690 (NR)PaclitaxelCarboplatin46079% vs. 70%NR34.4 vs. 22.5 mo (NS)36% vs. 24% (NS)Mattson et al97274 (274)Docetaxel28NR77% vs. 76%e9 vs. 7.6 mo (NS)14.8 vs. 12.6 mo (NS)NRa3-year survival.bOptions included MVP (mitomycin C, vindesine, and platinum), MIC (mitomycin, ifosfamide, and cisplatin), NP (cisplatin and vinorelbine), PacCarbo (paclitaxel and carboplatin), GemCis (gemcitabine and cisplatin), and DocCarbo (docetaxel and carboplatin).c4-year survival.d113 patients (32%) were reported to have stage IIB or IIIA disease.e22 patients in the chemotherapy arm and 29 patients in the control arm had resectable disease.Abbreviations: DFS = disease-free survival; NR = not recorded; NS = not significant; OS = overall survival; pCR = pathologic complete response; PFS = progression-free survival.Reproduced with permission from Allen J, Jahanzeb M: Neoadjuvant chemotherapy in stage III NSCLC, J Natl Compr Canc Netw. 2008 Mar;6(3):285-293.Brunicardi_Ch19_p0661-p0750.indd 70001/03/19 7:01 PM

CHAPTER 19701CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAOnce a treatment plan has been devised, two strategies for delivery are available. “Sequential” chemoradiation involves full-dose systemic chemotherapy (i.e., cisplatin combined with a second agent) followed by standard radiotherapy (approxi-mately 60 Gy). The combination of chemotherapy followed by radiation has improved 5-year survival from 6% with radio-therapy alone to 17%.76 An alternative approach, referred to as “concurrent chemoradiation,” administers chemotherapy and radiation at the same time. Certain chemotherapeutic agents sen-sitize tumor cells to radiation and, thus, enhance the radiation effect. The advantages of this approach are improved primary tumor and locoregional lymph node control and elimination of the delay in administering radiotherapy that occurs with sequential treatment. A disadvantage, however, is the necessary reduction in chemotherapy dosage in order to diminish over-lapping toxicities; this can potentially lead to undertreatment of systemic micrometastases. Randomized trials have shown a modest 5-year survival benefit as compared with chemotherapy. In a systematic review of 47 trials and six meta-analyses, an absolute survival benefit of 4% at 2 years was seen when con-current platinum-based chemoradiation was given compared to sequential radiation.77Definitive radiotherapy is predominantly used for pallia-tion of symptoms in patients with poor performance status; cure rates with radiation as a single modality in patients with N2 or N3 disease is less than 7%. Recent improvement has been seen with three-dimensional conformal radiotherapy and altered frac-tionation. Such poor results for patients with stage III lung cancer reflect the limitations of locoregional treatment in a disease where death results from systemic metastatic spread.Options for Thoracic Surgical ApproachesThoracic surgical approaches have changed over recent years with advancements in minimally invasive surgery. A surgeon trained in advanced minimally invasive techniques can now perform pleural-based, pulmonary and mediastinal procedures through multiple thoracoscopic ports without the need for a sub-stantial, rib-spreading incision. Subjective measures of quality of life after VATS, such as pain (Fig. 19-26) and perceived functional recovery, consistently and reproducibly favor VATS OpenVATSNoneMildModerateSeverep<0.001Figure 19-26. Pie chart comparison of pain control at 3 weeks after lobectomy by standard thoracotomy or video-assisted tho-racic surgery (VATS). The pie charts show that patients undergo-ing VATS have significantly less pain (P <.01) as measured by the most potent analgesic still required: severe—schedule II nar-cotic; moderate—schedule III or lower narcotic; mild–nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen. (Reproduced with permission from Demmy TL, Nwoque C. Is video-assisted thoracic surgery lobectomy better? Quality of life considerations, Ann Thorac Surg. 2008 Feb;85(2):S719-S728.)over thoracotomy. Objective measures such as functional sta-tus as measured by 6-minute walk, return to work, and ability to tolerate chemotherapy also favor VATS over thoracotomy. Finally, recovery of respiratory function occurs earlier in VATS patients. These findings are pronounced in patients with chronic obstructive pulmonary disease and in the elderly—populations whose quality of life can be dramatically impacted by changes in their respiratory symptoms and function, thoracic pain, and physical performance. Table 19-16 provides a summary of pop-ulations that may benefit from VATS approaches.Video-Assisted (VATS)/Robotic-Assisted Thoraco-scopic Surgery (RATS). VATS/RATS has become the rec-ommended approach to diagnosis and treatment of pleural effusions, recurrent pneumothoraces, lung biopsies, lobec-tomy or segmental resection, resection of bronchogenic and mediastinal cysts, and intrathoracic esophageal mobilization for esophagectomy.78 These approaches are also utilized for pneumonectomy in some centers of excellence with very high Table 19-16Special circumstances under which lobectomy by video-assisted thoracic surgery may be preferableCONDITIONEXAMPLESPulmonary compromisePoor FEV1/Dlco, heavy smoking, sleep apnea, recent pneumoniaCardiac dysfunctionCongestive heart failure, severe coronary artery disease, recent myocardial infarction, valvular diseaseExtrathoracic malignancySolitary brain metastasis from lung cancer, deep pulmonary metastases requiring lobectomyPoor physical performancePerformance status equivalent to a Zubrod score of 2 or 3, morbid obesityRheumatologic/orthopedic conditionSpinal disease, severe rheumatoid arthritis, severe kyphosis, lupus erythematosus, osteomyelitisAdvanced ageAge >70 yearsVascular problemsAneurysm, severe peripheral vascular diseaseRecent or impending major operationUrgent abdominal operation, joint replacement requiring use of crutches, need for contralateral thoracotomyPsychological/neurologic conditionsSubstance abuse, poor command following, pain syndromesImmunosuppression/ impaired wound healingRecent transplantation, diabetesAbbreviations: Dlco = carbon monoxide diffusion capacity; FEV1 = forced expiratory volume in 1 second.Reproduced with permission from Demmy TL, Nwoque C. Is video-assisted thoracic surgery lobectomy better? Quality of life considerations, Ann Thorac Surg. 2008 Feb;85(2):S719-S728.Brunicardi_Ch19_p0661-p0750.indd 70101/03/19 7:01 PM 702SPECIFIC CONSIDERATIONSPART IIvolumes of VATS lung resection. VATS is performed via two to four incisions measuring 0.5 to 1.2 cm in length to allow insertion of the thoracoscope and instruments. An access incision, typically in the fourth or fifth intercostal space in the anterior axillary line, is used for dissection of the hilum during lung resection. The incision location varies accord-ing to the procedure. With respect to VATS lobectomy, port placement varies according to the lobe being resected and is highly variable among surgeons.79 The basic principle is to position the ports high enough on the thoracic cage to have access to the hilar structures. Endoscopic staplers are used to divide the major vascular structures and bronchus (Fig. 19-27). Robotic approaches are similarly tailored to the side and lobe under-going resection, with the entire operation performed using DissectBADCERetractRetractRetractRetractRetractViewViewViewViewHoldViewDissectFigure 19-27. Selected video-assisted thoracic surgery lobectomy maneuvers. All the maneuvers are shown with the patient positioned in the left lateral decubitus position. The same maneuvers can be performed in mirror image for left-sided work. A. Medial viewing and inferior holding of lung to allow dissection through the access incision. Example shows dissection of the apical hilum. B. Medial viewing and access holding of lung to allow stapling of hilar structures from below. Example shows division of the apical pulmonary artery trunk to the right upper lobe (upper lobe branch of vein divided and reflected away). C. Standard viewing and use of working port to dissect and divide structures while lung is retracted through access incision. Example shows use of stapler to divide pulmonary artery to right lower lobe. D. Standard viewing and use of working port to retract lung and access incision to dissect structures. This method is commonly used to dis-sect the pulmonary artery in the major fissure. Example shows inferior pulmonary vein after the pulmonary ligament was divided using this maneuver. E. Standard viewing and use of access incision to deliver stapler to divide fissures. Example shows division of the posterior fissure between the right lower lobe and the upper lobe.Brunicardi_Ch19_p0661-p0750.indd 70201/03/19 7:01 PM

CHAPTER 19703CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATrapeziusLatissimus dorsidividedLatissimus dorsiBADCSerratus anterior5th rib6th ribRhomboidmajorScapularetractedIncisionTrapeziusrobotic arms, except for one assistant port through which spec-imens can be removed and suctioning and stapling performed (in early models; the newest robotic models have robotic sta-plers, allowing the surgeon to have complete control of the entire operation).Open Approaches to Thoracic Surgery. When a thoraco-scopic approach is not possible, an open approach, most fre-quently the posterolateral thoracotomy, is used to gain access to the intrathoracic space.80,81 The posterolateral thoracotomy incision can be used for most pulmonary resections, esopha-geal operations, and operations in the posterior mediastinum and vertebral column (Fig. 19-28). The anterolateral thora-cotomy has traditionally been used in trauma victims. This approach allows quick entry into the chest with the patient supine. In the face of hemodynamic instability, the lateral decubitus position significantly compromises control over the patient’s cardiopulmonary system and resuscitation efforts, whereas the supine position allows the anesthesiologist full access to the patient. A bilateral anterior thoracotomy incision with a transverse sternotomy (“clamshell” thoracotomy) is a standard operative approach to the heart and mediastinum in certain elective circumstances. It is the preferred incision for double-lung transplantation in many centers. A partial median sternotomy can also be added to an anterior thoracotomy (“trap-door” or “hemiclamshell” thoracotomy) for access to mediastinal structures. A hypesthetic nipple is a frequent com-plication of this approach. The median sternotomy incision allows exposure of anterior mediastinal structures and is prin-cipally used for cardiac operations. Although the surgeon has access to both pleural cavities, incision into the pleural cavity can be avoided if entry is unnecessary (Fig. 19-29).Postoperative CareChest Tube Management. At the conclusion of most thoracic operations, the pleural cavity is drained with a chest tube(s). If the visceral pleura has not been violated and there is no concern Figure 19-28. The posterolateral thoracotomy incision. A. Skin incision from the anterior axillary line to the lower extent of the scapula tip. B and C. Division of the latissimus dorsi and shoulder girdle musculature. D. The pleural cavity is entered after dividing the intercostal muscles along the lower margin of the interspace, taking care not to injure the neurovascular bundle lying below each rib.Brunicardi_Ch19_p0661-p0750.indd 70301/03/19 7:01 PM 704SPECIFIC CONSIDERATIONSPART IIABThymusR. atrialappendageR. ventriclePreperitonealfatDiaphragmL. atrialappendageAortic archInnominate v.Pulmonary a.Figure 19-29. The median sternotomy incision. A. Skin incision from the suprasternal notch to the xiphoid process. B. Exposure of the pleural space. a. = artery; v. = vein.for pneumoor hemothorax (e.g., after VATS sympathectomy), a chest tube is unnecessary. After chest tube placement, the lung is reexpanded with positive-pressure ventilation. There are two reasons for the use of pleural tubes in this setting: first, the tube allows evacuation of air if an air leak is present; sec-ond, blood and pleural fluid can be drained, thereby preventing accumulation within the pleural space that would compromise the patient’s respiratory status. The tube is removed when the air leak is resolved and when the volume of drainage decreases below an acceptable level over 24 hours.Historically, many surgeons have somewhat arbitrarily required less than 150 mL of drainage volume over 24 hours prior to removing a chest tube to minimize risk of reaccu-mulation. The pleural lymphatics, however, can absorb up to 0.40 mL/kg per hour in a healthy individual, which may be as much as 500 mL over a 24-hour period. In fact, studies have shown that pleural tubes can be removed after VATS lobec-tomy or thoracotomy with 24-hour drainage volumes as high as 400 mL, without subsequent development of pleural effusions.82 It is our current practice to remove chest tubes with 24-hour outputs of 400 mL or less after lobectomy or lesser pulmonary resections. In settings where normal pleural fluid dynamics have been altered, such as malignant pleural effusion, pleural space infections or inflammation, and pleurodesis, strict adherence to a volume requirement before tube removal is appropriate (typi-cally 100 to 150 mL over 24 hours).For operations involving lung resection or parenchymal injury, suction levels of –20 cm H2O are routinely used to eradi-cate residual air spaces and to control postoperative parenchy-mal air leaks for the first 12 to 24 hours. The following day, however, the decision to continue suction or place the patient to water seal (off suction) must be made. Applying suction to an air leak has been shown to prolong the duration of the air leak and extend the time frame during which tube thoracostomy is needed.83 The main guidelines for the continued use of suction if an air leak is present depend on the expansion of the remain-ing lung as determined by CXR. If the lung is well expanded, the chest tube can remain to water seal drainage. If an und-rained pneumothorax is present on CXR, the chest tube and its attached tubing should be examined to ensure that the chest tube is patent and the attached tubing is not kinked or mechanically obstructed, such as occurs when the patient is lying on the tube. If the tube is a small caliber tube (pigtail catheter), it should be flushed with sterile saline through a three-way stopcock that has been cleaned with alcohol because these tubes tend to become clogged with fibrin. These catheters are also prone to kinking at the insertion site into the skin. Once the surgeon has con-firmed that the chest tube is patent, the patient is asked to volun-tarily cough or perform the Valsalva maneuver. This maneuver increases the intrathoracic pressure and will push air that is contained within the hemithorax out of the chest tube. During the voluntary cough, the fluid level in the water seal chamber should move up and down with the cough and with deep respira-tion, reflecting the pleural pressure changes occurring with these maneuvers. A stationary fluid level implies either a mechanical blockage (e.g., due to external tube compression or to a clot/debris within the tube) or pleurodesis. If bubbles pass through the water seal chamber, an air leak is presumed. If the leak is significant enough to induce atelectasis or collapse of the lung during use of water seal, suction should be used to achieve lung reexpansion.Pain Control. Good pain control after intrathoracic proce-dures is critical; it permits the patient to actively clear and manage secretions and promotes ambulation and a feeling of well-being. The most common techniques of pain management are epidural, paravertebral, and intravenous. Epidural catheters are commonly used, although we prefer to use paravertebral catheters in our center. Epidural catheters should be inserted at about the T6 level, roughly at the level of the scapular tip. Lower placement risks inadequate pain control, and higher placement may provoke hand and arm numbness. Typically, combinations of fentanyl at 0.3 µg/mL with either bupivacaine (0.125%) or ropivacaine (0.1%) are used. Ropivacaine has less cardiotoxicity than bupivacaine; thus, in the case of inadver-tent intravenous injection, the potential for refractory complete heart block is significantly less with ropivacaine. Paravertebral blocks can be placed using the same epidural catheter kit 2.5 cm lateral to the spinous process at T4 to T6. Combinations of narcotic and topical analgesia are then infused as with the epi-dural catheter.When properly placed, a well-managed epidural can provide outstanding pain control without significant systemic sedation.84 Thoracic epidurals do not commonly cause urinary retention, although a low thoracic epidural may block the sen-sory fibers to the bladder. Motor function, however, remains intact. In some patients who are having difficulty voiding, it Brunicardi_Ch19_p0661-p0750.indd 70401/03/19 7:01 PM

CHAPTER 19705CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAmay be possible to avoid Foley catheterization by simply reminding the patient to void on a regular basis. In male patients with voiding difficulty prior to surgery, urinary catheterization may be required. In addition, the use of local anesthetics may cause sympathetic outflow blockade, leading to vasodilation and hypotension often requiring intravenous vasoconstrictors (an α-agonist such as phenylephrine) and/or fluid administration. In such circumstances, fluid administration for hypotension may be undesirable in pulmonary surgery patients, particularly after pneumonectomy. Paravertebral catheters provide equivalent pain control with less effect on hemodynamics.85 Recently, lipo-somal bupivacaine was introduced and has become the standard approach to pain management after thoracic surgery in several centers. The formulation allows for slow-release of bupivacaine for up to 72 hours after injection. Injected directly into the inter-costal spaces immediately prior to chest closure, the formulation has shown great promise in several retrospective reports, with randomized trials not yet completed. One limiting factor in use of the formulation is the cost; future trials are needed, with cost-analysis, to determine whether the benefits in pain, reduction in narcotic use, shorter hospital stay and possibly decreased pul-monary complications justify the cost.Alternatively, intravenous narcotics via patient-controlled analgesia can be used, often in conjunction with ketorolac, gabapentin, and intravenous Tylenol. Dosing must be titrated to balance the degree of pain relief with the degree of seda-tion. Oversedated patients are as ominous as patients without adequate pain control because of the significant risk of secre-tion retention, atelectasis/pneumonia, and pulmonary aspiration, especially in elderly patients who should be carefully assessed for aspiration risk when ordered for dietary advancement. Proper pain control with intravenous narcotics requires a care-fully regulated balance of pain relief and sedation to maximize the benefits of pain control while minimizing these very real and potentially life-threatening complications.Whether on epidural, paravertebral, or intravenous pain control, the patient is typically transitioned to oral pain medica-tion on the third or fourth postoperative day. During both the parenteral and oral phase of pain management, a standardized regimen of stool softeners and laxatives is advisable in order to prevent severe constipation.Respiratory Care. The best respiratory care is achieved when the patient is able to deliver an effective cough to clear secre-tions and results from the commitment and proper training of all involved healthcare providers. The process begins preopera-tively, with clear instructions on using pillows (or other support techniques) over the wound and then applying pressure.Postoperatively, proper pain control without oversedation (as outlined earlier) is essential. Daily morning rounds should include a careful assessment of the patient’s pulmonary status, reminders to the patient and family about the importance of coughing and deep breathing, including use of adjunctive respi-ratory equipment if ordered, and mobilization of the patient. Early transition to a chair and to ambulation is the best respira-tory therapy and should be strongly encouraged. When avail-able, physical and/or cardiopulmonary rehabilitation services are vital additional members of the care team.Postoperative ComplicationsPostoperative complications after pulmonary resection range from minor to life-threatening. Strict attention to volume sta-tus, early and aggressive pulmonary toilet, and good pain control can reduce the risk of most complications, but does not completely eliminate them, even in centers of excellence. The most devastating complication after pulmonary resection is postpneumonectomy pulmonary edema, which occurs in 1% to 5% of patients undergoing pneumonectomy and more often after right compared to left pneumonectomy. Clinically, symp-toms of respiratory distress manifest hours to days after sur-gery. Radiographically, diffuse interstitial infiltration or frank alveolar edema is seen. The pathophysiologic causes are related increased permeability and filtration pressure and decreased lymphatic drainage from the affected lung. Judicious use of intravenous fluids perioperatively, including use of vasopres-sors rather than fluid boluses for hypotension intraand post-operatively, is critical to minimizing the risk of this syndrome. Treatment consists of ventilatory support, fluid restriction, and diuretics. Extracorporeal membrane oxygenation may be life-saving in centers where this option is available. The syndrome reportedly has a nearly 100% mortality rate despite aggressive therapy.Other postoperative complications include air leak and bronchopleural fistula. Although these are two very differ-ent problems, distinguishing between them may be difficult. Postoperative air leaks are common after pulmonary resection, particularly in patients with emphysematous lung, because the fibrosis and destroyed blood supply impairs healing of surface injuries. Prolonged air leaks (i.e., those lasting >5 days) may be treated by diminishing or discontinuing suction (if used), by continuing chest drainage, or by instilling a pleurodesis agent, usually doxycycline or talcum powder, which will cause pleurodesis of the lung within the chest cavity and minimize the possible collapse of the lung due to persistent air leak. This is useful only in patients in whom full lung expansion is achieved, either with suction or on water seal, as patients with a persistent pneumothorax on CXR will not have adequate lung-to-parietal pleural apposition to achieve adequate pleurodesis.If the leak is moderate to large, a high index of suspicion for bronchopleural fistula from the resected bronchial stump should be maintained, particularly if the patient is immunocom-promised or had induction chemoand/or radiation therapy. If suspected, flexible bronchoscopy is performed to evaluate the bronchial stump. Management options include continued pro-longed chest tube drainage, reoperation, and reclosure (with stump reinforcement with intercostal or pedicled serratus mus-cle flap). If the fistula is very small (<4 mm), bronchoscopic fibrin glue application has been used successfully to seal the hole in some patients. Patients often have concomitant empy-ema, and open drainage may be necessary.Spontaneous PneumothoraxSpontaneous pneumothorax is secondary to intrinsic abnormali-ties of the lung and can be classified as primary and secondary. Primary spontaneous pneumothorax is defined as a spontaneous pneumothorax without underlying lung disease. The most com-mon cause is rupture of an apical subpleural bleb. The cause of these blebs is unknown, but they occur more frequently in smokers and males, and they tend to predominate in young postadolescent males with a tall thin body habitus. Treatment is generally chest tube insertion with water seal. If a leak is present and persists for greater than 3 days, thoracoscopic man-agement (i.e., bleb resection with pleurodesis by talc or pleural abrasion) is performed. Recurrences or complete lung collapse with the first episode are generally indications for thoracoscopic Brunicardi_Ch19_p0661-p0750.indd 70501/03/19 7:01 PM 706SPECIFIC CONSIDERATIONSPART IIintervention.86 Additional indications for intervention on the first episode include occupational hazards such as air travel, deep-sea diving, or travel to remote locations. CT findings of multiple small bullae or a large bleb are associated with an increased risk of recurrent pneumothorax.87 Many surgeons are now using screening CT scan to recommend VATS bleb resection with pleurodesis for first-episode spontaneous pneumothorax.Secondary spontaneous pneumothorax occurs in the set-ting of underlying lung disease, such as emphysema (rupture of a bleb or bulla), cystic fibrosis, acquired immunodeficiency syndrome (AIDS), metastatic cancer (especially sarcoma), asthma, lung abscess, and occasionally lung cancer. Catame-nial pneumothorax, a rare but interesting cause of spontaneous pneumothorax in women in their second and third decades, occurs within 72 hours of the onset of menses and is possibil-ity related to endometriosis. Management of pneumothorax in these circumstances is similar to that of primary spontane-ous pneumothorax in that drainage and lung reexpansion are required. Additional therapy, however, is often tied to therapy of the specific disease process and may involve lung resection, thoracoscopic pleurectomy, or talc pleurodesis.Pulmonary InfectionsLung Abscess. A lung abscess is a localized area of pulmonary parenchymal necrosis caused by an infectious organism; tissue destruction results in a solitary or dominant cavity measuring at least 2 cm in diameter. Less often, there may be multiple, smaller cavities (<2 cm). In that case, the infection is typically referred to as a necrotizing pneumonia. An abscess that is pres-ent for more than 6 weeks is considered chronic.Based on the etiology (Table 19-17), lung abscesses are further classified as primary or secondary. A primary lung abscess occurs, for example, in immunocompromised patients, as a result of highly virulent organisms inciting a necrotizing pulmonary infection, or in patients who have a predisposition to aspirate oropharyngeal or gastrointestinal secretions. A second-ary lung abscess occurs in patients with an underlying condition such as a partial bronchial obstruction, a lung infarct, or adjacent suppurative infections (subphrenic or hepatic abscesses).88Pathogenesis Lung abscesses result when necrotizing micro-organisms infect the lower respiratory tract via inhalation of aerosolized particles, aspiration of oropharyngeal secretions, or hematogenous spread from distant sites. Direct extension from a contiguous site is less frequent. Most primary lung abscesses are suppurative bacterial infections secondary to aspiration. Risk factors for pulmonary aspiration include advanced age, conditions of impaired consciousness, suppressed cough reflex, dysfunctional esophageal motility, laryngopharygeal reflux disease, and centrally acting neurologic diseases (e.g., stroke). At the time of aspiration, the composition of the oropharyn-geal flora determines the etiologic organisms. With increasing use of proton pump inhibitors to suppress acid secretion in the stomach, the oropharyngeal flora has shifted, and the risk of developing bacterial lung infections after an aspiration event has increased.89 Secondary lung abscesses occur most often distal to an obstructing bronchial carcinoma. Infected cysts or bullae are not considered true abscesses.Microbiology Normal oropharyngeal secretions contain many more Streptococcus species and more anaerobes (approxi-mately 1 × 108 organisms/mL) than aerobes (approximately 1 × 107 organisms/mL). Pneumonia that follows from Table 19-17Causes of lung abscess I. Primary A. Necrotizing pneumonia 1. Staphylococcus aureus, Klebsiella, Pseudomonas, Mycobacterium 2. Bacteroides, Fusobacterium, Actinomyces 3. Entamoeba, Echinococcus B. Aspiration pneumonia 1. Anesthesia 2. Stroke 3. Drugs or alcohol C. Esophageal disease 1. Achalasia, Zenker’s diverticulum, gastroesophageal reflux D. Immunodeficiency 1. Cancer (and chemotherapy) 2. Diabetes 3. Organ transplantation 4. Steroid therapy 5. Malnutrition II. Secondary A. Bronchial obstruction 1. Neoplasm 2. Foreign body B. Systemic sepsis 1. Septic pulmonary emboli 2. Seeding of pulmonary infarct C. Complication of pulmonary trauma 1. Infection of hematoma or contusion 2. Contaminated foreign body or penetrating injury D. Direct extension from extraparenchymal infection 1. Pleural empyema 2. Mediastinal, hepatic, subphrenic abscessAdapted with permission from Schwartz SI, Fischer JE, Daly JM, et al: Principles of Surgery, 7th ed. New York, NY: McGraw-Hill Education; 1999.aspiration, with or without abscess development, is typically polymicrobial. An average of two to four isolates present in large numbers have been cultured from lung abscesses sam-pled percutaneously. Overall, at least 50% of these infections are caused by purely anaerobic bacteria, 25% are caused by mixed aerobes and anaerobes, and 25% or fewer are caused by aerobes only. In nosocomial pneumonia, 60% to 70% of the organisms are gram-negative bacteria. Immunosuppressed patients may develop abscesses because of the usual pathogens as well as less virulent and opportunistic organisms such as Salmonella species, Legionella species, Pneumocystis carinii, atypical mycobacteria, and fungi.Clinical Features and Diagnosis The typical presentation may include productive cough, fever (>38.9°C), chills, leuko-cytosis (>15,000 cells/mm3), weight loss, fatigue, malaise, pleu-ritic chest pain, and dyspnea. Lung abscesses may also present in a more indolent fashion, with weeks to months of cough, mal-aise, weight loss, low-grade fever, night sweats, leukocytosis, and anemia. After aspiration pneumonia, 1 to 2 weeks typically elapse before cavitation occurs; 40% to 75% of such patients produce putrid, foul-smelling sputum. Severe complications Brunicardi_Ch19_p0661-p0750.indd 70601/03/19 7:01 PM

CHAPTER 19707CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAABCFigure 19-30. Lung abscess resulting from emesis and aspi-ration after an alcoholic binge. A. Chest X-ray showing an abscess cavity in the left upper lobe. B. A coronal tomogram highlights the thin wall of the abscess. C. Healing of the abscess cavity after 4 weeks of antibiotic therapy and pos-tural drainage.such as massive hemoptysis, endobronchial spread to other portions of the lungs, rupture into the pleural space and devel-opment of pyopneumothorax, or septic shock and respiratory failure are rare in the modern antibiotic era. The mortality rate is about 5% to 10%, except in the presence of immunosuppres-sion, where rates range from 9% to 28%.The CXR is the primary tool for diagnosing a lung abscess (Fig. 19-30). Its distinguishing characteristic is a density or mass with a relatively thin-walled cavity. An air-fluid level observed within the abscess indicates communication with the tracheobronchial tree. CT scan of the chest clarifies the diag-nosis when CXR is equivocal and identifies endobronchial obstruction and/or an associated mass and other pathologic anomalies. A cavitating lung carcinoma is frequently mistaken for a lung abscess. Differential diagnosis also includes loculated or interlobar empyema, infected lung cysts or bullae, tuberculo-sis, bronchiectasis, fungal infections, and noninfectious inflam-matory conditions (e.g., Wegener’s granulomatosis).Ideally, the specific etiologic organism is identified before antibiotic administration. Bronchoscopy, which is essential to Brunicardi_Ch19_p0661-p0750.indd 70701/03/19 7:01 PM 708SPECIFIC CONSIDERATIONSPART IIrule out endobronchial obstruction due to tumor or foreign body, is ideal for obtaining uncontaminated cultures using bronchoal-veolar lavage. Culture samples can also be obtained by percu-taneous, transthoracic FNA under ultrasound or CT guidance. Routine sputum cultures are often of limited usefulness because of contamination with upper respiratory tract flora.Actinomycosis and nocardiosis, although rare, are particu-larly virulent infections associated with lung abscess. Diagnosis can be difficult.90 Both frequently masquerade as other clinical syndromes; thus, it is important for the surgeon to keep these bacteria in mind when considering the differential diagnosis for cavitary lung lesions. Actinomyces, a normal oropharyngeal bacterium, causes extensive pulmonary damage. Actinomyco-sis lung infection typically begins as acute pneumonitis after pulmonary aspiration. The symptoms mimic pulmonary tuber-culosis, including chronic cough, night sweats, weight loss, and hemoptysis.Ongoing infection leads to chronic inflammation and fibrosis; cavitation occurs due to destruction of the pulmonary tissues. Without treatment, the infection continues to destroy surrounding structures, resulting in fistula formation to adja-cent structures, including the adjacent lung, interlobar fissures, pleural space, chest wall, and mediastinum. Actinomyces israelii is the most common of the species to cause disease. Nocardi-osis is also a rare opportunistic infection that usually occurs in an immunocompromised host (HIV or cancer patients) and causes both local and systemic suppurative infections. The most common site is pulmonary, caused by Nocardia asteroides in 90% of cases. Infection is slowly progressive, with weight loss, fatigue, cough, and hemoptysis. An acute pulmonary infec-tion is common, with necrotizing pneumonia and cavitation or slowly enlarging pulmonary nodule. In some cases, empyema also develops.Management of Lung Abscess Systemic antibiotics directed against the causative organism represent the mainstay of therapy. The duration of antimicrobial therapy varies from 3 to 12 weeks for necrotizing pneumonia and lung abscess. It is likely best to treat until the cavity is resolved or until serial radiographs show significant improvement. Parenteral therapy is generally used until the patient is afebrile and able to demonstrate consistent enteral intake. Oral therapy can then be used to complete the course of therapy. For community-acquired infections second-ary to aspiration, likely pathogens are oropharyngeal streptococci and anaerobes. Penicillin G, ampicillin, and amoxicillin are the main therapeutic agents, but a β-lactamase inhibitor or metro-nidazole should be added to cover the increasing prevalence of gram-negative anaerobes that produce β-lactamase. Clindamycin is also a primary therapeutic agent. For hospital-acquired infec-tions, Staphylococcus aureus and aerobic gram-negative bacilli are common organisms of the oropharyngeal flora. Piperacillin with a β-lactamase inhibitor (or equivalent alternatives) provide better coverage of likely pathogens.Surgical drainage of lung abscesses is uncommon since drainage usually occurs spontaneously via the tracheobron-chial tree. Indications for intervention are listed in Table 19-18. Drainage and resection may be required for actinomycosis and nocardiosis; diagnosis is often delayed because the bacteria are difficult to culture; invasion of the infection into surrounding structures is, therefore, common. Once identified, long-term antibiotics (months to years) are typically required along with drainage, debridement, and resection as needed. While penicil-lin derivatives are effective against most Actinomyces species, the infections are typically polymicrobial, and broad-spectrum parenteral antibiotics may be required. Nocardia species, in contrast, are highly variable; specific identification of the infect-ing species with antibiotic sensitivities is needed to direct appro-priate therapy. Evaluation for malignant spread, particularly to the brain, is also required in the management of nocardiosis, as systemic dissemination occurs early and frequently.External drainage may be accomplished with tube tho-racostomy, percutaneous drainage, or surgical cavernostomy. The choice between tube thoracostomy versus radiographically guided catheter placement depends on the treating physician’s preference and institutional technical expertise in placing image-guided thoracostomy tubes. Surgical resection is required in fewer than 10% of lung abscess patients. Lobectomy is the preferred intervention for bleeding from a lung abscess or pyo-pneumothorax. An important intraoperative consideration is to protect the contralateral lung with a double-lumen tube, bron-chial blocker, or contralateral main stem intubation. Surgical treatment has a 90% success rate, with associated mortality of 1% to 13%.Bronchiectasis. Bronchiectasis is defined as a pathologic and permanent dilation of bronchi with bronchial wall thickening. This condition may be localized to certain bronchial segments, or it may be diffuse throughout the bronchial tree, typically affecting the medium-sized airways. Overall, this is a rare clini-cal entity in the United States with a prevalence of less than 1 in 10,000, although the incidence has increased in recent years and noncystic fibrosis–related bronchiectasis is now thought to affect 27.5 out of every 10,000 persons over age 75.Pathogenesis Development of bronchiectasis can be attributed to either congenital or acquired causes. The principal congeni-tal diseases that lead to bronchiectasis include cystic fibrosis, primary ciliary dyskinesia, and immunoglobulin deficiencies (e.g., selective IgA deficiency). Congenital causes commonly produce a diffuse pattern of bronchial involvement. Acquired causes are categorized broadly as infectious and inflammatory. Bronchial obstruction from cancer, inhaled objects, extrinsic airway compression, or inspissated sputum promotes localized infection and subsequent medium airway destruction. Diffuse pneumonic processes from pathogens including necrotizing bacterial pneumonia, pertussis and measles pneumonia, severe influenza, or varicella pneumonia can lead to widespread bron-chiectasis. Chronic granulomatous disease, immunodeficiency disorders, and hypersensitivity disorders can also lead to diffuse bronchiectasis.Noninfectious causes of bronchiectasis include inhala-tion of toxic gases such as ammonia, which results in severe Table 19-18Indications for surgical drainage procedures for lung abscesses 1. Failure of medical therapy 2. Abscess under tension 3. Abscess increasing in size during appropriate treatment 4. Contralateral lung contamination 5. Abscess >4–6 cm in diameter 6. Necrotizing infection with multiple abscesses, hemoptysis, abscess rupture, or pyopneumothorax 7. Inability to exclude a cavitating carcinomaBrunicardi_Ch19_p0661-p0750.indd 70801/03/19 7:01 PM

CHAPTER 19709CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAFigure 19-31. Multiple cystic-type bronchiectatic cavities can be seen on a cut section of right lower lobe lung.and destructive airway inflammatory responses. Allergic bronchopulmonary aspergillosis, Sjögren’s syndrome, and α1-antitrypsin deficiency are some additional examples of presumed immunologic disorders that may be accompanied by bronchiectasis.In addition, recent studies have suggested an association between chronic gastroesophageal reflux disease, acid sup-pression, and nontuberculous mycobacterial infection with bronchiectasis.91,92 This interaction is thought to be related to chronic aspiration of colonized gastric secretions in the setting of acid suppression; while not proven to be causative, these findings suggest a role for gastroesophageal reflux dis-ease in the pathogenesis of bronchiectasis. The process shared by all causes of bronchiectasis is impairment of airway defenses or deficits in immunologic mechanisms, which permit bacterial colonization and chronic infection. Common organisms include Haemophilus species (55%), Pseudomonas species (26%), and Streptococcus pneu-moniae (12%).93 Both the bacterial organisms and the inflamma-tory cells recruited to thwart the bacteria elaborate proteolytic and oxidative molecules, which progressively destroy the mus-cular and elastic components of the airway walls; those compo-nents are then replaced by fibrous tissue. Thus, chronic airway inflammation is the essential pathologic feature of bronchiec-tasis. The dilated airways are usually filled with thick purulent material; more distal airways are often occluded by secretions or obliterated by fibrous tissue. Bronchial wall vascularity increases, bronchial arteries become hypertrophied, and abnor-mal anastomoses form between the bronchial and pulmonary arterial circulation.There are three principal types of bronchiectasis, based on pathologic morphology: cylindrical—uniformly dilated bronchi; varicose—an irregular or beaded pattern of dilated bronchi; and saccular (cystic)—peripheral balloon-type bronchial dilation. The saccular type is the most common after bronchial obstruc-tion or infection (Fig. 19-31).Clinical Manifestations and Diagnosis Typical symptoms are a daily persistent cough and purulent sputum production; the quantity of daily sputum production (10 mL to >150 mL) corre-lates with disease extent and severity. Other patients may appear asymptomatic or have a dry nonproductive cough (“dry bronchi-ectasis”). These patients are prone to have involvement of the upper lobes. The clinical course is characterized by progressive 9symptoms and respiratory impairment. Increasing resting and exertional dyspnea are the result of progressive airway obstruc-tion. Acute exacerbations may be triggered by viral or bacterial pathogens. Bleeding attributable to chronically inflamed, friable airway mucosa causes increasingly more frequent hemoptysis with disease progression. Massive bleeding may result from ero-sion of the hypertrophied bronchial arteries.Both mild and severe forms of bronchiectasis are read-ily demonstrated with chest CT scanning because it provides a highly detailed, cross-sectional view of bronchial architecture. CXRs, although less sensitive, may reveal characteristic signs of bronchiectasis such as lung hyperinflation, bronchiectatic cysts, and dilated, thick-walled bronchi forming train track–like pat-terns radiating from the lung hila. Sputum culture may identify characteristic pathogens.Sputum acid-fast bacillus smears/cultures should be performed to evaluate for nontuberculous mycobacteria, which is common in this setting. Spirometry provides assessment of the severity of airway obstruction and can be followed to track the course of disease. Management of Bronchiectasis Standard therapy includes optimizing airway clearance, use of bronchodilators to reverse any airflow limitation, and correction of reversible underly-ing causes whenever possible.94 Chest physiotherapy based on vibration, percussion, and postural drainage is widely accepted, although randomized trials demonstrating efficacy are lacking. Acute exacerbations should be treated with a 2to 3-week course of broad-spectrum intravenous antibiotics tailored to culture and sensitivity profiles, followed by an oral regimen; this will result in a longer-lasting remission.Macrolide antibiotics have been shown to decrease sputum production, inhibit cytokine release, and inhibit neutrophil adhe-sion and formation of reactive oxygen species. They also inhibit migration of Pseudomonas, disrupt biofilm, and prevent release of virulence factors.95 While macrolide therapy does appear to be efficacious, it is important to remember that macrolides have sig-nificant activity against nontuberculous mycobacteria, and wide-spread prophylactic use for patients with bronchiectasis may lead to multidrug-resistant nontuberculous mycobacterial species. It has also been suggested that inhaled antibiotics, such as tobramy-cin and colistin, improve rates of bacterial clearance and slow the decline in pulmonary function associated with bronchiectasis. Meta-analysis of 12 randomized trials involving 1154 patients showed efficacy of inhaled antibiotics compared to controls, but did not reduce risk of acute exacerbation. Quality of life, like-wise, was not improved and antibiotic-resistant Pseudomonas rates were similar. Importantly, inhaled antibiotics were associ-ated with a statistically significant reduction in forced expiratory volume in 1 second measures over time.96,97In addition to antibiotics, daily nebulized hypertonic saline appears to be effective. A recent randomized crossover study comparing lung function and quality of life has shown that 7% normal saline, compared to isotonic saline, results in a statisti-cally significant 15% increase in FEV1 and an 11% increase in forced vital capacity (compared to 1.8% and 0.7%, respec-tively, with isotonic saline). Antibiotic use and emergency room utilization were significantly decreased; from this, hypertonic saline appears to be a reasonable adjunct to maintaining quality of life and decreasing exacerbations by reducing sputum vol-ume, improving mucociliary clearance, and slowing the decline in lung function.98 Studies supporting mucolytics such as DNase and Mucomyst for non–cystic fibrosis bronchiectasis have Brunicardi_Ch19_p0661-p0750.indd 70901/03/19 7:01 PM 710SPECIFIC CONSIDERATIONSPART IIshown either no change or a worsening of pulmonary status and require further study in the non–cystic fibrosis population.Surgical resection of a localized bronchiectatic segment or lobe, preserving as much functional lung as possible, may bene-fit patients with refractory symptoms while on maximal medical therapy. Multifocal disease must be excluded before any attempt at surgery; any uncorrectable predisposing factor (e.g., ciliary dyskinesia) must also be excluded. Patients with end-stage lung disease from bronchiectasis may be potential candidates for a bilateral lung transplant. Surgical resection is also indicated in patients with significant hemoptysis, although bronchial artery embolization is the preferred first option. Antireflux surgery may also prove beneficial in patients with chronic aspiration, but further studies are required. It is particularly important to recognize that antireflux surgery in patients with severe under-lying pulmonary dysfunction has higher risk for perioperative adverse outcomes than in the general population. It should be undertaken only by very experienced surgeons with direct involvement of the pulmonary medicine physicians to minimize postoperative pulmonary compromise.Mycobacterial Infections Epidemiology Tuberculosis is a widespread problem that affects nearly one-third of the world’s population. It is the ninth lead-ing cause of death worldwide and the leading infectious cause of death. The rate of death from tuberculosis has declined, from 1.7 million in 2000 to 1.3 million among HIV-negative people in 2016. There were 6.3 million new cases of tubercu-losis worldwide in 2016 according to the World Health Orga-nization (WHO); 56% are in the countries of India, Indonesia, China, the Philippines, and Pakistan. Treatment success rate was 83%. Only 9257 new cases were reported to the WHO in the United States in 2016. HIV infection is the strongest risk fac-tor for developing active tuberculosis. The elderly, minorities, and recent immigrants are the most common populations to have clinical manifestations of infection, yet no age group, sex, or race is exempt from infection. In most large urban centers, reported cases of tuberculosis are more numerous among the homeless, prisoners, and drug-addicted populations. Immunocompromised patients additionally contribute to an increased incidence of tuber-culosis infection, often developing unusual systemic as well as pulmonary manifestations.99 As compared with past decades, presently surgical intervention is required more frequently in patients with multidrug-resistant or rifampicin-resistant (but isoniazid-susceptible) tuberculosis organisms (MDR/RR-TB) who do not respond to medical treatment and in selected patients with nontuberculous mycobacterial infections (NTM).Microbiology Mycobacterial species are obligate aerobes. They are primarily intracellular parasites with slow rates of growth. Their defining characteristic is the property of acid-fastness, which is the ability to withstand decolorization by an acidalcohol mixture after being stained. Mycobacterium tuberculosis is the highly virulent bacillus of this species that produces invasive infection among humans, principally pulmonary tuberculosis.100 Infections with M tuberculosis are primary when they are the first infection in a previously unsensitized host and secondary or postprimary when reactivation of a previous infection occurs.Because of improper application of antimycobacterial drugs and multifactorial interactions, MDR-TB organisms, defined by their resistance to at least two of the first-line anti-mycobacterial drugs (isoniazid and rifampin), and rifampicin-resistant (but isoniazid-susceptible) (RR-TB), have emerged. According to the WHO Global Tuberculosis Report 2017, in 2014, there were 108 reported cases of TB from MDR/RR-TB organisms, with 78% of cases successfully treated. In addition, there is another rare variant termed extensively drug-resistant tuberculosis (XDR-TB). These organisms are resistant to iso-niazid and rifampin and have also developed resistance to either fluoroquinolones and injectable second-line drugs (e.g., capreomycin, amikacin, kanamycin), the two other classes of medications in the MDR-TB treatment regimen. In 2014, there were 109,680 MDRTB cases globally, with 6777 (6.2%) extensively drug resistant. Successful treatment was achieved in 54% of MDRTB and only 30% of XDR-TB. In 2016, it was estimated that MDR/RR was the responsible organism for more than 4% of new cases and nearly 20% of previously treated cases.The more important NTM organisms include Mycobacte-rium kansasii, M avium and M intracellulare complex (MAC), and M fortuitum. The highest incidence of M kansasii infection is in Midwestern U.S. cities among middle-aged men from good socioeconomic surroundings. MAC organisms are important infections in elderly and immunocompromised patient groups. M fortuitum infections are common complications of underly-ing severe debilitating disease. None of these organisms are as contagious as M tuberculosis.Pathogenesis and Pathology The main route of transmission is via airborne inhalation of viable mycobacteria. Three stages of primary infection have been described. In the first stage, alveolar macrophages become infected through ingesting the bacilli. In the second stage, from days 7 to 21, the patient typi-cally remains asymptomatic while the bacteria multiply within the infected macrophages. The third stage is characterized by the onset of cell-mediated immunity (CD4+ helper T cells) and delayed-type hypersensitivity. Activated macrophages acquire an increased capacity for bacterial killing. Macrophage death increases, resulting in the formation of a granuloma, the charac-teristic lesion found on pathologic examination.Tuberculous granulomas are composed of blood-derived macrophages, degenerating macrophages or epithelioid cells, and multinucleated giant cells (fused macrophages with nuclei around the periphery; also known as Langerhans cells). The low oxygen content of this environment inhibits macrophage func-tion and bacillary growth, with subsequent central caseation as macrophage death occurs. A Ghon complex is a single, small lung lesion that is often the only remaining trace of a primary infection. The primary infection is usually located in the periph-eral portion of the middle zone of the lungs.Reactivation tuberculosis may occur after hydrolytic enzymes liquefy the caseum. Typically, the apical and posterior segments of the upper lobes and the superior segments of the lower lobes are involved. Edema, hemorrhage, and mononuclear cell infiltration are also present. The tuberculous cavity may become secondarily infected with other bacteria, fungi, or yeasts, all of which may con-tribute to enhanced tissue destruction.The pathologic changes caused by NTM organisms are similar to those produced by M tuberculosis. M intracellulare complex infections commonly occur, not only in immunocom-promised patients but also in patients with previously damaged lungs. Caseous necrosis is uncommon and is characterized by clusters of tissue macrophages filled with mycobacteria. It has a poor granulomatous response and confinement of immune cell infiltration to the interstitium and alveolar walls. Cavitary dis-ease is infrequent, although nodules may be noted.Brunicardi_Ch19_p0661-p0750.indd 71001/03/19 7:01 PM

CHAPTER 19711CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAClinical Presentation and Diagnosis The clinical course of infection and the presentation of symptoms are influenced by many factors, including the site of primary infection, the stage of disease, and the degree of cell-mediated immunity. About 80% to 90% of tuberculosis patients present with clinical dis-ease in the lungs. In 85% to 90% of these patients, involution and healing occur, leading to a dormant phase that may last a lifetime. The only evidence of tuberculosis infection may be a positive skin reaction to tuberculin challenge or a Ghon com-plex observed on CXR. Within the first 2 years of primary infec-tion, reactivation may occur in up to 10% to 15% of infected patients. In 80%, reactivation occurs in the lungs; other reacti-vation sites include the lymph nodes, pleura, and the musculo-skeletal system.After primary infection, pulmonary tuberculosis is fre-quently asymptomatic. Systemic symptoms of low-grade fever, malaise, and weight loss are subtle and may go unnoticed. A productive cough may develop, usually after tubercle cavita-tion. Many radiographic patterns can be identified at this stage, including local exudative lesions, local fibrotic lesions, cavita-tion, bronchial wall involvement, acute tuberculous pneumonia, bronchiectasis, bronchostenosis, and tuberculous granulomas. Hemoptysis often develops from complications of disease such as bronchiectasis or erosion into vascular malformations associ-ated with cavitation.Extrapulmonary involvement is due to hematogenous or lymphatic spread from pulmonary lesions. Virtually any organ can become infected, giving rise to the protean manifestations of tuberculosis. The pleura, chest wall, and mediastinal organs may all be involved. More than one-third of immunocompro-mised patients have disseminated disease, with hepatomegaly, diarrhea, splenomegaly, and abdominal pain.The definitive diagnosis of tuberculosis requires identi-fication of the mycobacterium in a patient’s bodily fluids or involved tissues. Skin testing using purified protein deriva-tive is important for epidemiologic purposes and can help exclude infection in uncomplicated cases. For pulmonary tuberculosis, sputum examination is inexpensive and has a high diagnostic yield.Bronchoscopy with alveolar lavage may also be a useful diagnostic adjunct and has high diagnostic accuracy. Chest CT scan can delineate the extent of parenchymal disease.Management Medical therapy is the primary treatment of pul-monary tuberculosis and is often initiated before a mycobacte-rial pathogen is definitively identified. Combinations of two or more drugs are routinely used in order to minimize resistance, which inevitably develops with only single-agent therapy. A current treatment algorithm is outlined in Fig. 19-32. Gener-ally, therapy lasts about 26 weeks (2 months intensive therapy followed by 4 months continuation therapy). A 7-month con-tinuation phase should be considered for patients with cavitary pulmonary TB who remain positive on sputum culture after the 2-month intensive therapy, those patients who did not receive pyrazinamide during the intensive phase, HIV-positive patients who did not receive concomitant antiretroviral therapy, and patients treated with INH and rifapentine once weekly (not rec-ommended) who have persistent positive sputum after 2 months of intensive therapy.In the United States, surgical intervention is most often required in order to treat patients with MDR/RR-TB organ-isms whose lungs have been destroyed and who have persis-tent thick-walled cavitation.101 The indications for surgery related to mycobacterial pulmonary infections are presented in Table 19-19. The governing principle of mycobacterial surgery is to remove all gross disease while preserving any uninvolved lung tissue. Scattered nodular disease may be left intact, given its low mycobacterial burden. Antimycobacterial medications should be given preoperatively (for about 3 months) and con-tinued postoperatively for 12 to 24 months. Overall, more than 90% of patients who were deemed good surgical candidates are cured when appropriate medical and surgical therapy is used.Pulmonary Fungal Infections. The incidence of fungal infections has increased significantly, with many new opportu-nistic fungi emerging. This increase is attributed to the growing population of immunocompromised patients (e.g., organ trans-plant recipients, cancer patients undergoing chemotherapy, HIV patients, and young and elderly patients) who are more likely to become infected with fungi.102 Clinically significant examples include species of Aspergillus, Cryptococcus, Candida, and Mucor. Other at-risk patient populations include those who are malnourished, severely debilitated, or diabetic or who have hematologic disorders.Patients receiving high-dose, intensive antibiotic therapies are also susceptible. There are, however, some fungi that are primary or true pathogens, able to cause infections in other-wise healthy patients. Some endemic examples in the United States include species of Histoplasma, Coccidioides, and Blastomyces.103Direct identification of the organism in body exudates or tissues, preferably as growth in culture, provides definitive diag-nosis. Serologic testing to identify mycotic-specific antibodies may also be useful. Several new classes of antifungal agents have proven effective against many life-threatening fungi and are less toxic than older agents. In addition, thoracic surgery may be a useful therapeutic adjunct for patients with pulmonary mycoses.Aspergillosis The genus Aspergillus comprises over 150 spe-cies and is the most common cause of mortality due to inva-sive mycoses in the United States. It is typically acute in onset and life-threatening and occurs in the setting of neutropenia, chronic steroid therapy, or cytotoxic chemotherapy. It can also occur in the general intensive care unit population of critically ill patients, including patients with underlying chronic obstruc-tive pulmonary disease (COPD), postoperative patients, patients with cirrhosis or alcoholism, and postinfluenza patients, with-out any of these factors present. The species most commonly responsible for clinical disease include A fumigatus, A flavus, A niger, and A terreus. Aspergillus is a saprophytic, filamentous fungus with septate hyphae. Spores (2.5 to 3 µm in diameter) are released and easily inhaled by susceptible patients; because the spores are microns in size, they are able to reach the distal bronchi and alveoli.Diagnosis of aspergillosis requires one or more cavities on lung imaging, with or without fungal ball or nodules, micros-copy or culture positive for Aspergillus, or antibodies (precipi-tins) to Aspergillus on serum testing. The characteristics must have been present for 3 months. Aspergillus can manifest as one of three clinical syndromes: Aspergillus hypersensitivity lung disease, aspergilloma, or invasive pulmonary aspergil-losis. Overlap occurs between these syndromes, depending on the patient’s immune status.104 Aspergillus hypersensitiv-ity manifests as a productive cough, fever, wheezing, pulmo-nary infiltrates, eosinophilia, and elevation of IgE antibodies Brunicardi_Ch19_p0661-p0750.indd 71101/03/19 7:01 PM 712SPECIFIC CONSIDERATIONSPART IIINH/RIFINH/RIFINH/RIFINH/RIFINH/RIF/EMB*/PZA†0123469Time (months)INH/RPT‡§INH/RIF2-monthculture negativeHigh clinicalsuspicionfor activetuberculosis2-monthculture positiveCavitation on CXRorpositive AFB smearat 2 monthsNo cavitation on CXRandnegative AFB smearat 2 monthsNo cavitationCavitationFigure 19-32. Treatment algorithm for tuberculosis. Patients in whom tuberculosis is proven or strongly suspected should have treatment initiated with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for the initial 2 months. A repeat smear and cul-ture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph (CXR) or the acid-fast bacillus (AFB) smear results are positive at completion of 2 months of treatment, the continuation phase of treatment should consist of INH and RIF daily or twice daily for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial CXR and the culture results at the time of completion of 2 months of therapy are positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4+ cell count is <100/µL, the continuation phase should consist of daily or three times weekly INH and RIF. In HIV-uninfected patients with no cavitation on CXR and negative results on AFB smears at completion of 2 months of treatment, the continuation phase may consist of either once weekly INH and rifapentine (RPT) or daily or twice weekly INH and RIF to complete a total of 6 months of treatment (bottom). For patients receiving INH and RPT whose 2-month culture results are positive, treatment should be extended by an additional 3 months (total of 9 months). *EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. †PZA may be discontinued after it has been taken for 2 months (56 doses). ‡RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. §Therapy should be extended to 9 months if results of 2-month culture are positive. (Reproduced with permission from Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis, Am J Respir Crit Care Med. 2003 Feb 15;167(4):603-662.)Table 19-19Indications for surgery to treat mycobacterial pulmonary infections 1. Complications resulting from previous thoracic surgery to treat tuberculosis 2. Failure of optimized medical therapy (e.g., progressive disease, lung gangrene, or intracavitary aspergillosis superinfection) 3. Need for tissue acquisition for definitive diagnosis 4. Complications of pulmonary scarring (e.g., massive hemoptysis, cavernomas, bronchiectasis, or bronchostenosis) 5. Extrapulmonary thoracic involvement 6. Pleural tuberculosis 7. Nontuberculous mycobacterial infectionto Aspergillus, whereas aspergilloma (fungal ball) is a matted sphere of hyphae, fibrin, and inflammatory cells that tends to colonize preexisting intrapulmonary cavities. Grossly, aspergil-loma appears as a round or oval, friable, gray (or red, brown, or even yellow), necrotic-looking mass (Fig. 19-33). This form is the most common presentation of noninvasive pulmonary asper-gillosis. The most common symptoms are hemoptysis, chronic and productive cough, clubbing, malaise, or weight loss. CXR can suggest the diagnosis by the finding of a crescentic radiolu-cency above a rounded radiopaque lesion (Monad sign).The natural history varies greatly between patients and, therefore, treatment is individualized. Factors associated with poor prognosis include severe underlying pulmonary disease, growth in the number or size of the aspergilloma(s) during observation, immunosuppression or HIV infection, history of lung transplantation, chronic pulmonary sarcoidosis, and increasing Aspergillus-specific IgG titers. 10Brunicardi_Ch19_p0661-p0750.indd 71201/03/19 7:01 PM

CHAPTER 19713CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAACBFigure 19-33. Pulmonary aspergilloma. A. The chest X-ray shows a solid mass within a cavity surrounded by a rim of air between the mass and cavity wall (Monad sign, arrows). B. A cut section shows the “fungus ball” occupying an old, fibrotic cavity. C. Histologic stain reveals characteristic Aspergillus hyphae invading the wall of the cavity.Asymptomatic patients can be observed without any additional therapy. Antifungals have limited utility due to the poor blood supply to the aspergilloma. Oral triazole therapy is now consid-ered the standard of care for chronic, cavitary pulmonary asper-gillosis. Hemoptysis is a harbinger of erosion of the disease into adjacent bronchial arteries and typically requires intervention. In the setting of very mild hemoptysis (e.g., blood-streaked spu-tum), cough suppression is warranted while further therapeutic evaluation is performed.Bronchial artery embolization is the first-line therapy for massive hemoptysis and may be definitive therapy.105 This is particularly important to consider for patients with severely impaired pulmonary function who may not have sufficient reserve to tolerate even a very small pulmonary resection. Operative intervention may be required for recur-rent hemoptysis, particularly after bronchial artery emboli-zation, chronic cough with systemic symptoms, progressive infiltrate around the mycetoma, and a pulmonary mass of unknown cause.106When operative intervention is indicated, the surgeon must remain cognizant of the goals of the procedure. In the setting of simple aspergilloma, VATs wedge resection is pre-ferred. As this disease typically occurs in patients with signifi-cantly impaired pulmonary function, attempts should be made to excise all diseased tissue with as limited a resection as pos-sible. Once resection is completed, the postresection space in the hemithorax should be obliterated with a pleural tent, pneu-moperitoneum, decortication of the remaining lung, intratho-racic rotation of a muscle or omental flap, or thoracoplasty. If completely resected for single aspergilloma, antifungal therapy is not needed. If multiple nodules are present or the disease is incompletely resected, however, antifungal therapy should be considered. Long-term follow-up is necessary, given that the recurrence rate after surgery is about 7%.Brunicardi_Ch19_p0661-p0750.indd 71301/03/19 7:01 PM 714SPECIFIC CONSIDERATIONSPART IIInvasive pulmonary aspergillosis typically affects immu-nocompromised patients who have dysfunctional cellular immu-nity, namely defective polymorphonuclear leukocytes. Invasion of pulmonary parenchyma and blood vessels by a necrotizing bronchopneumonia may be complicated by thrombosis, hemor-rhage, and then dissemination. Patients present with fever that is nonresponsive to antibiotic therapy in the setting of neutro-penia. They may also have pleuritic chest pain, cough, dys-pnea, or hemoptysis. Characteristic signs on CT scan include the halo sign and cavitary lesions. Treatment with voriconazole must be prompt and aggressive, including reversal of neutrope-nia, if there is to be any chance for recovery. Mortality ranges from 93% to 100% in bone marrow transplant recipients, to approximately 38% in kidney transplant recipients, although this improves to approximately 60% at 12 weeks with antifun-gal therapy. Several other advances in diagnosis and treatment, including CT scans in high-risk populations and development of additional triazoles and echinocandins, have improved the early identification and response to therapy in this patient population. Additional treatment considerations include the use of hema-topoietic growth factors to minimize the neutropenic period, which contributes to uncontrolled disease. Surgical removal of the infectious nidus is advocated by some groups because medical treatment has such poor outcomes. Treatment continues until microbiologic clearance is achieved and clinical signs and radiographic imaging indicate resolution of disease. In addition, the patient should no longer be immunosuppressed. If continu-ation of immunosuppressive medications is required, antifungal therapy should also continue to prevent recurrence of invasive disease.Cryptococcosis Cryptococcosis is a subacute or chronic infec-tion caused by Cryptococcus neoformans, a round, budding yeast (5 to 20 µm in diameter) that is sometimes surrounded by a characteristic wide gelatinous capsule. Cryptococci are typically present in soil and dust contaminated by pigeon drop-pings. When inhaled, such droppings can cause a nonfatal dis-ease primarily affecting the pulmonary and central nervous systems. At present, cryptococcosis is one of the most common opportunistic infection in patients with HIV infection, affecting ∼3% of that population. Four basic pathologic patterns are seen in the lungs of infected patients: granulomas; granulomatous pneumonia; diffuse alveolar or interstitial involvement; and pro-liferation of fungi in alveoli and lung vasculature. Symptoms are nonspecific, as are the radiographic findings. Cryptococcus neoformans may be isolated from sputum, bronchial washings, percutaneous needle aspiration of the lung, or cerebrospinal fluid. If disease is suspected, serum cryptococcal antigen titers should be obtained; if positive or if the patient has persistent fever, evidence of progression, physiologic compromise, or dissemination, treatment should be promptly initiated. Accord-ing to the CDC, multiple antifungal agents are effective against C neoformans; asymptomatic infections, such as those identified through targeted screening, should be treated with fluconazole while severe lung infections require amphotericin B combined with flucytosine followed by fluconazole for an extended length of time. Duration of therapy is longer in patients who are immunocompromised.Candidiasis Candida organisms are oval, budding cells (with or without mycelial elements) that colonize the oropharynx of many healthy individuals. The fungi of this genus are com-mon hospital and laboratory contaminants. Usually, Candida albicans causes disease in the oral or bronchial mucosa, among other anatomic sites. Approximately 95% of all invasive Candida infections are caused by five species: C albicans, C tropicalis, C parapsilosis, C glabrata, and C krusei. The specific pathogen varies between patient populations and geo-graphic regions. Non–C albicans infections now constitute nearly 70% of all cases in the United States, with C glabrata leading the list. Resistance to fluconazole is common in the non–C albicans species, either natural or developed in response to antifungal therapy, and the shift is likely related to the wide-spread use of this antifungal agent.107The incidence of Candida infections has increased and is no longer confined to immunocompromised patients. Increasing incidence of infection has been identified in patients with any of the following risk factors: critical illness of long duration; use of long-term antibiotics, particularly multiple; indwelling urinary or vascular catheter; gastrointestinal perforation; or burn wounds.108 With respect to the thorax, such patients commonly have candidal pneumonia, pulmonary abscess, esophagitis, and mediastinitis. Pulmonary candidal infections typically result in an acute or chronic granulomatous reaction. Because Candida can invade blood vessel walls and a variety of tissues, systemic or disseminated infections can occur, but are less common.Treatment for candidal infection includes both fungicidal and fungistatic agents. The fungicidal medications include poly-enes (amphotericin B deoxycholate [AmB-D] and various lipid-associated amphotericin B preparations) and the echinocandins (caspofungin, micafungin, and anidulafungin). Fungistatic drugs include the triazoles (fluconazole, itraconazole, voricon-azole, and posaconazole). The availability of multiple effective therapies allows for specific tailoring of treatment, including combination regimens, based on the patient’s ability to toler-ate associated toxicities, the microbiologic information for the specific candidal species, and the route of administration. While demonstrated efficacy is similar, the triazoles and echinocan-dins appear to have fewer side effects and are better tolerated than the other classes of antifungal drugs. The current initial recommended regimen for adults with invasive candidiasis is an echinocandin.107In addition to prompt institution of antifungal therapy, it is advisable to remove all central venous catheters as soon as can be safely achieved. For fungemia, an eye examination should be performed. Treatment should continue for at least 2 weeks after the last positive blood culture. For patients with Candida medi-astinitis (which has a mortality rate of >50%), surgical inter-vention to debride all infected tissues is required, in addition to prolonged administration of antifungal drugs.Mucormycosis The Mucor species, rare members of the class Zygomycetes, are responsible for rapidly fatal disease in immunocompromised patients. Other disease-causing spe-cies of the class Zygomycetes include Absidia, Rhizopus, and Mortierella.109 Characteristic of these fungi are nonsep-tate, branching hyphae that are difficult to culture. Infec-tion occurs via inhalation of spores. Immunocompromised patients, including patients with neutropenia, acidosis, dia-betes, and hematologic malignancy all predispose to clinical susceptibility. In the lungs, disease consists of blood vessel invasion, thrombosis, and infarction of infected organs.Tissue destruction is significant, along with cavitation and abscess formation. Initial treatment is to correct underly-ing risk factors and administer antifungal therapies, although Brunicardi_Ch19_p0661-p0750.indd 71401/03/19 7:01 PM

CHAPTER 19715CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAthe optimal duration and optimal total dose are unknown. Lipid formulations of amphotericin B are recommended at this time. Surgical resection of any localized disease should be performed after initial medical treatment attempts fail.Primary Fungal Pathogens Histoplasma capsulatum Histoplasma capsulatum is a dimor-phic fungus existing in mycelial form in soil contaminated by fowl or bat excreta and in yeast form in human hosts. The most common of all fungal pulmonary infections, histoplasmosis, primarily affects the respiratory system after spores are inhaled. It is endemic in the Midwest and Mississippi River Valley of the United States, where about 500,000 new cases arise each year. In immunocompromised patients, the infection becomes systemic and more virulent; because cell-mediated immunity is impaired, uninhibited fungal proliferation occurs within pulmo-nary macrophages and then spreads. Acute forms of the disease present as primary or disseminated pulmonary histoplasmosis; chronic forms present as pulmonary granulomas (histoplasmo-mas), chronic cavitary histoplasmosis, mediastinal granulomas, fibrosing mediastinitis, or bronchiolithiasis. Histoplasmosis is definitively diagnosed by fungal smear, culture, direct biopsy of infected tissues, or serologic testing.The clinical presentation depends on the inoculum size and on host factors.Symptoms of acute pulmonary histoplasmosis are fever, chills, headache, chest pain, musculoskeletal pain, and nonpro-ductive cough. CXRs may be normal or may show mediastinal lymphadenopathy and patchy parenchymal infiltrates. Most patients improve in a few weeks; mild to moderate disease can be treated with itraconazole. Amphotericin B is the treatment of choice if moderate symptoms persist for 2 to 4 weeks or if the illness is extensive, including dyspnea and hypoxia, and if patients are immunosuppressed.110As the pulmonary infiltrates from acute histoplasmosis heal, consolidation into an asymptomatic solitary nodule or histoplasmoma may occur and is usually seen incidentally on radiographs as a coin-shaped lesion. Central and concentric calcification may occur; if so, no further treatment is required. Noncalcification of the lesion requires further diagnostic workup including chest CT scan, needle biopsy, or surgical excision to rule out a malignancy. Figure 19-34 demonstrates the differ-ences in pathologic findings between infections in normal and immunocompromised hosts.111When lymph nodes and pulmonary granulomas calcify over time, pressure atrophy on the bronchial wall may result in erosion and migration of the granulomatous mass into the bronchus, causing bronchiolithiasis. Typical symptoms include cough, hemoptysis, and dyspnea. Life-threatening complica-tions include massive hemoptysis or bronchoesophageal fistula. In addition to radiography, bronchoscopy should be performed to aid in diagnosis. Definitive treatment requires surgical exci-sion of the bronchial mass and repair of the airway and contigu-ous structures. Endobronchial debridement is not advised as this can result in massive, fatal bleeding.Fibrosing mediastinitis is an uncommon manifestation of histoplasmosis but can be fatal due to progressive distortion and compression of the major vessels and central airways.Diagnosis can be difficult, and symptoms may be present for extended periods, even years, before the diagnosis is made. The differential diagnosis for the disease process includes granu-lomatous mediastinitis related to recent infection, malignancy, and chronic pulmonary thromboembolism. A trial of itracon-azole is worthwhile, although it is not proven to be effective. In cases where radiographic or physiologic improvement is achieved after a trial of 12 week of therapy, continuation of therapy is con-sidered for a full 12 months. In the majority of patients, how-ever, antifungal therapy has not been proven. There is no role for corticosteroids at this time or for antifibrotics. Occasionally, intravascular stents have been helpful for severe vascular compro-mise. Balloon dilatation and endobronchial silicone stents may be needed for airway compromise, although this should be directed by a surgeon with expertise in mediastinal and airway disease management.Chronic pulmonary histoplasmosis occurs in about 10% of patients who become symptomatic after infection. Most such patients have preexisting lung pathology, particularly emphy-sema, which becomes colonized, and subsequent pneumonitis and necrosis, cavity enlargement, new cavity formation, and pulmonary dissemination occur. Nonspecific symptoms, such as cough, sputum production, fever, weight loss, weakness, and hemoptysis are common. Chest radiography may reveal intrapulmonary cavitation and scarring. Occasionally, par-tial resolution of the inflammatory changes may be observed. Itraconazole provides effective therapy, but must be given for 12 to 24 months. It is superior to ketoconazole and fluconazole; these should only be used if itraconazole is not tolerated. Vori-conazole and posaconazole have been found to be useful for salvage therapy. Serum itraconazole levels should be monitored to ensure that the drug is being absorbed. Occasionally, lipid-associated amphotericin B is necessary for more severe infec-tions. Surgical excision should be considered in patients with adequate pulmonary reserve and localized, thick-walled cavities that have been unresponsive to antifungal therapy.Disseminated histoplasmosis occurs most frequently in patients who are severely immunocompromised, such as post-transplantation patients, patients with HIV, and patients using immunosuppressive medications. Presentation ranges from non-specific signs of fever, weight loss, and malaise, to shock, respi-ratory distress, and multiorgan failure. Diagnosis can be made with a combination of Histoplasma urine antigen, serologic assay, and fungal culture and should be suspected in patients with the above symptoms in any endemic area, particularly if the patient is immunosuppressed.112 Any of the antifungal thera-pies can be used in treatment of disseminated histoplasmosis. Use of amphotericin B has decreased the mortality rate to less than 25% in this type of serious infection.Coccidioides immitis Coccidioides immitis is an endemic fun-gus found in soil and dust of the southwestern United States. Agricultural workers, military personnel, and other occupa-tions with extensive exposure to soil, especially in areas of endemic growth, are at highest risk, as are immunocompro-mised individuals.113 Spores (arthroconidia) are inhaled, swell into spherules, and subdivide into endospores, and subsequent infection develops. Diagnosis can be achieved through serum analysis for anticoccidioidal antibody, spherule identification in tissue, or by isolating the fungus in cultures from sputum, other body fluid, or tissue.Inhalation of the fungus causes pulmonary involvement in 95% of patients with symptomatic disease. Three main cat-egories of pulmonary involvement, based on the associated signs and symptoms, are possible: primary, complicated, and residual pulmonary coccidioidomycosis. Primary pulmonary Brunicardi_Ch19_p0661-p0750.indd 71501/03/19 7:01 PM 716SPECIFIC CONSIDERATIONSPART IIABCDEFFigure 19-34. Pathologic findings of infection in normal and immunocompromised hosts. Histopathologic preparations are shown contrast-ing acute diffuse pulmonary involvement in a lung segment of a normal host with a probable primary infection (A through D) with pulmonary granulomas from an immunocompromised patient who had an opportunistic reinfection with Histoplasma capsulatum (E, F). A. Diffuse interstitial pneumonitis in an adult (normal host) with recent heavy environmental exposure and subsequent development of progressive pulmonary disease. There is an inflammatory cell infiltrate primarily involving the interalveolar interstitial spaces but present within many alveolar spaces as well. The exudate consists mostly of mononuclear phagocytes, lymphocytes, and occasional plasma cells. Many of the alveolar walls are markedly thickened (hematoxylin and eosin stain [H&E], ×50). B. Another area from the same lung as in A showing focal vasculitis with an infiltrate of lymphocytes and macrophages (H&E, ×25). C. Relatively large alveolar macrophages packed with single and budding yeasts 2 to 4 µm in diameter (same lung as in A and B). The basophilic cytoplasm of these yeasts is retracted from their thin outer cell walls, leaving halo-like clear areas that can be confused with capsules (H&E, ×500). D. Intracellular and extracellular yeasts, 2 to 4 µm in diameter, some of which are single, budding, or in short chains (Gomori methenamine silver stain, ×500). E. Nonnecrotizing (sometimes called epithelioid cell or noncaseating) granuloma from a patient who had recently received chemotherapy for a germ cell tumor (different patient than in A through D). This lesion consists of a focal collection of macrophages (sometimes referred to as histiocytes or epithelioid cells) plus lymphocytes and occasional plasma cells. A few multinucleated macrophages are present. A thin layer of fibroblasts circumscribes the lesion. Yeasts of H capsulatum, probably present within macrophages of this lesion at an earlier stage, were not identified in this granuloma or in any of several other nonnecrotizing granulomas within the specimen. Lesions of this type often undergo necrosis to become necrotiz-ing granulomas (H&E, ×50). F. Necrotizing (sometimes referred to as caseating) granuloma from the same lung as in E. This lesion has a necrotic center surrounded by macrophages, encapsulating fibroblasts, fibrous connective tissue in the periphery, and scattered lymphocytes. A prominent giant cell is present in the lower left of the granuloma (at approximately 8 o’clock). Microorganisms are usually present only in relatively small numbers in these types of lesions. They are most frequently detected within the most central necrotic material in these granulomas (H&E, ×25). (Reproduced with permission from Hage CA, Wheat LJ, Loyd J, et al: Pulmonary histoplasmosis, Semin Respir Crit Care Med. 2008 Apr;29(2):151-165.)Brunicardi_Ch19_p0661-p0750.indd 71601/03/19 7:01 PM

CHAPTER 19717CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAcoccidioidomycosis occurs in about 40% of people who inhale spores. The other 60% will remain asymptomatic and develop life-long immunity. The constellation of symptoms of “valley fever,” including fever, chills, headache, erythema multiforme, erythema nodosum, polyarthralgias, nonproductive cough, and chest pain, and a CXR showing hilar and paratracheal adenopa-thy are highly suggestive of pulmonary coccidioidomycosis. In many patients, initial diagnosis is community-acquired pneumo-nia, and it is only when the patient fails to respond to appropriate antibiotic therapy that pulmonary coccidioidomycosis is consid-ered. The disease is self-limited in the majority of patients, and treatment is not required in these cases.Therapy should be considered for (a) patients with impaired cellular immunity; (b) comorbid illnesses that are adversely impacted by the infection, including chronic pulmo-nary dysfunction, renal failure, and congestive heart failure; and (c) when symptoms and radiographic findings persist for more than 6 to 8 weeks, at which time the disease is considered to be persistent coccidioidal pneumonia and occurs in approximately 1% of patients. Progression to caseous nodules, cavities, and calcified, fibrotic, or ossified lesions indicates complicated or residual stages of coccidioidomycosis.There are several relative indications for surgery in pulmo-nary coccidioidomycosis. A rapidly expanding (>4 cm) cavity that is close to the visceral pleura is a high risk for rupture into the pleural space and subsequent empyema. Other indications for operative intervention include life-threatening hemoptysis; hemoptysis that is persistent despite medical therapy; symptom-atic fungus ball; bronchopleural fistula; cavitary lesions with persistent positive sputum; and pulmonary nodules that degen-erate over time. Finally, any nodule with signs that are concern-ing for malignancy should undergo further evaluation, including biopsy or resection, to determine the underlying etiology.Diagnosis of coccidioidomycosis is confirmed by histo-pathologic, mycologic, and serologic evaluation. Extrapulmo-nary disease may develop in approximately 0.5% of infected patients, with involvement of meninges, bones, joints, skin, or soft tissues. Immunocompromised patients are especially sus-ceptible to disseminated coccidioidomycosis, which carries a mortality rate over 40%. Treatment options for this disease vary depending on the severity of the disease as well as the stage. Amphotericin B deoxycholate or the triazoles continue to be the primary antifungal medications. If meningeal involvement is identified, fluconazole or itraconazole therapy is required for the remainder of the patient’s life. Intrathecal amphotericin B can also be administered in some cases.Blastomyces dermatitidis Blastomyces dermatitidis is a round, single-budding yeast with a characteristic thick, refrac-tile cell wall. It resides in the soil as a nonmotile spore called conidia. Exposure occurs when contaminated soil is disturbed and the conidia are aerosolized. The spore is inhaled and trans-forms into a yeast phase at body temperature.114 Infection is typically self-limited. A small minority of patients will develop chronic pulmonary infection or disseminated disease, includ-ing cutaneous, osteoarticular, and genitourinary involvement. B dermatitidis has a worldwide distribution; in the United States, it is endemic in the central states.115 With chronic infec-tion, the organism induces a granulomatous and pyogenic reac-tion with microabscesses and giant cells; caseation, cavitation, and fibrosis may also occur. Symptoms are nonspecific and con-sistent with chronic pneumonia in 60% to 90% of patients. They include cough, mucoid sputum production, chest pain, fever, malaise, weight loss, and, uncommonly, hemoptysis. In acute disease, radiographs are either completely negative or have nonspecific findings; in chronic disease, fibronodular lesions (with or without cavitation) similar to tuberculosis are noted. Pulmonary parenchymal abnormalities in the upper lobe(s) may be noted. Mass lesions similar to carcinoma are frequent, and lung biopsy is frequently used. Over 50% of patients with chronic blastomycosis also have extrapulmonary manifesta-tions, but less than 10% of patients present with severe clinical manifestation.114Once a patient manifests symptoms of chronic blastomy-cosis, antifungal treatment is required to achieve resolution. Mortality approaches 60% if untreated.114 While controversial, a short course of triazole therapy (oral itraconazole 200 mg daily) for 6 months is the treatment of choice for most patients with mild to moderate forms of the disease. Because itraconazole has poor CNS penetration, the most common site of recurrence after apparently successful therapy is in the CNS. In the absence of therapy, close follow-up is warranted for evidence of progres-sion to chronic or extrapulmonary disease. Amphotericin B is warranted for patients with severe or life-threatening disease, CNS involvement, disseminated disease, or extensive lung involvement and in immunocompromised patients. After ade-quate drug therapy, surgical resection of known cavitary lesions should be considered because viable organisms are known to persist in such lesions.Massive HemoptysisMassive hemoptysis is generally defined as expectoration of over 600 mL of blood within a 24-hour period. It is a medi-cal emergency associated with a mortality rate of 30% to 50%. Most clinicians would agree that losing over a liter of blood via the airway within 1 day is significant, yet use of an abso-lute volume criterion presents difficulties. First, it is difficult for the patient or caregivers to quantify the volume of blood being lost. Second, and most relevant, the rate of bleeding nec-essary to incite respiratory compromise is highly dependent on the individual’s prior respiratory status. For example, the loss of 100 mL of blood over 24 hours in a 40-year-old male with normal pulmonary function would be of little immediate con-sequence, because his normal cough would ensure his ability to clear the blood and secretions. In contrast, the same amount of bleeding in a 69-year-old male with severe COPD, chronic bronchitis, and an FEV1 of 1.1 L may be life-threatening.Anatomy. The lungs have two sources of blood supply: the pulmonary and bronchial arterial systems. The pulmonary sys-tem is a high-compliance, low-pressure system, and the walls of the pulmonary arteries are very thin and delicate. The bronchial arteries, part of the systemic circulation, have systemic pres-sures and thick walls; most branches originate from the proxi-mal thoracic aorta. Most cases of massive hemoptysis involve bleeding from the bronchial artery circulation or from the pul-monary circulation pathologically exposed to the high pres-sures of the bronchial circulation. In many cases of hemoptysis, particularly those due to inflammatory disorders, the bronchial arterial tree becomes hyperplastic and tortuous. The systemic pressures within these arteries, combined with a disease process within the airway and erosion, lead to bleeding.Causes. Significant hemoptysis has many causes, most com-monly including pulmonary, extrapulmonary, and iatrogenic. Table 19-20 summarizes the most common causes of hemopty-sis. Most are secondary to inflammatory processes. Aneurysms Brunicardi_Ch19_p0661-p0750.indd 71701/03/19 7:01 PM 718SPECIFIC CONSIDERATIONSPART IITable 19-20Pulmonary and extrapulmonary causes of massive hemoptysisPULMONARYEXTRAPULMONARYIATROGENICPulmonary parenchymal diseaseBronchitisBronchiectasisTuberculosisLung abscessPneumoniaCavitary fungal infection (e.g., aspergilloma)Lung parasitic infection (ascariasis, schistosomiasis, paragonimiasis)Pulmonary neoplasmPulmonary infarction or embolismTraumaArteriovenous malformationPulmonary vasculitisPulmonary endometriosisWegener’s granulomatosisCystic fibrosisPulmonary hemosiderosisCongestive heart failureCoagulopathyMitral stenosisMedicationsIntrapulmonary catheterTable 19-21Treatment priorities in the management of massive hemoptysis 1. Achieve respiratory stabilization and prevent asphyxiation. 2. Localize the bleeding site. 3. Control the hemorrhage. 4. Determine the cause. 5. Definitively prevent recurrence.of the pulmonary artery (referred to as Rasmussen’s aneurysm) can develop within pulmonary cavities and can result in massive bleeding. Hemoptysis due to lung cancer is usually mild, result-ing in blood-streaked sputum. Massive hemoptysis in patients with lung cancer is typically caused by malignant invasion of pulmonary artery vessels by large central tumors. Although rare, it is often a terminal event.Management. Life-threatening hemoptysis is best managed by a multidisciplinary team of intensive care physicians, interven-tional radiologists, and thoracic surgeons. Treatment priorities begin with respiratory stabilization; intubation with isolation of the bleeding lung may be required to prevent asphyxiation. This can be done with main-stem intubation into the nonbleeding lung, endobronchial blockers into the bleeding lung, or double-lumen endotracheal intubation, depending on the urgency of the situation and the expertise of the providers. Once adequate ven-tilation has been achieved, the bleeding site should be localized; bronchoscopy can often provide direct visualization of blood coming from a specific area of the tracheobronchial anatomy. Control of the hemorrhage is then achieved endobronchially with laser or bronchial occlusion, endovascularly with bronchial and/or pulmonary artery embolization, or surgically with resec-tion of the involved area.116 The order of priorities in manage-ment is detailed in Table 19-21.The clinically pragmatic definition of massive hemoptysis is a degree of bleeding that threatens respiratory stability. There-fore, clinical judgment of respiratory compromise is the first step in evaluating a patient.117,118 Two scenarios are possible: (a) bleeding is significant and persistent, but its rate allows a rapid but sequential diagnostic and therapeutic approach, and (b) bleeding is so rapid that emergency airway control and ther-apy are necessary.Scenario 1: Significant, Persistent, but Nonmassive Bleeding  Although bleeding is brisk in scenario 1, the patient may be able to maintain clearance of the blood and secretions with his or her own respiratory reflexes. Immediate measures are admission to an intensive care unit; strict bed rest; Trendelenburg position-ing with the affected side down (if known); administration of humidified oxygen; cough suppression; monitoring of oxygen saturation and arterial blood gases; and insertion of large-bore intravenous catheters. Strict bed rest with sedation may lead to slowing or cessation of bleeding, and the judicious use of intravenous narcotics or other relaxants to mildly sedate the patient and diminish some of the reflexive airway activity is often necessary. Also recommended are administration of aero-solized adrenaline, intravenous antibiotic therapy if needed, and correction of abnormal blood coagulation study results. Finally, unless contraindicated, intravenous vasopressin (20 U over 15 minutes, followed by an infusion of 0.2 U/min) can be given.A CXR is the first test and often proves to be the most revealing. Localized lesions may be seen, but the effects of blood soiling of other areas of the lungs may predominate, obscuring the area of pathology. Chest CT scan provides more detail and is nearly always performed if the patient is stable. Pathologic areas may be obscured by blood soiling.Flexible bronchoscopy is the next step in evaluating the patient’s condition. Some clinicians argue that rigid bronchos-copy should always be performed. However, if the patient is clinically stable and the ongoing bleeding is not imminently threatening, flexible bronchoscopy is appropriate. It allows diagnosis of airway abnormalities and will usually permit Brunicardi_Ch19_p0661-p0750.indd 71801/03/19 7:01 PM

CHAPTER 19719CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAlocalization of the bleeding site to either a lobe or even a seg-ment. The person performing the bronchoscopy must be pre-pared with excellent suction and must be able to perform saline lavage with a dilute solution of epinephrine.Most cases of massive hemoptysis arise from the bron-chial arterial tree; therefore, the next therapeutic option fre-quently is selective bronchial arteriography and embolization. Prearteriogram bronchoscopy is extremely useful to direct the angiographer. However, if bronchoscopy fails to localize the bleeding site, then bilateral bronchial arterio-grams can be performed. More recently, use of multidetec-tor CT angiography in patients with hemoptysis that is not immediately life-threatening has been shown to facilitate endovascular intervention; reformatting of the images in mul-tiple projections allows clear delineation of the pulmonary vascular anatomy.105 With this approach, abnormal bronchial and nonbronchial arteries can be visualized and subsequently targeted for therapeutic arterial embolization.119 Once the tar-geted arterial system has been embolized, immediate control and cessation of the hemoptysis is achieved in more than 80% of patients. If bleeding persists after bronchial artery emboli-zation, a pulmonary artery source should be suspected and a pulmonary angiogram performed at the same setting.Recurrence is seen in 30% to 60% of cases and is very common in the setting of invasive fungal infections such as aspergilloma. Recurrence after bronchial artery embolization is less common in the setting of malignancy and active tuberculo-sis but does occur and can ultimately result in patient death.120 Repeat embolization can be effective and is warranted for ini-tial management of recurrent hemoptysis, but early surgical intervention should be considered, particularly in the setting of aspergilloma or other cavitary lesions.105If respiratory compromise is impending, orotracheal intu-bation should be performed. After intubation, flexible bronchos-copy should be performed to clear blood and secretions and to attempt localization of the bleeding site. Depending on the pos-sible causes of the bleeding, bronchial artery embolization or (if appropriate) surgery can be considered.Scenario 2: Significant, Persistent, and Massive Bleeding  Life-threatening bleeding requires emergency airway control and preparation for potential surgery. Such patients are best cared for in an operating room equipped with rigid bronchos-copy. Immediate orotracheal intubation may be necessary to gain control of ventilation and suctioning. However, rapid trans-port to the operating room with rigid bronchoscopy should be facilitated. Rigid bronchoscopy allows adequate suctioning of bleeding with visualization of the bleeding site; the nonbleed-ing side can be cannulated with the rigid scope and the patient ventilated. After stabilization, ice-saline lavage of the bleeding site can then be performed (up to 1 L in 50-mL aliquots); bleed-ing stops in up to 90% of patients.121Alternatively, blockade of the main stem bronchus of the affected side can be accomplished with a double-lumen endo-tracheal tube, with a bronchial blocker, or by intubation of the nonaffected side by an uncut standard endotracheal tube. Place-ment of a double-lumen endotracheal tube is challenging in these circumstances, given the bleeding and secretions. Proper placement and suctioning may be difficult, and attempts could compromise the patient’s ventilation. The best option is to place a bronchial blocker in the affected bronchus with inflation. Endovascular embolization can be performed to stop the bleeding after control has been achieved with the bronchial blocker. The blocker is left in place for 24 hours; after 24 hours, the area is reexamined bronchoscopically.Surgical Intervention. In most patients, bleeding can be stopped, recovery can occur, and plans to definitively treat the underlying cause can be made. In scenario 1 (significant, persis-tent, but nonmassive bleeding), the patient may undergo further evaluation as an inpatient or outpatient. A chest CT scan and pulmonary function studies should be obtained preoperatively. In scenario 2 (patients with significant, persistent, and massive bleeding), surgery, if appropriate, will usually be performed during the same hospitalization as the rigid bronchoscopy or main stem bronchus blockade. In a small number of patients (<10%), immediate surgery will be necessary due to the extent of bleeding. The bleeding site in these patients is localized using rigid bronchoscopy with immediate thoracotomy or sternotomy to follow.Surgical treatment is individualized according to the source of bleeding and the patient’s medical condition, prog-nosis, and pulmonary reserve. General indications for urgent surgery are presented in Table 19-22. In patients with significant cavitary disease or with fungus balls, the walls of the cavities are eroded and necrotic; rebleeding will likely ensue. In addi-tion, bleeding from cavitary lesions may be due to pulmonary artery erosion, which requires surgery for control.End-Stage Lung DiseaseLung Volume Reduction Surgery. The ideal patient for lung volume reduction surgery (LVRS) has heterogeneous emphy-sema with apical predominance, meaning the worst emphyse-matous changes are in the apex (seen on chest CT scan) of the lungs. The physiologic lack of function of these areas is dem-onstrated by quantitative perfusion scan, which shows minimal or no perfusion. By surgically excising these nonfunctional areas, the volume of the lung is reduced, theoretically restor-ing respiratory mechanics. Diaphragm position and function are improved, and there may be an improvement in the dynamic small airway collapse in the remaining lung.Operative mortality in the initial experience was 16.9%, with a 1-year mortality of 23%. In response, the National Emphysema Treatment Trial (NETT) performed a randomized trial of 1218 patients in a noncrossover design to medical versus surgical management after a 10-week pretreatment pulmonary rehabilitation program. Subgroup analysis demonstrated that in patients with the anatomic changes delineated by Cooper and colleagues, LVRS significantly improved exercise capacity, lung function, quality of life, and dyspnea compared to medi-cal therapy. After 2 years, functional improvements began to decline toward baseline. Similar parameters in medically treated patients steadily decline below baseline. LVRS was associated with increased short-term morbidity and mortality and did not confer a survival benefit over medical therapy.122Table 19-22General indications for urgent operative intervention for massive hemoptysis 1. Presence of a fungus ball 2. Presence of a lung abscess 3. Presence of significant cavitary disease 4. Failure to control the bleedingBrunicardi_Ch19_p0661-p0750.indd 71901/03/19 7:01 PM 720SPECIFIC CONSIDERATIONSPART IISurvival123BOS-free survival1.00.80.60.40.2Years posttransplantFigure 19-36. The survival rate after lung transplantation in the absence of bronchiolitis obliterans syndrome (BOS) at the University of Minnesota.Survival123Primary graft failure1.00.80.60.40.2No PGFPGFYears posttransplantFigure 19-37. The survival rate after lung transplantation at the University of Minnesota as a function of primary graft failure (PGF).Lung Transplantation. The most common indications for lung transplant are COPD and idiopathic pulmonary fibrosis (IPF). Most patients with IPF and older patients with COPD are offered a single-lung transplant. Younger COPD patients and patients with α1-antitrypsin deficiency and severe hyperinflation of the native lungs are offered a bilateral-lung transplant. Most patients with primary pulmonary hypertension and almost all patients with cystic fibrosis are treated with a bilateral-lung transplant. A heart-lung transplant is reserved for patients with irreversible ventricular failure or uncorrectable congenital cardiac disease.Patients with COPD are considered for placement on the transplant waiting list when their FEV1 has fallen to below 25% of its predicted value. Patients with significant pulmonary hyper-tension should be listed earlier. IPF patients should be referred when their forced vital capacity has fallen to less than 60% or their Dlco has fallen to less than 50% of their predicted values.In the past, patients with primary pulmonary hypertension and New York Heart Association (NYHA) class III or IV symp-toms were listed for a lung transplant. However, treatment of such patients with intravenous prostacyclin and other pulmonary vasodilators has now markedly altered that strategy. Virtually all patients with primary pulmonary hypertension are now treated with intravenous epoprostenol. Several of these patients have experienced a marked improvement in their symptoms associ-ated with a decrease in their pulmonary arterial pressures and an increase in exercise capacity. Listing of these patients is deferred until they develop NYHA class III or IV symptoms or until their mean pulmonary artery pressure rises above 75 mmHg.Medium-term and bronchiolitis obliterans syndrome (BOS)–free survival rates of patients who underwent a lung transplant at the University of Minnesota are shown in Figs. 19-35 and 19-36. The mortality of patients while waiting for transplants is about 10%. In an effort to expand the number of lung donors, many transplant groups have liberalized their criteria for donor selection. Still, the partial pressure of arterial oxygen (Pao2) should be greater than 300 mmHg on a fraction of inspired oxygen (Fio2) of 100%. In special circumstances, lungs may be used from donors with a smoking history; from donors older than 50 years of age; and from donors with positive Gram stains or infiltrates on CXR.123,124 The use of two living donors, each donating a single lower lobe, is another strategy for increasing the donor pool. Recipient outcomes are similar to those with cadaver donors in carefully selected patients.Survival123Overall survival1.00.80.60.40.2Years posttransplantFigure 19-35. The overall survival rate after lung transplantation at the University of Minnesota.Most of the early mortality after lung transplant is related to primary graft failure resulting from a severe ischemia-reper-fusion injury to the lung(s) (Fig. 19-37). Reperfusion injury is characterized radiographically by interstitial and alveolar edema and clinically by hypoxia and ventilation-perfusion mismatch. Donor neutrophils and recipient lymphocytes prob-ably play an important role in the pathogenesis of reperfu-sion injury. The most important impediment to longer-term survival after a lung transplant is the development of BOS, a manifestation of chronic rejection. Episodes of acute rejection are the major risk factors for developing BOS. Other injuries to the lung (including early reperfusion injury and chronic gas-troesophageal reflux disease) may also adversely affect long-term outcomes of patients.125,126CHEST WALLChest Wall MassClinical Approach. Surgeons confronted with a patient with a chest wall mass must be cognizant that their approach to diagno-sis and treatment has significant impact on the patient’s chances Brunicardi_Ch19_p0661-p0750.indd 72001/03/19 7:01 PM

CHAPTER 19721CHEST WALL, LUNG, MEDIASTINUM, AND PLEURADiagnosis is clear;a surgical resection is theprimary treatmentLesion <2.0 cmBenign Tumors Fibrous dysplasia Chondroma Osteochondroma Eosinophilic granulomaMalignant Tumors ChondrosarcomaWide surgical excisionCT or MRI or bothChest wall massFigure 19-38. Systematic approach for evaluating a chest wall mass when the clinical scenario is uncomplicated and initial imag-ing studies suggest a clear diagnosis. CT = computed tomography; MRI = magnetic resonance imaging.for long-term survival. All chest wall tumors should be consid-ered malignant until proven otherwise. It is critically important that the surgeon(s) be mindful of this tenet and well versed in the diagnostic and treatment principles for chest wall malignan-cies. These tenets must be applied from the initial biopsy, as the placement of the incision can impact significantly on the successful complete resection and reconstruction of the chest wall. Complete resection is imperative if there is any hope for cure and/or long-term survival. A general approach is outlined in Figs. 19-38 and 19-39.Patients with chest wall tumors, regardless of etiology, typically complain of a slowly enlarging palpable mass (50% to 70%), chest wall pain (25% to 50%), or both. Interestingly, growing masses are often not noticed by the patient until they suffer a trauma to the area. Pain from a chest wall mass is typi-cally localized to the area of the tumor; it occurs more often and more intensely with malignant tumors, but it can also be present in up to one-third of patients with benign tumors. With Ewing’s sarcoma, fever and malaise may also be present. Benign chest wall tumors tend to occur in younger patients (average age 26 years), whereas malignant tumors tend to be found in older patients (average age 40 years). Overall, between 50% and 80% of chest wall tumors are malignant.Evaluation and Management. Laboratory evaluations are useful in assessing chest wall masses for the following:1. Plasmacytoma. Serum protein electrophoresis demon-strates a single monoclonal spike, which is measuring the overproduction of one immunoglobulin from the malignant plasma cell clone.Chest wall massCT or MRI or bothDiagnosis is NOT clearPreoperative chemotherapyWide surgical excisionOsteosarcomaRhabdomyosarcomaNonrhabdomyosarcomaPNET/Ewing’s sarcomaNonrhabdosarcoma Fibrosarcoma Malignant fibrous histiocytoma Liposarcoma Synovial cell sarcoma DesmoidNeedle biopsyor incisional biopsyFigure 19-39. Systematic approach for evaluating a chest wall mass for which the diagnosis is not unequivocal. A tissue diagnosis is critical for effective management of chest wall masses. CT = computed tomography; MRI = magnetic resonance imaging; PNET = primitive neuroectodermal tumor.2. Osteosarcoma. Alkaline phosphatase levels may be elevated.3. Ewing’s sarcoma. Erythrocyte sedimentation rates may be elevated.Radiography CXR may reveal rib destruction, calcification within the lesion, and if old films are available, a clue to growth rate. CT scanning, however, is necessary to determine the rela-tionship of the chest wall mass to contiguous structures (e.g., mediastinum, lung, soft tissues, and other skeletal elements), evaluate for pulmonary metastases, and assess for extraosseous bone formation and bone destruction, both typically seen with osteosarcoma.Because MRI provides multiple planes of imaging (coronal, sagittal, and oblique), better definition of the relationship between tumor and muscle, and tumor and contiguous or nearby neurovascular structures or the spine, it is an important radio-graphic adjunct for preoperative planning. Compared to CT scan alone, MRI may further delineate tissue abnormalities, poten-tially enhancing the ability to distinguish benign from malignant sarcoma.Biopsy The first step in the management of all chest wall tumors is to obtain a tissue diagnosis. Inappropriate or mis-guided attempts at tissue diagnosis through casual open biopsy techniques have the potential (if the lesion is a sarcoma) to seed surrounding tissues and contiguous body cavities (e.g., the pleural space) with tumor cells, potentially compromising local Brunicardi_Ch19_p0661-p0750.indd 72101/03/19 7:01 PM 722SPECIFIC CONSIDERATIONSPART IItumor control and patient survival. Tissue diagnosis is accom-plished using one of three methods: needle biopsy (typically CT-guided, FNA, or a core biopsy), incisional biopsy, or exci-sional biopsy in limited and specific situations.1. Needle biopsy. Pathologists experienced with sarcomas can accurately diagnose approximately 90% of patients using FNA cytology. A needle biopsy (FNA or core) has the advantage of avoiding wound and body cavity contami-nation (a potential complication with an incisional biopsy).2. Incisional biopsy. If a needle biopsy is nondiagnostic, an incisional biopsy may be performed, with caveats. First, the skin incision must be placed directly over the mass and ori-ented to allow subsequent scar excision and skin flaps, and drains should be avoided. If the surgeon believes a hema-toma is likely to develop, a drain is useful for limiting soft tissue contamination by tumor cells. At the time of definitive surgical resection, the en bloc resection includes the biopsy scar and the drain tract along with the tumor.3. Excisional biopsy. Any lesion less than 2.0 cm can be excised as long as the resulting wound is small enough to close primarily. Otherwise, excisional biopsy is per-formed only when the initial diagnosis (based on radio-graphic evaluation) indicates that the lesion is benign or when the lesion has the classic appearance of a chondro-sarcoma (in which case, definitive surgical resection can be undertaken).Benign Chest Wall Neoplasms1. Chondroma. Chondromas, seen primarily in children and young adults, are one of the more common benign tumors of the chest wall. They usually occur at the costochondral junction anteriorly and may be confused with costochondri-tis, except that a painless mass is present. Radiographically, the lesion is lobulated and radiodense; it may have diffuse or focal calcifications; and it may displace the bony cortex without penetration. Chondromas may grow to huge sizes if left untreated. Treatment is surgical resection with a 2-cm margin. Large chondromas may harbor well-differentiated chondrosarcoma and should be managed with a 4-cm mar-gin to prevent local recurrence.1272. Fibrous dysplasia. As with chondromas, fibrous dysplasia most frequently occurs in young adults and may be associ-ated with trauma. Pain is an infrequent complaint, and the lesion is typically located in the posterolateral aspect of the rib cage. Radiographically, an expansile mass is present, with cortical thinning and no calcification. Local excision with a 2-cm margin is curative.3. Osteochondroma. Osteochondromas, often found inciden-tally as a solitary lesion on radiograph, are the most common benign bone tumor. Osteochondromas occur in the first two decades of life, and they arise at or near the growth plate of bones. Osteochondromas in the thorax arise from the rib cortex. They are one of several components to the autosomal dominant syndrome, hereditary multiple exostoses. When part of this syndrome, osteochondromas have a high rate of degeneration into chondrosarcomas. Any patient with heredi-tary multiple exostoses syndrome who develops new pain at the site of an osteochondroma or who notes gradual growth in the mass over time should be carefully evaluated for osteosarcoma. Local excision of a benign osteochondroma is sufficient. If malignancy is determined, wide excision is performed with a 4-cm margin.4. Eosinophilic granuloma. Eosinophilic granulomas are benign osteolytic lesions. Eosinophilic granulomas of the ribs can occur as solitary lesions or as part of a more gener-alized disease process of the lymphoreticular system termed Langerhans cell histiocytosis (LCH). In LCH, the involved tissue is infiltrated with large numbers of histiocytes (similar to Langerhans cells seen in skin and other epithelia), which are often organized as granulomas. The cause is unknown. Of all LCH bone lesions, 79% are solitary eosinophilic granulomas, 7% involve multiple eosinophilic granulomas, and 14% belong to other forms of more systemic LCH. Iso-lated single eosinophilic granulomas can occur in the ribs or skull, pelvis, mandible, humerus, and other sites. They are diagnosed primarily in children between the ages of 5 and 15 years. Because of the associated pain and tenderness, they may be confused with Ewing’s sarcoma or with an inflammatory process such as osteomyelitis. Healing may occur spontaneously, but the typical treatment is limited sur-gical resection with a 2-cm margin.5. Desmoid tumors. Soft tissue neoplasms arising from fas-cial or musculoaponeurotic structures, desmoid tumors con-sist of proliferations of benign-appearing fibroblastic cells, abundant collagen, and few mitoses. Desmoid tumors pos-sess alterations in the adenomatous polyposis coli (APC)/β-catenin pathway. Cyclin D1 dysregulation is thought to play a significant role in their pathogenesis.128 Associations with other diseases and conditions are well documented, espe-cially those with similar alterations in the APC pathway, such as familial adenomatous polyposis (Gardner’s syn-drome). Other conditions with increased risk of desmoid tumor formation include increased estrogen states (preg-nancy) and trauma. Surgical incisions (abdominal and tho-rax) have been the site of desmoid development, either in or near the scar.  Clinically, patients are usually in the third to fourth decade of life and have pain, a chest wall mass, or both. The tumor is usually fixed to the chest wall, but not to the over-lying skin. There are no typical radiographic findings, but MRI may delineate muscle or soft tissue infiltration. Des-moid tumors do not metastasize, but they have a significant propensity to recur locally, with rates as high as 5% to 50%, sometimes despite complete initial resection with histologi-cally negative margins.129 Such locally aggressive behavior is secondary to microscopic tumor infiltration of muscle and surrounding soft tissues and prompts some to consider them a low-grade form of fibrosarcoma.  Because the lesions have low cellularity and poor yield with FNA, an open incisional biopsy for lesions over 3 to 4 cm is often necessary, following the caveats listed ear-lier (see biopsy section). Surgery consists of wide local excision with a 2to 4-cm margin and intraoperative fro-zen section assessment of resection margins. Typically, chest wall resection, including the involved rib(s) and one rib above and below the tumor with a 4to 5-cm margin of rib, is required. A margin of less than 1 cm results in much higher local recurrence rates. If a major neurovascu-lar structure would have to be sacrificed, leading to high morbidity, then a margin of less than 1 cm would have to suffice. Survival after wide local excision with negative margins is 90% at 10 years.130Brunicardi_Ch19_p0661-p0750.indd 72201/03/19 7:01 PM

CHAPTER 19723CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAPrimary Malignant Chest Wall TumorsMalignant tumors of the chest wall are either metastatic lesions from another primary tumor or sarcoma. Soft tissue sarcomas of the chest wall include fibrosarcomas, liposarcomas, malignant fibrous histiocytomas (MFHs), rhabdomyosarcomas, angiosar-comas, and other extremely rare lesions (Fig. 19-40). Despite the prevalence of localized disease, soft tissue sarcomas of the chest wall have significantly worse survival than similar tumors located on the extremities or the head and neck region. The fac-tors impacting on risk of death from soft tissue sarcomas of the chest wall are presented in Table 19-23. All sarcomas have a propensity to spread to the lungs.While many varieties of sarcoma exist, the primary features affecting prognosis are histologic grade and respon-siveness to chemotherapy (Table 19-24). Preoperative (neo-adjuvant) chemotherapy offers the ability to (a) assess tumor chemosensitivity by the degree of tumor size reduction and microscopic necrosis; (b) determine tumor sensitivity to spe-cific chemotherapeutic agents; and (c) improve resectability by reducing tumor size. Patients whose tumors are responsive to preoperative chemotherapy have a much better prognosis than those with a poor response. Information about tumor response to chemotherapy, the patient’s physiologic state and capacity to receive treatment, and metastatic disease status is used to determine optimal therapy. The initial treatment is either (a) preoperative chemotherapy (for patients with osteosarcoma, rhabdomyosarcoma, primitive neuroectoder-mal tumor, or Ewing’s sarcoma) followed by surgery and postoperative chemotherapy; (b) primary surgical resection and reconstruction (for patients with nonmetastatic MFH, fibrosarcoma, liposarcoma, or synovial sarcoma); or (c) preoperative chemotherapy followed by surgical resection if indicated in patients presenting with metastatic soft tis-sue sarcomas. Contiguous involvement of underlying lung or other soft tissues or the presence of pulmonary metasta-ses does not preclude successful surgery. In fact, patients receiving surgical intervention have significantly better overall survival. Median survival with surgical resection is 25 months compared to 8 months without resection. Addi-tional prognostic variables that are important for long-term survival include tumor size, grade, stage, and negative re-resection margin.131 With the exception of rhabdomyosar-comas, the primary treatment of these lesions is wide surgical resection with 4-cm margins and reconstruction.132The following is an overview of several chest wall sarcomas.1. Chondrosarcoma. Chondrosarcomas are the most common primary chest wall malignancy. As with chondromas, they usually arise anteriorly from the costochondral arches. CT scan shows a radiolucent lesion often with stippled calcifica-tions pathognomonic for chondrosarcomas (Fig. 19-41). The involved bony structures are also destroyed. Most chondro-sarcomas are slow-growing, low-grade tumors; these often painful masses can reach massive proportions.127 For this reason, any lesion in the anterior chest wall likely to be a low-grade chondrosarcoma should be treated with wide (4-cm) resection after metastatic disease to the lungs or bones is ruled out.  Chondrosarcomas are not sensitive to radiation or chemo-therapy. Prognosis is determined by tumor grade and extent of resection. With a low-grade tumor and wide resection, patient survival at 5 to 10 years can be as high as 60% to 80%.2. Osteosarcoma. While osteosarcomas are the most com-mon bone malignancy, they represent only 10% to 15% of all malignant chest wall tumors.133,134 They primarily occur in young adults as rapidly enlarging, painful masses; how-ever, osteosarcomas can occur in older patients as well, Figure 19-40. Chest computed tomography scan showing a right chest wall tumor (arrow). Tissue diagnosis revealed that this mass was a leiomyosarcoma.Brunicardi_Ch19_p0661-p0750.indd 72301/03/19 7:01 PM 724SPECIFIC CONSIDERATIONSPART IITable 19-23Cox proportional hazards model for risk of death from soft tissue sarcomaNHAZARD RATIO95% CIP VALUEGender Male Female39374113Reference group0.897Reference group0.843–0.955Reference group.001Age 50 years 51–70 years >70 years183730993114Reference group1.1311.538Reference group1.026–1.2471.395–1.697Reference group.013<.001Race Caucasian Non-Caucasian7152898Reference group1.212Reference group1.093–1.344Reference group<.001Histologic type Fibrosarcoma MFH Liposarcoma LMS/GIST489252915343498Reference group1.2810.8941.204Reference group1.097–1.4950.759–1.0541.033–1.403Reference group.002.182.018Location Head and neck Trunk Extremity Retroperitoneum57640542474946Reference group1.2551.0031.276Reference group1.096–1.4380.875–1.1511.093–1.489Reference group.001.960.002Stage Localized Regional Distant500617241320Reference group1.5752.897Reference group1.458–1.7022.660–3.155Reference group<.001<.001Surgical treatment Yes No67541296Reference group1.562Reference group1.443–1.691Reference group<.001Radiation therapy Yes No21755875Reference group1.151Reference group1.070–1.239Reference group<.001Chemotherapy Yes No10626988Reference group0.909Reference group0.829–0.996Reference group.041Abbreviations: CI = confidence interval; GIST = gastrointestinal stromal tumor; LMS = leiomyosarcoma; MFH = malignant fibrous histiocytoma.Reproduced with permission from Gutierrez JC, Perez EA, Franceschi D, et al: Outcomes for soft-tissue sarcoma in 8249 cases from a large state cancer registry, J Surg Res. 2007;141(1):105-114.Table 19-24Classification of sarcomas by therapeutic responseTUMOR TYPECHEMOTHERAPY SENSITIVITYOsteosarcoma+Rhabdomyosarcoma+Primitive neuroectodermal tumor+Ewing’s sarcoma+Malignant fibrous histiocytoma±Fibrosarcoma±Liposarcoma±Synovial sarcoma±sometimes in association with previous radiation, Paget’s disease, or chemotherapy. Radiographically, the typical appearance consists of spicules of new periosteal bone formation producing a sunburst appearance. Osteosarcomas have a propensity to spread to the lungs, and up to one-third of patients present with metastatic disease. Osteosarcomas are potentially sensitive to chemotherapy. Currently, pre-operative chemotherapy is common. After chemotherapy, complete resection is performed with wide (4-cm) margins, followed by reconstruction. In patients presenting with lung metastases that are potentially amenable to surgical resection, induction chemotherapy may be given, followed by surgical resection of the primary tumor and of the pul-monary metastases. Following surgical treatment of known disease, additional maintenance chemotherapy is usually recommended.Brunicardi_Ch19_p0661-p0750.indd 72401/03/19 7:01 PM

CHAPTER 19725CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAFigure 19-41. Chest computed tomography scan showing a right posterior lung tumor. In the appropriate clinical setting, stippled calcifica-tions (white streaks in right lung mass) are highly indicative of chondrosarcomas.3. Malignant fibrous histiocytoma. Originally thought to derive from histiocytes because of the microscopic appear-ance of cultured tumor cells, these tumors likely originate from the fibroblast. MFHs are generally the most common soft tissue sarcoma of late adult life, although they are rare on the chest wall. The typical age at presentation is between age 50 and 70 years. Presentation is pain, with or without a palpable mass. Radiographically, a mass is usually evident, with destruction of surrounding tissue and bone. Treatment is wide resection with a margin of 4 cm or more and recon-struction. Over two-thirds of patients suffer from distant metastasis or local recurrence.4. Liposarcoma. Liposarcomas make up 15% of chest wall sarcomas. Most liposarcomas are low-grade tumors that have a propensity to recur locally, given their infiltrative nature. They typically present as a painless mass. Treatment is wide resection and reconstruction. Intraoperative mar-gins should be evaluated (as with all sarcomas) and resec-tion continued, if feasible, until margins are negative. Local recurrence can be treated with reexcision, with occasional use of radiotherapy.5. Fibrosarcoma. Often presenting as a large, painful mass, these lesions are visible on plain radiograph or CT, with sur-rounding tissue destruction. Treatment is wide local excision with intraoperative frozen-section analysis of margins, fol-lowed by reconstruction. Local and systemic recurrence is frequent. Patient survival at 5 years is about 50% to 60%.6. Rhabdomyosarcoma. Rhabdomyosarcomas are rare tumors of the chest wall. Microscopically, they are a spindle cell tumor. The diagnosis often depends on immunohistochemi-cal staining for muscle markers. Rhabdomyosarcomas are sensitive to chemotherapy. Treatment consists of preopera-tive chemotherapy with subsequent surgical resection.Other Tumors of the Chest Wall1. Primitive neuroectodermal tumors (PNETs) and Ewing’s sarcoma. PNETs (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) derive from primordial neural crest cells that migrate from the mantle layer of the developing spinal cord. Histologically, PNETs and Ewing’s sarcomas are small, round cell tumors; both possess a translocation between the long arms of chromosomes 11 and 22 within their genetic makeup. They also share a consistent pattern of proto-oncogene expression and have been found to express the product of the MIC2 gene.  Ewing’s sarcoma occurs in adolescents and young adults who present with progressive chest wall pain, but without the presence of a mass. Systemic symptoms of malaise and fever are often present. Laboratory studies reveal an ele-vated erythrocyte sedimentation rate and mild white blood cell elevation. Radiographically, the characteristic onion peel appearance is produced by multiple layers of perios-teum in the bone formation. Evidence of bony destruction is also common. The diagnosis can be made by a percutaneous needle biopsy or an incisional biopsy.  These tumors have a strong propensity to metastasize to the lungs and skeleton; patient survival rates are thus only 50% or less at 3 years. Increasing tumor size is associated with decreasing survival. Treatment has improved sig-nificantly and now consists of multiagent chemotherapy, radiation therapy, and surgery. Patients are typically treated preoperatively with chemotherapy and reevaluated with radiologic imaging. When residual disease is identified, sur-gical resection and reconstruction are performed followed by maintenance chemotherapy.2. Plasmacytoma. Solitary plasmacytomas of the chest wall are very rare, with approximately 25 to 30 cases per year in the United States.133 The typical presentation is pain with-out a palpable mass. Plain radiographs show an osteolytic lesion in the region of the pain. As with other chest wall tumors, a needle biopsy under CT guidance is performed for diagnosis. Histologically, the lesion is identical to multiple myeloma, with sheets of plasma cells. It occurs at an aver-age age of 55 years. Evaluation for systemic myeloma is performed with bone marrow aspiration, testing of calcium levels, and measurement of urinary Bence Jones proteins. If the results of these studies are negative, then a solitary Brunicardi_Ch19_p0661-p0750.indd 72501/03/19 7:01 PM 726SPECIFIC CONSIDERATIONSPART IIplasmacytoma is diagnosed. Surgery is usually limited to a biopsy only, which may be excisional.134 Treatment consists of radiation with doses of 4000 to 5000 cGy. Up to 75% of patients develop systemic multiple myeloma with 10-year survival of approximately 20%.Chest Wall ReconstructionThe primary determinant of long-term freedom from recurrence and overall survival is margin status; therefore, adequate mar-gins of normal tissue must be included in the en bloc resec-tion. En bloc resection should include involved ribs, sternum, superior sulcus, or spine if necessary; invasion of these struc-tures should not be considered a contraindication to surgery in an otherwise fit patient. The resection should include at least one normal adjacent rib above and below the tumor, with all intervening intercostal muscles and pleura. In addition, an en bloc resection of overlying chest wall muscles is often neces-sary, such as of the pectoralis minor or major, serratus anterior, or latissimus dorsi. When the periphery of the lung is involved with the neoplasm, it is appropriate to resect the adjacent part of the pulmonary lobe in continuity (Fig. 19-42). Involvement of the sternum by a malignant tumor requires total resection of the sternum with the adjacent cartilage. Techniques for postop-erative respiratory support are now good enough that resection should not be compromised because of any concern about the patient’s ability to be adequately ventilated in the early postop-erative period.The extent of resection depends on the tumor’s location and on any involvement of contiguous structures. Laterally based lesions often require simple wide excision, with resec-tion of any contiguously involved lung, pleura, muscle, or skin. Anteriorly based lesions contiguous with the sternum require partial sternectomy. Primary malignant tumors of the sternum may require complete sternectomy. Posterior lesions involving the rib heads over their articulations with the vertebral bodies may, depending on the extent of rib involvement, require partial en bloc vertebrectomy.Optimal management of larger tumors includes care-ful preoperative planning and execution of the surgery by the thoracic surgeon and an experienced plastic surgeon in order to ensure optimal physiologic and cosmetic results. With these measures, reconstruction at the same operation can be accomplished.135 Reconstruction of a large defect in the chest wall requires the use of some type of material to prevent lung herniation and to provide stability for the chest wall (see Fig. 19-42). Mild degrees of paradoxical motion are often well tolerated if the area of instability is relatively small. Historically, a wide variety of materials have been used to reestablish chest wall stability, including rib autografts, steel struts, acrylic plates, and numerous synthetic meshes. The current preference is either a 2-mm polytetrafluoroethylene (Gore-Tex) patch or a double-layer polypropylene (Marlex) mesh sandwiched with methylmethacrylate. There are sev-eral properties that make Gore-Tex an excellent material for use in chest wall reconstruction: (a) it is impervious to fluid, which prevents pleural fluid from entering the chest wall and minimizes the formation of seromas, which can compromise the myocutaneous flap viability and provide a nidus for infec-tion; and (b) it provides excellent rigidity and stability when secured taut to the surrounding bony structure and, as a result, provides a firm platform for myocutaneous flap reconstruc-tion. Except for smaller lesions, tissue coverage requires the use of myocutaneous flaps (latissimus dorsi, serratus anterior, rectus abdominis, or pectoralis major muscles).136,137MEDIASTINUMAnatomy and Pathologic EntitiesThe mediastinum can be divided into compartments for classi-fication of anatomic components and disease processes, which, despite substantial overlap, facilitates understanding of general concepts of surgical interest. Several classification schemes exist, but for the purposes of this chapter, the three-compart-ment model is used (Fig. 19-43). The anterior compartment lies between the sternum and the anterior surface of the heart and great vessels. The visceral or middle compartment is located between the great vessels and the trachea. As the name implies, the posterior compartment lies posterior and includes the para-vertebral sulci, bilaterally, and the paraesophageal area.ABFigure 19-42. Principles of recon-struction after resection of a chest wall tumor (osteogenic sarcoma) are shown. A. En bloc resection of the involved chest wall, including nor-mal ribs above and below the tumor as well as pulmonary parenchyma, must be performed. The resected specimen is shown. B. A prosthesis has been sewn in place. In the lower third of the prosthesis, the line of diaphragm reattachment is seen. The skin defect was closed with a myo-cutaneous flap from the ipsilateral rectus muscle.Brunicardi_Ch19_p0661-p0750.indd 72601/03/19 7:01 PM

CHAPTER 19727CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAPosteriormediastinumAnterosuperiormediastinumMiddlemediastinumFigure 19-43. Anatomic division of the mediastinum.ThymusFigure 19-44. Normal appearance of the thymus gland in childhood. Ao = aorta; PA = pulmonary artery; VC = vena cava.The normal content of the anterior compartment includes the thymus gland or its remnant, the internal mammary artery and vein, lymph nodes, and fat. The thymus gland is large during childhood, occupying the entire anterior mediastinum (Fig. 19-44) but decreases in both thickness and length after adolescence and takes on a more fatty content, with only resid-ual islands of thymic cellular components (Fig. 19-45). The middle mediastinal compartment contains the pericardium and its contents, the ascending and transverse aorta, the superior and inferior venae cavae, the brachiocephalic artery and vein, the phrenic and upper vagus nerves, the trachea and main bronchi and corresponding lymph nodes, and the central portions of the pulmonary arteries and veins. The posterior compartment contains the descending aorta, esophagus, thoracic duct, azygos and hemiazygos veins, and lymph nodes. Numerous pathologic variants may be present in the various compartments, with much overlap. Table 19-25 includes the most common pathologic entities listed by compartment.138,139History and Physical ExaminationMediastinal pathology varies significantly by patient age. In children, neurogenic tumors of the posterior mediastinum are most common, followed by lymphoma, which is usually located in the anterior or middle compartment. Thymoma in child-hood is rare (Table 19-26). In adults, the most common tumors include neurogenic tumors of the posterior compartment, benign cysts occurring in any compartment, and thymomas of the ante-rior mediastinum (Table 19-27). In both age groups, about 25% of mediastinal tumors are malignant. Pediatric tumors will be discussed in Chapter 39.Up to two-thirds of mediastinal tumors in adults are dis-covered as asymptomatic abnormalities on radiologic studies ordered for other problems, particularly now that screening CT examinations are more prevalent. When symptomatic, these tumors are significantly more likely to be malignant. Charac-teristics such as size, location, rate of growth, and associated inflammation are important factors that correlate with symp-toms. Large, bulky tumors, expanding cysts, and teratomas can cause compression of mediastinal structures, in particular the trachea, and lead to cough, dyspnea on exertion, or stridor. Chest pain or dyspnea may be reported secondary to associated pleural effusions, cardiac tamponade, or phrenic nerve involve-ment. Occasionally, a mediastinal mass near the aortopulmonary window may be identified in a workup for hoarseness because of left recurrent laryngeal nerve involvement. The patient in Fig. 19-46 presented with hoarseness due to nodal compression of the left recurrent laryngeal nerve from a primary lung cancer with metastases to the level 5 and 6 lymph nodes in the region of the aortopulmonary window.The history and physical examination in conjunction with the imaging findings may suggest a specific diagnosis (Table 19-28). In one series, systemic symptoms were present in 50% of patients with a mediastinal mass and a lymphoproliferative dis-order, as compared with only 29% of patients with other masses (such as thymic or neurogenic). Laboratory signs of inflamma-tion were also noted; the erythrocyte sedimentation rate and C-reactive protein levels were elevated and leukocytosis was present in 86% of patients with a lymphoproliferative disorder, as compared with only 58% of patients with other types of medi-astinal masses.Imaging and Serum MarkersChest CT or MRI is required to fully delineate the anatomy.140 A contrast-enhanced CT scan enables clear delineation of the Brunicardi_Ch19_p0661-p0750.indd 72701/03/19 7:01 PM 728SPECIFIC CONSIDERATIONSPART IITable 19-25Usual location of the common primary tumors and cysts of the mediastinumANTERIOR COMPARTMENTVISCERAL COMPARTMENTPARAVERTEBRAL SULCIThymomaEnterogenous cystNeurilemoma-schwannomaGerm cell tumorLymphomaNeurofibromaLymphomaPleuropericardial cystMalignant schwannomaLymphangiomaMediastinal granulomaGanglioneuromaHemangiomaLymphoid hamartomaGanglioneuroblastomaLipomaMesothelial cystNeuroblastomaFibromaNeuroenteric cystParagangliomaFibrosarcomaParagangliomaPheochromocytomaThymic cystPheochromocytomaFibrosarcomaParathyroid adenomaThoracic duct cystLymphomaReproduced with permission from Shields TW: Mediastinal Surgery. Philadelphia, PA: Lea & Febiger; 1991.Table 19-26Mediastinal tumors in childrenTUMOR TYPEPERCENTAGE OF TOTALLOCATIONNeurogenic tumors40PosteriorLymphomas18Anterior/middleCysts18AllGerm cell tumors11AnteriorMesenchymal tumors9AllThymomasRareAnteriorReproduced with permission from Silverman NA, Sabiston DC: Mediastinal masses, Surg Clin North Am. 1980 Aug;60(4):757-777.Figure 19-45. Computed tomography scan showing the normal appearance of an involuted thymus gland in an adult. Note the near-total fatty appearance of the gland with only tiny islands of soft tissue scattered within it (small arrows).soft tissue structures from the vasculature and is preferred over noncontrast studies. If there is concern for invasion of vas-cular structures or spinal involvement, MRI is more accurate than CT scan and provides important information regarding respectability.If an endocrine origin is suspected, several other imaging modalities are available (Table 19-29). Single-photon emission CT (SPECT) technology may be used to improve image contrast and give information on three-dimensional localization, largely replacing conventional two-dimensional nuclear imaging studies. If a thyroid origin is suspected, a thyroid scan using 131I or 123I can identify most intrathoracic goiters and identify the extent of functioning thyroid tissue. If indicated, the thyroid scan should precede other scans requiring iodine-containing contrast agents because they would subsequently interfere with iodine tracer uptake by thyroid tissue. If a pheochromo-cytoma or neuroblastoma is suspected, the octreotide scan or 123I-metaiodobenzylguanidine (MIBG) scans are helpful in diag-nosis and localization. The sestamibi scan may be useful for diagnosing and localizing a mediastinal parathyroid gland. PET is useful for distinguishing malignant from benign tumors and may help detect distant metastases in some patients. However, the role of routine PET imaging for staging surgically resectable lesions of the mediastinum has not been established.The use of serum markers to evaluate a mediastinal mass can be invaluable in some patients. For example, nonsemino-matous and seminomatous germ cell tumors can frequently be diagnosed and often distinguished from one another by the lev-els of α-fetoprotein (AFP) and human chorionic gonadotropin (hCG). In over 90% of nonseminomatous germ cell tumors, either the AFP or the hCG level will be elevated. Results are close to 100% specific if the level of either AFP or hCG is greater than 500 ng/mL. Some centers institute chemotherapy based on this result alone, without biopsy confirmation of the diagnosis. In contrast, the AFP level in patients with mediastinal seminoma is always normal; only 10% will have elevated hCG, which is usually less than 100 ng/mL. Other serum markers, such as intact parathyroid hormone level for ectopic parathyroid Brunicardi_Ch19_p0661-p0750.indd 72801/03/19 7:01 PM

CHAPTER 19729CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAFigure 19-46. Computed tomography scan of a patient who pre-sented with hoarseness due to compression of the left recurrent laryngeal nerve caused by mediastinal lymph node metastases to the aortopulmonary window area (arrow) from a primary lung cancer.adenomas, may be useful for diagnosing and also for intraopera-tively confirming complete resection. After successful resection of a parathyroid adenoma, this hormone level should rapidly normalize.Diagnostic Nonsurgical Biopsies of the MediastinumThe treatment of up to 60% of patients with anterior mediastinal masses is ultimately nonsurgical, so it is essential to understand all options for obtaining adequate tissue for a definitive diagno-sis using the least invasive approach. CT-guided needle biopsy, EBUSand EUS-guided FNA, and even core-needle biopsy (either CT-guided and EUS-guided) have proven most useful for cytologic and tissue diagnosis of mediastinal masses and lymphadenopathy.When FNA and core-needle biopsy were combined, the accuracy was 98%, compared to 79% for each modality inde-pendently. In addition, core-needle biopsy changed the diagno-sis in nine cases that had been missed by FNA due to inadequate specimens. Finally, core-needle biopsy was better at diagnosis for benign diseases compared to FNA. Accessible nodal stations Table 19-27Mediastinal tumors in adultsTUMOR TYPEPERCENTAGE OF TOTALLOCATIONNeurogenic tumors21PosteriorCysts20AllThymomas19AnteriorLymphomas13Anterior/middleGerm cell tumors11AnteriorMesenchymal tumors7AllEndocrine tumors6Anterior/middleData from Shields TW: General Thoracic Surgery, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1994.include subcarinal (level 7), aortopulmonary (level 5), parae-sophageal (level 8), and inferior pulmonary ligament (level 9) as well as paratracheal (level 4).141 Technical expertise in these modalities should be pursued by thoracic and general surgeons.Historically, needle biopsies of anterior mediastinal masses were reportedly sensitive and specific for most carcinomatous tumors, but there were questions regarding accuracy for diagnos-ing lymphomas.142 However, advances in cytopathology as well as needle biopsy technology have substantially improved diag-nostic accuracy such that most centers are reporting yields rang-ing from 75% to 80% for the diagnosis of lymphoma as well. To achieve maximal diagnostic yield for mediastinal masses sug-gestive of a lymphoma, it is necessary to obtain multiple fine-needle aspirates, preferably with immediate onsite rapid cytologic analysis to confirm sampling of the target tissue and adequate cellularity. This also facilitates processing of the sample to ensure that proper studies for lymphoma, including flow cytometry, are obtained. If the needle biopsy is inconclusive, surgical biopsy can be performed.143,144 If the lesion is accessible by CT-guided or EUS-guided core-needle biopsy, intraoperative frozen section or immediate cytologic smear of a core biopsy can also be per-formed. Currently, core-needle biopsy with EBUS is not possible. The authors perform their own endobronchial, endoscopic, and CT-guided transbronchial and transthoracic biopsies, and in our experience, lack of cellularity in the aspirate is readily apparent. In general, plans to proceed with surgical biopsy are made in combination with the image-guided aspiration and, as such, are performed in the same setting. This enables the authors to avoid a more invasive surgical procedure when FNA or core-needle biopsy is sufficient without contributing to delays in diagnosis by having multiple attempts from multiple providers (such as inter-ventional radiology and pulmonology) before involvement of the surgeon in the diagnostic workup.Table 19-28Signs and symptoms suggestive of various diagnoses in the setting of a mediastinal massDIAGNOSISHISTORY AND PHYSICAL FINDINGSCOMPARTMENT LOCATION OF MASSLymphomaNight sweats, weight loss, fatigue, extrathoracic adenopathy, elevated erythrocyte sedimentation rate or C-reactive protein level, leukocytosisAny compartmentThymoma with myasthenia gravisFluctuating weakness, early fatigue, ptosis, diplopiaAnteriorMediastinal granulomaDyspnea, wheezing, hemoptysisVisceral (middle)Germ cell tumorMale gender, young age, testicular mass, elevated levels of human chorionic gonadotropin and/or α-fetoproteinAnteriorBrunicardi_Ch19_p0661-p0750.indd 72901/03/19 7:01 PM 730SPECIFIC CONSIDERATIONSPART IITable 19-29Nuclear imaging relevant to the mediastinumRADIOPHARMACEUTICAL, RADIONUCLIDE, OR RADIOCHEMICALLABELDISEASE OF INTERESTIodine131I, 123IRetrosternal goiter, thyroid cancerMonoclonal antibodies111In, 99mTcNSCLC, colon and breast cancer, prostate cancer metastasesOctreotide111InAmine precursor uptake decarboxylation tumors: carcinoid, gastrinoma, insulinoma, small cell lung cancer, pheochromocytoma, glucagonoma, medullary thyroid carcinoma, paragangliomaGallium67GaLymphoma, NSCLC, melanomaSestamibi99mTcMedullary thyroid carcinoma, nonfunctional papillary or follicular thyroid carcinoma, Hürthle cell thyroid carcinoma, parathyroid adenoma or carcinomaThallium201TlSee sestamibiMIBG131I, 123IPheochromocytoma, neuroblastoma; see also octreotideFluorodeoxyglucose18FGeneral oncologic imaging, breast and colon cancer, melanomaAbbreviations: MIGB = metaiodobenzylguanidine; NSCLC = non–small cell lung cancer.Reproduced with permission from Pearson FG, Cooper JD, Deslauriers J, et al: Thoracic Surgery, 2nd ed. New York, NY: Elsevier/Churchill Livingstone; 2002.Surgical Biopsies and Resection of Mediastinal MassesFor tumors of the mediastinum that are not amenable to an endo-scopic or CT-guided needle biopsy or that do not yield sufficient tissue for diagnosis, a surgical biopsy is indicated. The defini-tive approach to a surgical biopsy of the anterior mediastinum is through a median sternotomy. At the time of sternotomy, if the lesion is easily resectable, it should be completely removed. Given the invasiveness of the procedure and the inability in some patients to obtain a definitive diagnosis by frozen section, less invasive procedures are preferable if the lesion is large or if the CT scan or history suggests that surgery is not the best definitive treatment.Masses in the paratracheal region are easily biopsied by mediastinoscopy. For tumors of the anterior or posterior medi-astinum, a left or right VATS approach often allows safe and adequate surgical biopsies. In some patients, an anterior medi-astinotomy (i.e., Chamberlain procedure) may be ideal for an anterior tumor or a tumor with significant parasternal extension. Before a surgical biopsy is pursued, a discussion should be held with the pathologist regarding routine histologic assessment, spe-cial stains and markers, and requirements for lymphoma workup.Surgical resection using minimally invasive approaches, including video-assisted and robotic thoracoscopic surgery and transcervical, are now routine for the vast majority of middle and posterior tumors and for moderate sized (<5 to 6 cm) anterior mediastinal tumors.145-148 Outcomes comparing VATS to open thymectomy in patients with myasthenia gravis without thymoma were prospectively evaluated by Chang and colleagues in 2005, and no differences were seen in terms of response to therapy and recurrence of symptoms. Pain scores were significantly better in the VATS approach.149 These reports and others support application of VATS for the majority of ante-rior mediastinal masses.Other minimally invasive approaches are under study. For example, good results have been reported using a cervical incision with a sternal retractor for thymus removal. The upward lift allows the surgeon reasonable access to the anterior medi-astinum and has proven adequate in some centers for definitive resection of the thymus gland for myasthenia gravis.150For larger anterior mediastinal masses or in centers where expertise in thoracoscopy is not available, median sternotomy and thoracotomy remain excellent options for resection of ante-rior mediastinal masses. Occasionally, a lateral thoracotomy with sternal extension (hemi-clamshell) provides excellent exposure for extensive mediastinal tumors that have a lateral component.Most surgeons would agree that if a larger anterior medi-astinal tumor is seen or malignancy is suspected, a median ster-notomy with a more radical resection should be performed.Mediastinal NeoplasmsThymic Hyperplasia. Diffuse thymic hyperplasia was first described in children after successful chemotherapy for lym-phoma. It has now been described in adults and is referred to as “rebound thymic hyperplasia.”151 It is most frequently reported after chemotherapy for lymphoma or germ cell tumors. Ini-tially, atrophy of the thymic gland is seen with subsequent thymic gland enlargement, which can be dramatic. The usual time course for thymic hyperplasia is about 9 months after ces-sation of chemotherapy (range 2 weeks to 12 months). Benign hyperplasia must be clearly distinguished from recurrent lym-phoma or germ cell tumors, which may be difficult since thymic hyperplasia is dramatic in some patients; careful follow-up with serial CT scans is the minimum requirement. The role of PET scanning is unclear. Thymic hyperplasia is a known cause of false-positive PET scans; in many patients, CT scan will show a triangular soft tissue density in the retrosternal space that has a characteristic bilobed anatomic appearance consistent with thymus gland.152 In addition, a low standardized uptake value of tracer on PET scan suggests a benign tumor.153 Biopsies may be required if the clinical index of suspicion is high.Brunicardi_Ch19_p0661-p0750.indd 73001/03/19 7:01 PM

CHAPTER 19731CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAThymoma. While it is the most frequently encountered neo-plasm of the anterior mediastinum in adults (seen most fre-quently between 40 and 60 years of age), thymoma is rare in children. Between 10% and 50% of patients with thymoma will have symptoms suggestive of myasthenia gravis or have circulating antibodies to acetylcholine receptor, but less than 10% of patients with myasthenia gravis have a thymoma. Most patients with thymoma are asymptomatic. Thymectomy leads to improvement or resolution of symptoms of myasthe-nia gravis in only about 25% of patients with thymomas. In contrast, in patients with myasthenia gravis and no thymoma, thymectomy results are superior: up to 50% of patients have a complete remission, and 90% improve. In 5% of patients with thymomas, other paraneoplastic syndromes, including red cell aplasia, hypogammaglobulinemia, systemic lupus erythema-tosus, Cushing’s syndrome, or SIADH, may be present. Large thymic tumors may present with symptoms related to a mass effect, which may include cough, chest pain, dyspnea, or SVC syndrome.The diagnosis may be suspected based on CT scan and history, but imaging alone is not diagnostic. In most centers, the diagnosis is made after surgical resection because of the rela-tive difficulty of obtaining a needle biopsy and the likelihood that removal will ultimately be recommended. Biopsy should be avoided in cases where imaging is highly suggestive of thy-moma. In most patients, the distinction between lymphomas and thymomas can be made on CT scan since most lymphomas have marked lymphadenopathy and thymomas most frequently appear as a solitary encapsulated mass. PET scan may have a role in differentiating thymic cancer from thymoma, as thymic cancer tends to be very FDG avid.153 In addition, PET scan may facilitate identification of low-risk and minimally invasive thy-moma; a standardized uptake value (SUV) <5 was associated with Masaoka stage I or II thymoma, whereas invasive thymoma and mediastinal lymphoma were more likely when the SUV was >5.154 In cases where the diagnosis is unclear, transmediastinal, not transpleural, CT-guided FNA biopsy has a diagnostic sen-sitivity of 87% and a specificity of 95% in specialized centers.The most commonly accepted staging system for thymoma is that of Masaoka.155 It is based on the presence or absence of gross or microscopic invasion of the capsule and of surrounding structures, as well as on the presence or absence of metastases (Table 19-30). Histologically, thymomas are characterized by a mixture of epithelial cells and mature lymphocytes. Grossly, many thymomas remain well encapsulated. Even those with capsular invasion often lack histologic features of malignancy; they appear cytologically benign and identical to early-stage tumors. This lack of classic cellular features of malignancy is why most pathologists use the term “thymoma” or “invasive thymoma” rather than “malignant thymoma.” Thymic tumors with malignant cytologic features are classified separately and referred to as “thymic carcinoma.”The definitive treatment for thymoma is complete surgical removal; local recurrence rates and survival vary according to stage (Fig. 19-47). In centers with significant experience with VATS procedures, thymoma is not a contraindication to VATS approach, provided the principles of resection are adhered to, such as a complete resection without disrupting the capsule.156 Otherwise, resection is generally accomplished by median ster-notomy with extension to hemi-clamshell in more advanced cases. Even advanced tumors with local invasion of resectable structures such as the pericardium, SVC, or innominate vessels should be considered for resection with reconstruction.A multidisciplinary approach to nonresectable and more advanced lesions (stage ≥II) is mandatory to optimize patient care. The goal for surgical resection should be complete exci-sion of the mass with total thymectomy. All contiguous and noncontiguous disease is removed at the same setting; this may include resection of the pericardium or pleura, adjacent adher-ent lung, phrenic nerve, major vascular structures, and pleural metastasis. Bilateral phrenic nerve resection should be avoided, however, due to the major respiratory morbidity associated with bilateral paralyzed hemidiaphragms.The role of adjuvant or neoadjuvant therapies for advanced-stage tumors remains unclear. Traditionally, stage II thymomas have been treated by complete surgical resection fol-lowed by mediastinal radiation, but randomized trials have not been done. A recent retrospective review of a single-institution series of stage II thymoma patients showed no difference in survival or local recurrence after complete surgical resection alone, as compared with surgical resection with radiotherapy. Advanced thymomas have been shown to respond to platinum-based chemotherapy and to corticosteroids.157 One summary of chemotherapy trials showed an overall response rate of about 70%. Cisplatin/doxorubicin-based regimens appear to yield the best results. The combination radiotherapy and chemotherapy for local progression appears to prolong survival in some small series.158 Radiation therapy in surgically resected stage III thy-moma is likely beneficial in extending disease-specific survival; an analysis of the Surveillance, Epidemiology, and End Results (SEER) database identified 476 patients with stage III thymoma treated with primary surgery. Postoperative radiation was given Table 19-30Masaoka staging system for thymomaStage IEncapsulated tumor with no gross or microscopic evidence of capsular invasionStage IIGross capsular invasion or invasion into the mediastinal fat or pleura or microscopic capsular invasionStage IIIGross invasion into the pericardium, great vessels, or lungStage IVAPleural or pericardial disseminationStage IVBLymphogenous or hematogenous metastasis1.0.8.6.4.20Proportion surviving02010YearsP=.002Stage IStage IVStage IIIStage IIFigure 19-47. Stage-specific survival for thymomas.Brunicardi_Ch19_p0661-p0750.indd 73101/03/19 7:01 PM 732SPECIFIC CONSIDERATIONSPART IIFigure 19-48. Massive thymolipoma that was asymptomatic in an 18-year-old female.to 322 patients with a significant improvement in survival (127 months compared to 105 months, P = .038) despite the fact that these patients were more likely to have had debulking rather than curative resection. In multivariate analysis, disease-specific survival was better in the adjuvant radiation group.159 There-fore, it is imperative that all patients with thymomas undergo a thorough evaluation for potential resection. Current guidelines recommend radiation for patients with unresectable thymoma who have failed induction chemotherapy or for patients with incompletely resected invasive thymoma or thymic cancer. Planning the radiation ports requires input from the surgeon; it is important for the surgeon to carefully document areas of adherence between the thymoma and adjacent structures during the operation, with clips or other radiopaque markers placed to guide radiation therapy postoperatively. Extracapsular extension and positive surgical margins should be noted by the pathologist and correlated anatomically so that the surgeon and radiation oncologist can ensure appropriate radiation treatment.Thymic Carcinoma. Thymic carcinomas are unequivocally malignant at the microscopic level. Suster and Rosai classified thymic carcinomas into low-grade and high-grade tumors.160 Low-grade tumors are well differentiated with squamous cell, mucoepidermoid, or basaloid features. High-grade thymic car-cinomas include those with lymphoepithelial, small cell neu-roendocrine, sarcomatoid, clear cell, and undifferentiated or anaplastic features. Care must be taken to differentiate thymic carcinoma from lung cancer metastatic to the thymus gland as the histologic features can be similar between the two. Com-pared with thymomas, they are a more heterogeneous group of malignancies with a propensity for early local invasion and widespread metastases. Malignant pleural and pericardial effu-sions occur frequently.Five-year survival rates are between 30% and 50%. Com-plete resection is occasionally curative and leads to improved survival, but most thymic carcinomas will recur and are refractory to chemotherapy.157 Management, therefore, depends on the completeness of the resection. Postoperative care includes radiation therapy, guided by residual gross disease or microscopically positive margins from the resection specimen. Chemotherapy may also be given, with carboplatin/paclitaxel recommended based on the best response rates with the least toxicity in clinical trials. The prognosis of patients with thymic cancer remains poor.Thymolipoma. Thymolipomas are rare benign tumors that may grow to a very large size prior to diagnosis. On CT scan, their appearance can be dramatic, with a characteristic fat den-sity dotted by islands of soft tissue density representing islands of thymic tissue (Fig. 19-48). Thymolipomas are generally well-encapsulated, soft, and pliable masses that do not invade surrounding structures. Resection is recommended for large masses.Neurogenic Tumors. Most neurogenic tumors of the medi-astinum arise from the cells of the nerve sheath, from ganglion cells, or from the paraganglionic system (Table 19-31). The incidence, cell types, and risk of malignancy strongly correlate with patient age. Tumors of nerve sheath origin predominate in adults. Most present as asymptomatic incidental findings, and most are benign. In children and young adults, tumors of the autonomic ganglia predominate, with up to two-thirds being malignant.161Nerve Sheath Tumors. Nerve sheath tumors account for 20% of all mediastinal tumors. More than 95% of nerve sheath tumors are benign neurilemomas or neurofibromas. Malignant neurosarcomas are much less common.Neurilemoma. Neurilemomas, also called schwannomas, arise from Schwann cells in intercostal nerves. They are firm, well encapsulated, and generally benign. Two characteristic histo-logic components are referred to as Antoni type A and Antoni type B regions. Antoni type A regions contain compact spindle Brunicardi_Ch19_p0661-p0750.indd 73201/03/19 7:01 PM

CHAPTER 19733CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAFigure 19-49. Magnetic resonance image of a neurogenic tumor with extension into the spinal canal via the foramen, giving a typical dumbbell appearance.Table 19-31Classification of neurogenic tumors of the mediastinumTUMOR ORIGINBENIGNMALIGNANTNerve sheathNeurilemoma, neurofibroma, melanotic schwannoma, granular cell tumorNeurofibrosarcomaGanglion cellGanglioneuromaGanglioneuroblastoma, neuroblastomaParaganglionic cellChemodectoma, pheochromocytomaMalignant chemodectoma, malignant pheochromocytomaReproduced with permission from Pearson FG, Cooper JD, Deslauriers J, et al: Thoracic Surgery, 2nd ed. New York, NY: Elsevier/Churchill Livingstone; 2002.cells with twisted nuclei and nuclear palisading. Antoni type B regions contain loose and myxoid connective tissue with hap-hazard cellular arrangement. These characteristics distinguish neurilemoma from malignant fibrosarcomatous tumors, which lack encapsulation and have no Antoni features. If routine CT scan suggests extension of a neurilemoma into the intervertebral foramen, MRI is used to evaluate the extent of this “dumbbell” configuration (Fig. 19-49). Such a configuration may lead to cord compression and paralysis and requires a more complex surgical approach. Resection is recommended; VATS has been established as safe and effective for simple and, in experienced centers, even the more complex operations.162 It is reasonable to follow small, asymptomatic paravertebral tumors in older patients or in patients at high risk for surgery. In children, ganglioneuroblastomas or neuroblastomas are more common; therefore, all neurogenic tumors should be completely resected.Neurofibroma. Neurofibromas consist of both nerve sheath and nerve cells and account for up to 25% of nerve sheath tumors. Up to 40% of patients with mediastinal fibromas have general-ized neurofibromatosis (von Recklinghausen’s disease). About 70% of neurofibromas are benign, but malignant degeneration to neurofibrosarcoma occurs in 25% to 30% of patients.163 The risk of malignant degeneration increases with advancing age, von Recklinghausen’s disease, and exposure to previous radia-tion. Neurofibrosarcomas carry a poor prognosis because of rapid growth and aggressive local invasion along nerve bun-dles. Complete surgical resection is the mainstay of treatment. Adjuvant radiotherapy or chemotherapy does not confer a sig-nificant benefit, but may be added if complete resection is not possible.164 The 5-year survival rate is 53%, but it drops to 16% in patients with neurofibromatosis or with large tumors (>5 cm).Ganglion Cell Tumors Ganglion cell tumors (ganglioneuro-mas, ganglioneuroblastomas, and neuroblastomas) arise from the sympathetic chain or from the adrenal medulla.1. Ganglioneuroma. Well-differentiated, benign tumors char-acterized histologically by well-differentiated ganglion cells with a background of Schwann cells, these are most often found incidentally in asymptomatic young adults. Diarrhea related to secretion of a vasoactive intestinal peptide has been described in some patients. These tumors have a pro-pensity for intraspinal canal extension, although they remain well-encapsulated; complete resection is curative, with a low risk of local recurrence.Brunicardi_Ch19_p0661-p0750.indd 73301/03/19 7:01 PM 734SPECIFIC CONSIDERATIONSPART II2. Ganglioneuroblastoma. Ganglioneuroblastomas contain a mixture of benign ganglion cells and malignant neuro-blasts. The distribution of these cells within the tumor is predictive of the clinical course. The nodular pattern has a high incidence of metastatic disease, whereas the diffuse pattern rarely metastasizes. Gross examination typically reveals encapsulated tumor; histologically, there are focal calcifications around regions of neuroblasts. Ganglioneu-roblastomas arise most frequently in infants and children <3 years old. The majority are resectable, with 80% 5-year survival.3. Neuroblastoma. Highly malignant, neuroblastomas are the most common extracranial solid malignancy of childhood. The primary site is intrathoracic malignancy in 14%; exten-sion into the spinal canal and osseous invasion commonly present. These thoracic tumors are not as recalcitrant to chemotherapy and surgical resection as other chest malig-nancies; they are more likely to be resectable, with less inva-sion of surrounding organs. More than half occur in children under 2 years old; 90% arise within the first decade of life, and thus, these malignancies are discussed in more detail in Chapter 39.Paraganglionic Tumors. Paraganglionic tumors arising in the thoracic cavity include chemodectomas and pheochromo-cytomas. Only 10% of all pheochromocytomas are located in an extra-adrenal site. Intrathoracic pheochromocytomas are one of the rarest tumors.Approximately 10% of thoracic pheochromocytomas are malignant, a rate similar to that of adrenal tumors. The most common thoracic location is within the costovertebral sulcus, but paraganglionic tumors also arise within the visceral com-partment of the mediastinum. These catecholamine-producing lesions can lead to life-threatening hemodynamic problems, so complete removal is important. Diagnosis is generally confirmed by measuring elevated levels of urinary catecholamines and their metabolites. Localization is by CT scan, aided by MIBG scintigraphy. Preoperative care includes αand β-adrenergic blockade to prevent intraoperative malignant hypertension and arrhythmias. These tumors tend to be highly vascular and should be approached with care. Chemodectomas are rare tumors that may be located around the aortic arch, vagus nerves, or aor-ticosympathetics. They rarely secrete catecholamines and are malignant in up to 30% of patients.Lymphoma. Overall, lymphomas are the most common malig-nancy of the mediastinum. In about 50% of patients who have both Hodgkin’s and non-Hodgkin’s lymphoma, the mediasti-num may be the primary site. The anterior compartment is most commonly involved, with occasional involvement of the mid-dle compartment and hilar nodes. The posterior compartment is rarely involved. Chemotherapy and/or radiation results in a cure rate of up to 90% for patients with early-stage Hodgkin’s disease and up to 60% with more advanced stages.Mediastinal Germ Cell Tumors. Germ cell tumors are uncom-mon neoplasms, but they are the most common malignancy in young men 15 to 35 years of age. Most germ cell tumors are gonadal in origin; primary mediastinal germ cell tumors com-prise less than 5% of all germ cell tumors and less than 1% of all mediastinal tumors (usually occurring in the anterior com-partment). If a malignant mediastinal germ cell tumor is found, it is important to exclude a gonadal primary tumor. Primary mediastinal germ cell tumors (including teratomas, seminomas, and nonseminomatous malignant germ cell tumors) are a het-erogeneous group of benign and malignant neoplasms thought to originate from primitive pluripotent germ cells “misplaced” in the mediastinum during embryonic development. Previ-ously, most mediastinal germ cell tumors were thought to be metastatic. However, two lines of evidence suggest that many mediastinal germ cell tumors are primary, developing from plu-ripotent primordial germ cells in the mediastinum: (a) several autopsy series showed that patients with extragonadal sites of germ cell tumors, presumed previously to have originated from the gonads, had no evidence of an occult primary tumor or of any residual scar of the gonads, even after an exhaustive search; and (b) patients treated by surgery or radiation for their medi-astinal germ cell tumors had long-term survival with no late testicular recurrences.165About one-third of all primary mediastinal germ cell tumors are seminomatous. Two-thirds are nonseminomatous tumors or teratomas. Treatment and prognosis vary consider-ably within these two groups. Mature teratomas are benign and can generally be diagnosed by the characteristic CT findings of multilocular cystic tumors, encapsulated with combinations of fluid, soft tissue, calcium, and/or fat attenuation in the anterior compartment. FNA biopsy alone may be diagnostic for semi-nomas, usually with normal serum markers, including hCG and AFP. In 10% of seminomas, hCG levels may be slightly ele-vated. FNA findings, along with high hCG and AFP levels, can accurately diagnose nonseminomatous tumors. If the diagnosis remains uncertain after assessment of FNA findings and serum marker levels, then core-needle biopsies or surgical biopsies may be required. Thoracoscopy is the most frequent diagnostic surgical approach.1. Seminoma. Most patients with seminomas have advanced disease at the time of diagnosis and present with symptoms of local compression, including SVC syndrome, dyspnea, or chest discomfort. With advanced disease, the preferred treatment is combination cisplatin-based chemotherapy regimens with bleomycin and either etoposide or vinblas-tine. Complete responses have been reported in over 75% of patients treated with these regimens. Surgical resection may be curative for small asymptomatic seminomas that are found incidentally with screening CT scans. Surgical resection of residual masses after chemotherapy may be indicated.2. Nonseminomatous germ cell tumors. Nonseminomatous germ cell tumors include embryonal cell carcinomas, cho-riocarcinomas, endodermal sinus tumors, and mixed types. They are often bulky, irregular tumors of the anterior medi-astinum with areas of low attenuation on CT scan because of necrosis, hemorrhage, or cyst formation. Frequently, adjacent structures have been involved, with metastases to regional lymph nodes, pleura, and lungs. Lactate dehy-drogenase (LDH), AFP, and hCG levels are frequently elevated. Chemotherapy is the preferred treatment and includes combination therapy with cisplatin, bleomycin, and etoposide, followed by surgical resection of residual disease. With this regimen, survival is 67% at 2 years and 60% at 5 years. Surgical resection of residual masses is indicated, as it may guide further therapy. Up to 20% of residual masses contain additional tumors; in another 40%, mature teratomas; and the remaining 40%, fibrotic tissue. Brunicardi_Ch19_p0661-p0750.indd 73401/03/19 7:01 PM

CHAPTER 19735CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAIt is important to note that oxygen toxicity can occur in patients who have been exposed to bleomycin; high lev-els of oxygen supplementation in the perioperative setting should be avoided in these patients as respiratory failure and death can ensue.166 Factors independently predictive of survival after induction chemotherapy followed by resec-tion are elevated serum tumor markers after resection, postchemotherapy pathologic findings (complete necrosis vs. teratoma), and persistent germ cell or non–germ cell cancer in the pathologic specimen.1663. Teratoma. Teratomas are the most common type of medi-astinal germ cell tumors, accounting for 60% to 70% of mediastinal germ cell tumors. They contain two or three embryonic layers that may include teeth, skin, and hair (ectodermal), cartilage and bone (mesodermal), or bron-chial, intestinal, or pancreatic tissue (endodermal). Ther-apy for mature, benign teratomas is surgical resection, which confers an excellent prognosis. Rarely, teratomas may contain a focus of carcinoma; these malignant tera-tomas (or teratocarcinomas) are locally aggressive. Often diagnosed at an unresectable stage, they respond poorly to chemotherapy and in a limited manner to radiotherapy; prognosis is uniformly poor.Mediastinal CystsBenign cysts account for up to 25% of mediastinal masses and are the most frequently occurring mass in the middle medias-tinal compartment. A CT scan showing characteristic features of near water density in a typical location is virtually 100% diagnostic.1671. Pericardial cyst. Usually asymptomatic and detected inci-dentally in the right costophrenic angle, pericardial cysts typically contain a clear fluid and are lined with a single layer of mesothelial cells. For most simple, asymptomatic pericardial cysts, observation alone is recommended. Sur-gical resection or aspiration may be indicated for complex cysts or large symptomatic cysts.2. Bronchogenic cyst. Developmental anomalies that occur during embryogenesis and occur as an abnormal budding of the foregut or tracheobronchial tree, bronchogenic cysts arise most often in the mediastinum just posterior to the carina or main stem bronchus. Approximately 15% occur within the pulmonary parenchyma. Thin-walled and lined with respiratory epithelium, they contain a protein-rich mucoid material and varying amounts of seromucous glands, smooth muscle, and cartilage. They may commu-nicate with the tracheobronchial tree. In adults, over half of all bronchogenic cysts are found incidentally during workup for an unrelated problem or during screening. The natural history of an incidentally diagnosed, asymptomatic bronchogenic cyst is unknown, but it is clear that many such cysts do not lead to clinical problems. In one study of young military personnel, 78% of all bronchogenic cysts found on routine CXRs were asymptomatic. However, in other reports with more comprehensive follow-up, up to 67% of adults with incidentally found bronchogenic cysts eventu-ally became symptomatic. Symptoms include chest pain, cough, dyspnea, and fever. If large (>6 cm) or symptomatic, resection is generally recommended since serious compli-cations may occur if the cyst becomes larger or infected. Complications include airway obstruction, infection, rup-ture, and, rarely, malignant transformation.168,169  Traditionally, complete removal of the cyst wall has been via posterolateral thoracotomy.170 Resection of infected cysts may be quite difficult because of dense adhesions; elective removal is often recommended before infection has a chance to occur. Thoracoscopic exploration and resec-tion are possible for small cysts with minimal adhesions. With increasing experience using video-assisted or robotic-assisted thoracoscopy, a greater proportion of these lesions are amenable to minimally invasive resection.3. Enteric cyst. Most clinicians agree that in contrast to bronchogenic cysts, esophageal cysts should be removed, regardless of the presence or absence of symptoms. Esopha-geal cysts have a propensity for serious complications sec-ondary to enlargement, leading to hemorrhage, infection, or perforation. Thus, surgical resection is the treatment of choice in both adults and children. As with bronchogenic cysts, experienced surgeons are approaching enteric cyst resections using minimally invasive techniques with great success.4. Thymic cyst. Generally asymptomatic, thymic cysts are often discovered incidentally. Simple cysts are of no con-sequence; however, the occasional cystic neoplasm must be ruled out. Cystic components occasionally are seen in patients with thymoma and Hodgkin’s disease.5. Ectopic endocrine glands. Up to 5% of all mediastinal masses are of thyroid origin; most are simple extensions of thyroid masses. Usually nontoxic, over 95% can be com-pletely resected through a cervical approach. True ectopic thyroid tissue of the mediastinum is rare. About 10% to 20% of abnormal parathyroid glands are found in the mediasti-num; most can be removed during exploration from a cervi-cal incision. In cases of true mediastinal parathyroid glands, thoracoscopic or open resection may be indicated. Location can generally be pinpointed by a combination of CT scan and Sestamibi scans.MediastinitisAcute Mediastinitis. Acute mediastinitis is a fulminant infec-tious process that spreads rapidly along the continuous fascial planes connecting the cervical and mediastinal compartments. Infections originate most commonly from esophageal perfora-tions, sternal infections, and oropharyngeal or neck infections, but a number of less common etiologic factors can lead to this deadly process (Table 19-32). Clinical signs and symptoms include fever, chest pain, dysphagia, respiratory distress, and cervical and upper thoracic subcutaneous crepitus. In severe cases, the clinical course can rapidly deteriorate to florid sepsis, hemodynamic instability, and death. Thus, a high index of sus-picion is required in the context of any infection with access to the mediastinal compartments.A chest CT scan illuminates the extent of spread and guides selection of the best approach to surgical drainage. Acute mediastinitis is a true surgical emergency; treatment must be instituted immediately and aimed at correcting the primary problem, such as the esophageal perforation or oro-pharyngeal abscess, and debridement and drainage of the spreading infectious process within the mediastinum, neck, pleura, and other tissue planes. Antibiotics, fluid resusci-tation, and other supportive measures are also important. Brunicardi_Ch19_p0661-p0750.indd 73501/03/19 7:01 PM 736SPECIFIC CONSIDERATIONSPART IITable 19-32Etiologic factors in acute mediastinitisEsophageal perforation Iatrogenic  Balloon dilatation (for achalasia)  Bougienage (for peptic stricture)  Esophagoscopy  Sclerotherapy (for variceal bleeding) Spontaneous  Postemetic (Boerhaave’s syndrome) Straining during:  Elimination  Weight lifting Seizure  Pregnancy  Childbirth Ingestion of foreign bodies Trauma  Blunt  Penetrating Postsurgical  Infection  Anastomotic leak Erosion by cancerDeep sternotomy wound infectionOropharynx and neck infectionsLudwig’s anginaQuinsyRetropharyngeal abscessCellulitis and suppurative lymphadenitis of the neckInfections of the lung and pleuraSubphrenic abscessRib or vertebral osteomyelitisHematogenous or metastatic abscessReproduced with permission from Pearson FG, Cooper JD, Deslauriers J, et al: Thoracic Surgery, 2nd ed. New York, NY: Elsevier/Churchill Livingstone; 2002.Debridement may need to be repeated and other planes and cavities explored depending on the patient’s clinical status. Blood cell counts and serial CT scans may also be required. Persistent sepsis or collections on CT scan may require further radical surgical debridement.Chronic Mediastinitis. Sclerosing or fibrosing mediastinitis results from chronic mediastinal inflammation that originates in the lymph nodes, most frequently from granulomatous infec-tions such as histoplasmosis or tuberculosis. Chronic, low-grade inflammation leads to fibrosis and scarring, which can, in some patients, result in entrapment and compression of the low-pressure veins (including the SVC and innominate and azy-gos veins), the esophagus, and pulmonary arteries. There is no definitive treatment. Surgery is indicated only for diagnosis or in specific patients to relieve airway or esophageal obstruction or to achieve vascular reconstruction. Reports of palliative suc-cess with less invasive procedures (such as dilation and stenting of airways, the esophagus, or the SVC) are promising. In one series of 22 patients, ketoconazole was effective in controlling progression. In another series of 71 patients, 30% died from disease-associated complications during long-term follow-up. Chronic mediastinitis is similar to retroperitoneal fibrosis, scle-rosing cholangitis, and Riedel’s thyroiditis.PLEURA AND PLEURAL SPACEAnatomyEach hemithorax has a mesothelial lining that invaginates at the hilum of each lung and continues on to cover each lung. The portion lining the bony rib cage, mediastinum, and dia-phragm is called the parietal pleura, whereas the portion encas-ing the lung is known as the visceral pleura. Between these two surfaces is the potential pleural space, which is normally occupied by a thin layer of lubricating pleural fluid. A network of somatic, sympathetic, and parasympathetic fibers innervates the parietal pleura. Irritation of the parietal surface by inflam-mation, tumor invasion, trauma, and other processes can lead to a sensation of chest wall pain. The visceral pleura have no somatic innervation.171,172Pleural EffusionPleural effusion refers to any significant collection of fluid within the pleural space. Normally, between 5 and 10 L of fluid enters the pleural space each day by filtration through microves-sels supplying the parietal pleura (located mainly in the less dependent regions of the cavity). The net balance of pressures in these capillaries leads to fluid flow from the parietal pleural surface into the pleural space, and the net balance of forces in the pulmonary circulation leads to absorption through the vis-ceral pleura. Normally, 15 to 20 mL of pleural fluid is present at any given time. Any disturbance in these forces can lead to imbalance and accumulation of pleural fluid. Common patho-logic conditions in North America that lead to pleural effusion include congestive heart failure, bacterial pneumonia, malig-nancy, and pulmonary emboli (Table 19-33).173Access and Drainage of Pleural Fluid CollectionsMost patients with pleural effusions of unknown cause should undergo thoracentesis with the following exceptions: effusions in the setting of congestive heart failure, hepatic failure or renal fail-ure, or small effusions associated with an improving pneumonia. If the clinical history suggests congestive heart failure as a cause, particularly in the setting of bilateral effusions, a trial of diuresis may be indicated (rather than thoracentesis). Up to 75% of effu-sions due to congestive heart failure resolve within 48 hours with diuresis alone. Similarly, thoracentesis can be avoided in patients with small effusions associated with resolving pneumonia. These patients typically present with cough, fever, leukocytosis, and uni-lateral infiltrate, and the effusion is usually a result of a reactive, parapneumonic process. If the effusion is small and the patient responds to antibiotics, a diagnostic thoracentesis may be unneces-sary. If the effusion is large and compromising respiratory efforts, or if the patient has a persistent white blood cell count despite improving signs of pneumonia, an empyema of the pleural space must be considered. In these patients, early and aggressive drainage with chest tubes is required, possibly with surgical intervention.Once the decision is made to access a pleural effusion, the next step is to determine if a sample of the fluid or complete drainage of the pleural space is desired. This step is influenced by the clinical history, the type and amount of fluid present, the Brunicardi_Ch19_p0661-p0750.indd 73601/03/19 7:01 PM

CHAPTER 19737CHEST WALL, LUNG, MEDIASTINUM, AND PLEURATable 19-33Leading causes of pleural effusion in the United States, based on data from patients undergoing thoracentesisCAUSEANNUAL INCIDENCETRANSUDATEEXUDATECongestive heart failure500,000YesNoPneumonia300,000NoYesCancer200,000NoYesPulmonary embolus150,000SometimesSometimesViral disease100,000NoYesCoronary artery bypass surgery60,000NoYesCirrhosis with ascites50,000YesNoData from Light RW: Pleural diseases, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.nature of the collection (such as free-flowing or loculated), the cause, and the likelihood of recurrence. For small, free-flowing effusions, an outpatient diagnostic and/or therapeutic thora-centesis with a relatively small-bore needle or catheter (14to 16-gauge) can be performed (Fig. 19-50). The appearance of the fluid is informative: clear straw-colored fluid is often transuda-tive; turbid or bloody fluid is often exudative.The site of entry for drainage of a pleural effusion or pneumothorax may be based on the CXR alone if the effu-sion is demonstrated to be free-flowing. For free-flowing effu-sions, a low approach at the eighth or ninth intercostal space in the posterior midclavicular line facilitates complete drainage. If the effusion is loculated, CTor ultrasound-guided drainage may be indicated. If the goal is complete drainage, a small-bore pigtail catheter is inserted and connected to a closed drainage system with applied suction (typically –20 cm H2O). In general, the smallest-bore drainage catheter that will effec-tively drain the pleural space should be chosen. Smaller-diam-eter catheters significantly decrease the pain associated with the placement of chest tubes but are more prone to clogging and twisting.174,175 For clinical situations requiring biopsy or for potential interventions such as adhesiolysis or pleurodesis, minimally invasive surgery may be indicated, using a VATS approach.Figure 19-50. Techniques for aspiration and drainage of a pleural effusion. A. Needle aspiration. With careful appraisal of the x-ray findings, the best interspace is selected, and fluid is aspirated with a needle and syringe. Large volumes of fluid can be removed with a little patience and a large-bore needle. B. Chest tube insertion. After careful skin preparation, draping, and administration of local anesthesia, a short skin incision is made over the correct interspace. The incision is deepened into the intercostal muscles, and the pleura is penetrated (usually with a clamp). When any doubt exists about the status of the pleural space at the site of puncture, the wound is enlarged bluntly to admit a finger, which can be swept around the immediately adjacent pleural space to assess the situation and break down any adhesions. The tube is inserted, with the tip directed toward the optimal position suggested by the chest X-rays. In general, a high anterior tube is best for air (pneumothorax), and a low posterior tube is best for fluid. A 28F to 32F tube is adequate for most situations. A 36F tube is preferred for hemothorax or for a viscous empyema. Many surgeons prefer a very small tube (16F to 20F) for drainage of simple pneumothorax. C. The tube is connected to a water-seal drainage system. Suction is added, if necessary, to expand the lung; it usually will be required in a patient with a substantial air leak (bronchopleural fistula).Brunicardi_Ch19_p0661-p0750.indd 73701/03/19 7:01 PM 738SPECIFIC CONSIDERATIONSPART IITable 19-34Differential diagnosis of pleural effusions I. Transudative pleural effusions A. Congestive heart failure B. Cirrhosis C. Nephrotic syndrome D. Superior vena caval obstruction E. Fontan procedure F. Urinothorax G. Peritoneal dialysis H. Glomerulonephritis I. Myxedema J. Cerebrospinal fluid leaks to pleura K. Hypoalbuminemia L. Pulmonary emboli M. Sarcoidosis II. Exudative pleural effusions A. Neoplastic diseases 1. Metastatic disease 2. Mesothelioma 3. Body cavity lymphoma 4. Pyothorax-associated lymphoma B. Infectious diseases 1. Tuberculosis 2. Other bacterial infections 3. Fungal infections 4. Parasitic infections 5. Viral infections C. Pulmonary embolization D. Gastrointestinal disease 1. Pancreatic disease 2. Subphrenic abscess 3. Intrahepatic abscess 4. Intrasplenic abscess 5. Esophageal perforation 6. After abdominal surgery 7. Diaphragmatic hernia 8. Endoscopic variceal sclerosis 9. After liver transplantation E. Heart diseases 1. After coronary artery bypass graft surgery 2. Post-cardiac injury (Dressler’s) syndrome 3. Pericardial disease F. Obstetric and gynecologic diseases 1. Ovarian hyperstimulation syndrome 2. Fetal pleural effusion 3. Postpartum pleural effusion 4. Megis’ syndrome 5. Endometriosis G. Collagen vascular diseases 1. Rheumatoid pleuritis 2. Systemic lupus erythematosus 3. Drug-induced lupus 4. Immunoblastic lymphadenopathy 5. Sjögren’s syndrome 6. Familial Mediterranean fever 7. Churg-Strauss syndrome 8. Wegener’s granulomatosis H. Drug-induced pleural disease 1. Nitrofurantoin 2. Dantrolene 3. Methysergide 4. Ergot alkaloids 5. Amiodarone 6. Interleukin-2 7. Procarbazine 8. Methotrexate 9. Clozapine I. Miscellaneous diseases and conditions 1. Asbestos exposure 2. After lung transplantation 3. After bone marrow transplantation 4. Yellow nail syndrome 5. Sarcoidosis 6. Uremia 7. Trapped lung 8. Therapeutic radiation exposure 9. Drowning 10. Amyloidosis 11. Milk of calcium pleural effusion 12. Electrical burns 13. Extramedullary hematopoiesis 14. Rupture of mediastinal cyst 15. Acute respiratory distress syndrome 16. Whipple’s disease 17. Iatrogenic pleural effusions J. Hemothorax K. ChylothoraxReproduced with permission from Light RW: Pleural diseases, 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.Complications of Pleural Drainage. The most common complications of invasive pleural procedures are inadvertent injury to adjacent organs, including lung, with air leakage and pneumothorax; subdiaphragmatic entry and damage to the liver, spleen, or other intra-abdominal viscera; intercostal ves-sel injury with subsequent bleeding or larger vessel injury; and even cardiac puncture. Sometimes, bleeding may be the result of an underlying coagulopathy or anticoagulant therapy. Other technical complications include loss of a catheter, guidewire, or fragment in the pleural space and infections. Occasionally, rapid drainage of a large effusion can be followed by shortness of breath, clinical instability, and a phenomenon referred to as postexpansion pulmonary edema. For this reason, it is recom-mended to drain only up to 1500 mL initially. Most complica-tions can be avoided by consulting with a clinician experienced in pleural drainage techniques.Pleural Fluid Analysis. Pleural fluid collections are generally classified as transudates and exudates (Table 19-34). Transu-dates are protein-poor ultrafiltrates of plasma that result from alterations in the systemic hydrostatic pressures or colloid Brunicardi_Ch19_p0661-p0750.indd 73801/03/19 7:01 PM

CHAPTER 19739CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAosmotic pressures (for example, with congestive heart failure or cirrhosis). On gross visual inspection, a transudative effusion is generally clear or straw-colored. Exudates are protein-rich pleural fluid collections that generally result from inflamma-tion or pleural invasion by tumor. Grossly, they are often turbid, bloody, or purulent. Absent trauma, grossly bloody effusions are frequently malignant, but they may also occur in the setting of a pulmonary embolism or pneumonia.Transudates and exudates can be differentiated using Light’s criteria. An effusion is exudative if the pleural fluid-to-serum ratio of protein is greater than 0.5 and the LDH ratio is greater than 0.6 or the absolute pleural LDH level is greater than two-thirds of the normal upper limit for serum. If criteria suggest a transudate, a careful evaluation for congestive heart failure, cirrhosis, or conditions associated with transudates is under-taken. If criteria suggest an exudate, further diagnostic studies may be helpful. If total and differential cell counts reveal a pre-dominance of neutrophils (>50% of cells), the effusion is likely associated with an acute inflammatory process (such as a para-pneumonic effusion or empyema, pulmonary embolus, or pan-creatitis). A predominance of mononuclear cells suggests a more chronic inflammatory process (such as cancer or tuberculosis). Gram stains and cultures should be obtained if possible, with inoculation into culture bottles at the bedside. Pleural fluid glu-cose levels are frequently decreased (<60 mg/dL) with complex parapneumonic effusions or malignant effusions. It is important to note that while the distinction between transudate and exudate can be diagnostically useful, the ultimate decision for prolonged chest tube drainage or surgery depends on the effusion size and adequacy of drainage, presence of loculations, adequacy of lung reexpansion after drainage, and recurrence after initial drainage.A pleural effusion occurring in association with pleuritic chest pain, hemoptysis, or dyspnea out of proportion to the size of the effusion should raise concern for pulmonary embolism. These effusions may be transudative, but if an associated infarct near the pleural surface occurs, an exudate may be seen. If a pulmonary embolism is suspected in a postoperative patient, most clinicians would obtain a spiral CT scan. Alternatively, duplex ultrasonography of the lower extremities may yield a diagnosis of deep vein thrombosis, thereby indicating antico-agulant therapy and precluding the need for a specific diagnosis of pulmonary embolism. In some patients, a blood test for levels of d-dimer may be helpful; if a sensitive d-dimer blood test is negative, pulmonary embolism may be ruled out.Malignant Pleural EffusionMalignant pleural effusions may occur in association with a number of different malignancies, most commonly lung can-cer, breast cancer, and lymphomas, depending on the patient’s age and gender (Tables 19-35 and 19-36).176 Cytologic testing should be done on exudative effusions to rule out an associated malignancy; accuracy is 70% when associated with adenocarci-nomas, but it is less sensitive for mesotheliomas (<10%), squa-mous cell carcinomas (20%), or lymphomas (25% to 50%). If the diagnosis remains uncertain after drainage and fluid analy-sis, thoracoscopy and direct biopsies are indicated.177,178 Malig-nant effusions are exudative and often tinged with blood. An effusion in the setting of a malignancy means a more advanced stage; mean survival ranges from 3 to 11 months, depending on the primary tumor location.Occasionally, effusions associated with a bronchogenic NSCLC are benign, and surgical resection may still be indicated.Table 19-35Primary organ site or neoplasm type in male patients with malignant pleural effusionsPRIMARY SITE OR TUMOR TYPENO. OF MALE PATIENTSPERCENTAGE OF MALE PATIENTSLung14049.1Lymphoma/leukemia6021.1Gastrointestinal tract207.0Genitourinary tract176.0Melanoma41.4Miscellaneous less common tumors103.5Primary site unknown3110.9Total285100.0Reproduced with permission from Johnston WW. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients, Cancer. 1985 Aug 15;56(4):905-909.Table 19-36Primary organ site or neoplasm type in female patients with malignant pleural effusionsPRIMARY SITE OR TUMOR TYPENO. OF FEMALE PATIENTSPERCENTAGE OF FEMALE PATIENTSBreast7037.4Female genital tract3820.3Lung2815.0Lymphoma148.0Gastrointestinal tract84.3Melanoma63.2Urinary tract21.1Miscellaneous less common tumors31.6Primary site unknown179.1Total187100.0Reproduced with permission from Johnston WW. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients, Cancer. 1985 Aug 15;56(4):905-909.Effusion size and degree of associated dyspnea influence management. Symptomatic, moderate to large effusions should be drained by tunneled indwelling pleural catheter, tube thora-costomy (chest tube or pigtail catheter) with subsequent instilla-tion of a sclerosing agent, or VATS with talc instillation. Management is based on patient preference, degree of known or anticipated lung reexpansion, and patient tolerance for operative intervention. Lung entrapment by tumor or adhesions limits reexpansion and generally predicts a poor result with pleurode-sis; it is the primary indication for placement of indwelling pleu-ral catheters. Patient preference is also considered, as is their life expectancy. Tunneled indwelling pleural catheters have dramati-cally changed the management of end-stage cancer treatment Brunicardi_Ch19_p0661-p0750.indd 73901/03/19 7:01 PM 740SPECIFIC CONSIDERATIONSPART IITable 19-37Pathogenesis of empyemaContamination from a source contiguous to the pleural space (50%–60%) Lung Mediastinum Deep cervical area Chest wall and spine Subphrenic areaDirect inoculation of the pleural space (30%–40%) Minor thoracic interventions Postoperative infections Penetrating chest injuriesHematogenous infection of the pleural space from a distant site (<1%)Reproduced with permission from Pearson FG, Cooper JD, Deslauriers J, et al: Thoracic Surgery, 2nd ed. New York, NY: Elsevier/Churchill Livingstone; 2002.Outpatient referral for management of MPEPlacement ofindwelling pleuralcatheterLoculatedfluid/trapped lungFree-flowing with fulllung expansion Excellent performancestatus/long life expectancyVATS pleurodesisPoor performancestatus/short life expectancyPlacement of indwellingpleural catheterDecubitus films and/or CT scan Figure 19-51. Treatment decision algorithm for the management of malignant pleural effusion (MPE). CT = computed tomography; VATS = video-assisted tho-racic surgery.because they substantially shorten the amount of time patients spend in the hospital during their final weeks of life.179 If the lung is expected to fully expand and the patient has a longer life expectancy (e.g., malignant effusions in the setting of breast cancer), drainage with sclerosis is the preferred option. The choice of sclerosant includes mechanical pleurodesis or pleurectomy, talc, bleomycin, or doxycycline. Success rates range from 60% to 90% and are highest with talc. Typically, talc is administered as an aerosolized powder during video-assisted thoracoscopy, whereas doxycycline or a talc slurry is infused at the bedside through a previously placed pigtail catheter or larger bore chest tube. Figure 19-51 presents a decision algorithm for the management of malignant pleural effusion.EmpyemaThoracic empyema is defined by a purulent pleural effusion. Patients of all ages can develop empyema, but the frequency is increased in older or debilitated patients. Common associ-ated conditions include a pneumonic process in patients with pulmonary disorders and neoplasms, cardiac problems, diabe-tes mellitus, drug and alcohol abuse, neurologic impairments, postthoracotomy problems, and immunologic impairments. The mortality of empyema frequently depends on the degree of severity of the comorbidity; it may range from as low as 1% to over 40% in immunocompromised patients.Pathophysiology. The most common causes are parapneu-monic, but postsurgical, posttraumatic, and GI-associated (e.g., subphrenic or hepatic abscess, perforation of esophagus or other viscus) empyema is also common (Table 19-37). The spectrum of organisms involved in pneumonic processes that progress to empyema is changing. Pneumococci and staphylococci continue to be the most common, but gram-negative aerobic bacteria and anaerobes are becoming more prevalent. Cases involving myco-bacteria or fungi are rare. Multiple organisms may be found in up to 50% of patients. Cultures may be sterile, however, if antibiotics were initiated before the culture or if the culture pro-cess was not efficient. It is also fairly common for Pneumococ-cus to grow in blood cultures but not to grow in the pleural fluid cultures. The choice of antibiotics, therefore, is guided 11by the clinical scenario and not just the organisms found on culture. Broad-spectrum coverage may be required even when cultures do not grow out an organism or if a single organism is grown when the clinical picture is more consistent with a mul-tiorganism process. For example, a polymicrobial gram stain, particularly including yeast, is strongly suggestive of esopha-geal perforation. Common gram-negative organisms include Escherichia coli, Klebsiella, Pseudomonas, and Enterobacte-riaceae. Anaerobic organisms may be fastidious and difficult to document by culture and are associated with periodontal dis-eases (especially Streptococcus species), aspiration syndromes, alcoholism, general anesthesia, drug abuse, or other functional associations with gastroesophageal reflux.Organisms gain entry into the pleural cavity through con-tiguous spread from pneumonia, lung abscess, liver abscess, or another, adjacent infectious processes. Organisms may also enter the pleural cavity by direct contamination from thora-centesis, thoracic surgical procedures, esophageal injuries, Brunicardi_Ch19_p0661-p0750.indd 74001/03/19 7:01 PM

CHAPTER 19741CHEST WALL, LUNG, MEDIASTINUM, AND PLEURAor trauma. As organisms enter the pleural space, an influx of polymorphonuclear cells and fluid occurs, with subsequent release of inflammatory mediators and toxic oxygen radi-cals. These mechanisms lead to variable degrees of endothe-lial injury and capillary instability. This process overwhelms the normal pleural lymphatic drainage. This early effusion is watery and free-flowing in the pleural cavity. Thoracentesis at this stage yields fluid with a pH typically above 7.3, a glucose level greater than 60 mg/dL, and a low LDH level (<500 U/L). At this stage, the decision to use antibiotics alone or perform a repeat thoracentesis, chest tube drainage, thoracoscopy, or open thoracotomy depends on the amount of pleural fluid, its consis-tency, the clinical status of the patient, the degree of expansion of the lung after drainage, and the presence of loculated fluid in the pleural space (vs. free-flowing purulent fluid). Early in the parapneumonic process, when the purulent fluid is relatively thin, complete drainage with simple large-bore thoracentesis is possible. If complete lung expansion is obtained and the pneu-monic process is responding to antibiotics, no further drainage may be necessary. Pleural fluid with a pH lower than 7.2 and with a glucose level of less than 40 mg/dL means that a more aggressive approach to drainage should be pursued.The pleural fluid may become thick and loculated over the course of hours to days and may be associated with fibrinous adhesions (the fibrinopurulent stage). At this stage, chest tube insertion with closed-system drainage or drainage with thora-coscopy may be necessary to remove the fluid and adhesions and facilitate complete lung expansion.180 Further progression of the inflammatory process leads to the formation of a pleu-ral peel, which may be flimsy and easy to remove early on. However, as the process progresses, a thick pleural rind may develop, leaving a trapped lung; complete lung decortication by either thoracoscopy or thoracotomy would then be necessary.The use of intrapleural fibrinolytic therapy for manage-ment of empyema has been investigated in several large pro-spective trials. Intrapleural infusion of tissue plasminogen activator (t-PA) alone did not improve outcomes, whereas combined intrapleural t-PA and DNase was associated with a reduction in hospital stay of nearly 7 days, 77% fewer refer-rals for surgical intervention at 3 months, and more than double the reduction in the infected pleural fluid collection by CXR imaging.181 In this trial, the medications were given twice daily by intrapleural injection; the dose was 5 mg for the DNase and 10 mg for t-PA. The chest drain was clamped for 1 hour after injection and released. This study suggests that the combination of fibrinolysis (t-PA) and cleavage of uncoiled DNA by DNase reduces fluid viscosity and facilitates pleural clearance.Management. If there is a residual space, persistent pleural infection is likely to occur. A persistent pleural space may be secondary to contracted, but intact, underlying lung; or it may be secondary to surgical lung resection. If the space is small and well drained by a chest tube, a conservative approach may be possible. This requires leaving the chest tubes in place and attached to closed-system drainage until symphysis of the vis-ceral and parietal surfaces takes place. At this point, the chest tubes can be removed from suction; if the residual pleural space remains stable, the tubes can be cut and advanced out of the chest over the course of several weeks. If the patient is stable, tube removal can frequently be done in the outpatient setting, guided by the degree of drainage and the size of the residual space visualized on serial CT scans. Larger spaces may require open thoracotomy and decortication in an attempt to reexpand the lung to fill this residual space. If reexpansion has failed or appears too high risk, then open drainage, rib resection, and prolonged packing may be required, with delayed closure with muscle flaps or thoracoplasty.182 Most chronic pleural space problems can be avoided by early specialized thoracic surgi-cal consultation and complete drainage of empyema, allowing space obliteration by the reinflated lung.ChylothoraxChylothorax develops most commonly after surgical trauma to the thoracic duct or a major branch, but may be also associ-ated with a number of other conditions (Table 19-38).183 It is generally unilateral; for example, it may occur after dissection of the distal esophagus where the duct lies in close proximity to the esophagus as it enters the right chest from its origin in the Table 19-38Etiology of chylothoraxCongenital Atresia of thoracic duct Thoracic duct-pleural space fistula Birth traumaTraumatic and/or iatrogenic Blunt injury Penetrating injury Surgery  Cervical   Excision of lymph nodes   Radical neck dissection  Thoracic   Correction of patent ductus arteriosus   Correction of coarctation of the aorta   Vascular procedure involving the origin of the left subclavian artery   Esophagectomy   Sympathectomy   Resection of thoracic aneurysm   Resection of mediastinal tumors   Left pneumonectomy  Abdominal   Sympathectomy   Radical lymph node dissection  Diagnostic procedures   Translumbar arteriography   Subclavian vein catheterization   Left-sided heart catheterizationNeoplasmsInfections Tuberculous lymphadenitis Nonspecific mediastinitis Ascending lymphangitis FilariasisMiscellaneous Venous thrombosis  Left subclavian-jugular vein  Superior vena cava Pulmonary lymphangiomatosisReproduced with permission from Sabiston DC, Spencer FC: Surgery of the Chest, 6th ed. Philadelphia, PA: Elsevier; 1995.Brunicardi_Ch19_p0661-p0750.indd 74101/03/19 7:01 PM 742SPECIFIC CONSIDERATIONSPART IIabdomen at the cisterna chyli (Fig. 19-52). If the mediastinal pleura are disrupted on both sides, bilateral chylothoraces may occur. Left-sided chylothoraces may develop after a left-sided neck dissection, especially in the region of the confluence of the subclavian and internal jugular veins. Chylothorax may also follow nonsurgical trauma, including penetrating or blunt inju-ries to the chest or neck area, central line placements, and other surgical misadventures. It may be seen in association with a variety of benign and malignant diseases that generally involve the lymphatic system of the mediastinum or neck.Pathophysiology. Most commonly, the thoracic duct origi-nates in the abdomen from the cisterna chyli, which is located in the midline, near the level of the second lumbar vertebra. From this origin, the thoracic duct ascends into the chest through the aortic hiatus at the level of T10 to T12, and courses just to the right of the aorta (see Fig. 19-52). As the thoracic duct courses cephalad above the diaphragm, it most commonly remains in the right chest, lying just behind the esophagus, between the aorta and azygos vein. The duct continues superiorly, lying just to the right of the vertebral column. Then, at the fourth thoracic ver-tebra, it crosses behind the aorta and the aortic arch into the left posterior mediastinum and travels superiorly, staying near the esophagus and mediastinal pleura as it exits the thoracic inlet. As it exits the thoracic inlet, it passes to the left, just behind the carotid sheath and anterior to the inferior thyroid and vertebral bodies. Just medial to the anterior scalene muscle, it courses inferiorly and drains into the union of the internal jugular and subclavian veins. Given the extreme variability in the main duct and its branches, accumulation of chyle in the chest or flow from penetrating wounds may be seen after a variety of trau-matic and medical conditions.184The main function of the duct is to transport fat absorbed from the digestive system along with variable amounts of protein and lymphatic material (Table 19-39). Given the high volume of chyle that flows through the thoracic duct, signifi-cant injuries can cause leaks in excess of 2 L per day; if left untreated, protein, lymphocyte, and volume depletion can lead to serious metabolic effects and death. Thoracentesis is usually grossly suggestive, revealing milky, nonpurulent pleural fluid. However, if the patient is taking nothing by mouth, the pleural fluid may not be grossly abnormal. Laboratory analysis of the pleural fluid shows the presence of chylomicrons, a high lym-phocyte count and high triglyceride levels. If the triglyceride level is greater than 110 mg/100 mL, a chylothorax is almost certainly present (a 99% accuracy rate). If the triglyceride level is less than 50 mg/mL, there is only a 5% chance of chylothorax. In many clinical situations, the accumulation of chyle may be slow because of minimal digestive fat flowing through the gas-trointestinal tract after major trauma or surgery, so the diagnosis may be more difficult to establish.Management. The treatment plan for any chylothorax depends on its cause, the amount of drainage, and the patient’s clinical status (Fig. 19-53). In general, most patients are treated with a short period of chest tube drainage, nothing by mouth (NPO) orders, total parenteral nutrition (TPN), and observation. In cen-ters with interventional radiology expertise, thoracic duct embo-lization as soon as possible after diagnosis should be considered. Thoracic d.Cisterna chyliFigure 19-52. Normal thoracic duct anatomy. The esophagus comes into close proximity with the thoracic duct as it enters the chest from its origin in the abdomen at the cisterna chyli.Table 19-39Composition of chyleCOMPONENTAMOUNT (PER 100 ML)Total fat0.4–5 g Total cholesterol65–220 mgTotal protein2.21–5.9 g Albumin1.1–4.1 g Globulin1.1–3.1 g Fibrinogen16–24 gSugars48–200 gElectrolytesSimilar to levels in plasmaCellular elements  Lymphocytes400–6800/mm3 Erythrocytes50–600/mm3Antithrombin globulin>25% of plasma concentrationProthrombin>25% of plasma concentrationFibrinogen>25% of plasma concentrationReproduced with permission from Miller JI: Diagnosis and management of chylothorax, Chest Surg Clin N Am. 1996 Feb;6(1):139-148.Brunicardi_Ch19_p0661-p0750.indd 74201/03/19 7:02 PM

CHAPTER 19743CHEST WALL, LUNG, MEDIASTINUM, AND PLEURARadiationtherapyMedicallyunstablePleuralperitonealshuntDrainagepersists(Nonmalignant)Drainage persists(>500 mL/d)MalignantchylothoraxThoracentesisConfirm diagnosisMedicallystableThoracotomyChest tubeConservative management NPOChest tube to suctionCentral hyperalimentationWait 2 weeks*Drainage decrease(<250 mL/d)Continue1 weekThoracotomyDuct ligationMass ligationDecorticationPleurectomyDrainagestopsRemovechest tube Figure 19-53. Algorithm for the management of chylothorax. *If high output persists (>50 mL/d), early surgical ligation of the thoracic duct may be considered. NPO = nothing by mouth.Chest cavity drainage must be adequate to allow complete lung reexpansion. Somatostatin has been advocated by some authors, with variable results. If significant chyle drainage (>500 mL per day in an adult, >100 mL in an infant) continues despite TPN and good lung expansion, early surgical duct ligation or embo-lization is recommended (within 4–7 days following diagnosis). Ligation can be approached best by right thoracotomy, and in some experienced centers, by right thoracoscopy. Chylothoraces due to malignant conditions often respond to radiation and/or chemotherapy and less commonly require surgical ligation. Significant nutritional and immunologic depletion results from untreated chylothorax; associated mortality is in excess of 50%. With early recognition and aggressive medical management as well as early surgical ligation or embolization for persistent leaks, the mortality rate of chylothorax is now less than 10%.Tumors of the PleuraMalignant mesothelioma is the most common type of primary tumor of the pleura, with approximately 3000 cases per year in the United States. Other, less common tumors include benign and malignant fibrous tumors of the pleura, lipomas, and cysts.Malignant Mesothelioma. The only known risk factor for mesothelioma is exposure to asbestos, identified in over 50% of cases. Exposure is typically work-related in industries using asbestos in the manufacturing process, such as shipbuilding and brake pad linings. The risk extends to family members who are Brunicardi_Ch19_p0661-p0750.indd 74301/03/19 7:02 PM 744SPECIFIC CONSIDERATIONSPART IIexposed to the dust of the clothing or to the work environment. Asbestos exposure and smoking synergistically increase the risk for lung cancer, but smoking does not increase risk for malig-nant mesotheliomas. Male predominance is 2:1, and it occurs most commonly after the age of 40.Risk of developing mesothelioma after asbestos exposure differs depending on the physical characteristics of the asbestos and similar fibers (either serpentine or amphibole). The serpen-tine fibers are large and curly and are generally not able to travel beyond larger airways. However, the narrow, straight amphibole fibers, in particular the crocidolite fibers, may navigate distally into the pulmonary parenchyma and are most clearly associated with mesotheliomas. Like many carcinogens, the latency period between asbestos exposure and the development of mesothe-lioma is at least 20 years. The tumor generally is multicentric, with multiple pleural-based nodules coalescing to form sheets of tumor. This process initially involves the parietal pleura, gener-ally with early spread to the visceral surfaces and with a variable degree of invasion of surrounding structures. Autopsy studies have shown that most patients have distant metastases, but the natural history of the disease in untreated patients culminates in death due to local extension and effective strangulation of the lung.Clinical Presentation Most patients present with dyspnea and chest pain. Over 90% have a pleural effusion, but thora-centesis is diagnostic in less than 10% of patients. Frequently, a thoracoscopy or open pleural biopsy with special stains is required to differentiate mesotheliomas from adenocarcinomas (Table 19-40). Epithelial subtypes are associated with a more favorable prognosis, and long-term survival may be seen in rare patients with no treatment. Sarcomatous and mixed tumors share a more aggressive course.Management The treatment of malignant mesotheliomas remains controversial. Treatment options include supportive care only, surgical resection, and multimodality approaches (using a combination of surgery, chemotherapy, and radia-tion therapy).186 Surgical approaches range from extrapleural pneumonectomy (removal of the lung, entire parietal pleural, ipsilateral pericardium, and hemidiaphragm with patch recon-struction), pleurectomy and decortication (removal of the vis-ceral and parietal pleura only), and palliative procedures such as talc pleurodesis and insertion of long-term tunneled indwelling pleural catheters.Table 19-40Differentiation of mesothelioma from adenocarcinoma MESOTHELIOMAADENOCARCINOMAImmunohistochemical results   Carcinoembryonic antigenNegativePositive VimentinPositiveNegative Low molecular weight cytokeratinsPositiveNegativeElectron microscopic featuresLong, sinuous villiShort, straight villi with fuzzy glycocalyxFibrous Tumors of the Pleura. Fibrous tumors of the pleura are unrelated to asbestos exposure or malignant mesotheliomas. They generally occur as a single pedunculated mass arising from the visceral pleura but can occasionally arise from the parietal pleura. They can grow to be quite large, with most ranging from 5 to 10 cm and 100 to 400 g in size by the time they are dis-covered. Architecturally, the most common microscopic feature is the “patternless pattern.” This is characterized by randomly situated areas of hypercellularity, containing spindle cells with bland, vesicular, ovoidal nuclei and scarce cytoplasm, and hypo-cellularity, with fibrous connective tissue, hemorrhage, myxoid, or necrosis. They can also have an hemangiopericytoma-like appearance. The neoplastic cells are immunoreactive for CD34 and CD99 but negative for cytokeratins and desmin. Immuno-reactivity for Bcl-2 is variably positive.187They are frequently discovered incidentally on routine CXRs, without an associated pleural effusion. They occur with equal frequency in males and females and are most common in the sixth to seventh decade of life. Fibrous tumors of the pleura may be benign or malignant.188 Symptoms such as cough, chest pain, and dyspnea occur in 30% to 40% of patients but are found in 75% of patients with malignant tumors. Malignant tumors are differentiated from benign tumors based on high cellularity, more than four mitotic figures per 10 high-power fields, nuclear pleomorphism, tumor necrosis, and hemorrhage. They are more likely to arise from the parietal pleura of the chest wall, dia-phragm, or mediastinum, or in the fissures or invaginating into the lung parenchyma. Hypoglycemia, associated pleural effu-sion, and hypertrophic pulmonary osteoarthropathy (clubbed digits, long bone ossifying periostitis, and arthritis) are associ-ated with these lesions in approximately 25% of patients. Less common are fever and hemoptysis.Symptoms resolve with surgical resection. 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