DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 1 

# Draft Guideline for the Prevention of Surgical Site Infection

Sandra I. Berríos

- Torres, MD 1 , Craig A. Umscheid, MD, MSCE 2 , Dale W. Bratzler, DO, MPH 3

, Brian Leas, MA, MS 2 , Erin C. Stone, MS 1 , Rachel R. Kelz, MD, MSCE, FACS 2 , Caroline Reinke, MD, MPH 2 , Sherry Morgan, RN, MLS, PhD 2 , Joseph S. Solomkin, MD 4 , John E. Mazuski, MD, PhD 5 , E. Patchen Dellinger, MD 6

, Kamal Itani, MD 7 , Elie F. Berbari, MD 8 , John S egreti, MD 9 , Javad Parvizi, MD 10 , Joan Blanchard, MSS,BSN,RN,CNOR,CIC 11 , George Allen, PhD, CIC, CNOR 12 , J. A. J. W. Kluytmans, MD 13 , Rodney Donlan, PhD 1 , William P. Schecter, MD 4 and the Healthcare Infection Control Practices Advisory Committee 15

1 Division of Healthcare Quality Promotion
, Centers for Disease Control and Prevention
, Atlanta, GA ; 2 Center for Evidence

- based Practice
, University of Pennsylvania Health System
, Philadelphia, PA ; 3 University of Oklahoma Health Sciences Center
, College of Public Health
, Oklahoma City, OK ; 4 University of Cincinnati
, University of Cincinnati College of Medicine
, Cincinnati, OH ; 5 Washington University
, Washington University School of Medicine
, Saint Louis, MO ; 6 University of Washington Medical Center
, Seattle, WA ; 7 Veterans A ffairs Boston Healthcare System , Boston, MA ; 8 Mayo Clinic College of Medicine
, Rochester, MN ; 9 Rush University Medical Center , C hicago, IL ; 1 0

, Rothman Institute
, Philadelphia, PA ; 1 1 Littleton Adventist Hos pital
, Quality Department , Denver, CO ; 1 2 Downstate Medical Center
, Brooklyn, NY ; 1 3 Laboratory for Microbiology and Infection Control Amphia Hospital
, Breda, t he Netherlands ; 14 University of California, San Francisco
, San Francisco General Hospital San Francisco, CADISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 2 15 

### Healthcare Infection Control Practices Advisory Committee (HICPAC) Membership List, as of November 2013

Chair: Neil O. Fishman, MD , University of Pennsylvania Health System
, Philadelphia, PA

Designated Federal Officer: Jeffrey C. Hageman, MHS, Division of Healthcare Quality, Promotion, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta, GA

Members: Dale W. Bratzler , DO, MPH , University of Oklahoma Health Sciences Center
, Oklahoma City, OK ; Ruth M. Carrico , PhD, RN, CIC
, University of Louisville School of Medicine
, Louisville, KY ; Daniel J. Diekema , MD , University of Iowa Carver College of Medicine
, I owa City, IA; A lexis Elward , MD , Washington University School of Medicine
, St. Louis, MO ; Mary K. Hayden , MD , Rush University Medical Center and Rush Medica l College , Chicago, IL; Susan Huang , MD, MPH , University of California Irvine School of Medicine , Orange, CA; G ina Pugliese , RN, MS , Premier H ealthcare A lliance
, St. Joseph, Michigan ; Selwyn O. Rogers Jr., MD, MPH, FACS , Temple University School of Medicin e , Philadelphia, PA ; Tom Talbot , MD MPH , Vanderbilt University School of Medicine and Medical Center
, Nashville, TN ; Michael L. Tapper , MD , Lenox Hill Hospital
, New York City, NY ; Deborah S. Yokoe , MD, MPH , Brigham & Women's Hospital and Harvard Medical School , Boston, MA.

Ex

- Officio Members: Agency for Healthcare Research and Quality
, William B. Baine , MD , Rockville, MD; Center for Medicare & Medicaid Services
, Daniel Schwartz , MD, MBA , Baltimore, MD; Fo od and Drug Administration, vacant, Rockville, MD ; Health Resources an d Services Administration, Paul D. Moore , PhD
, Rockville, MD ; Nat ional Institutes of Health, David Henderson , MD , Bethesda, MD; Department of Veterans Affairs
, Gary A. Roselle , MD , Cincinnati, OH.

Liaison Representatives: America’s Essential Hospitals
, Silvia Munoz

- Price , MD , Miami, FL ; American College of Occupational and Environmental Medicine
, Mark Russi , MD, MPH , New Haven, CT; Am erican Health Care Association, Sandra L. Fitzler , RN , Washington, DC ; Amer ican Hospital Association, Nancy Foster , Washington, DC ; A ssociation of periOperative Registered Nurse, Amber Wood , MSN, RN, CNOR, CIC, CPN ; Denver, CO ; Association of Professionals of Infection Control and Epidemiology, Inc., Michael Anne Preas , RN, CIC , Baltimore MD; Association of State and Territorial Health Officials
, Emily Lutterloh , MD, MPH , Albany, NY ; Council of State and Territorial Epidemiol ogists, Marion Kainer MD, MPH , Nashville, TN ; Consumers Union , Lisa McGiffert , Yonkers, NY; D NV Healthcare, Inc., Janet Franck , RN, MBA, CIC , Chicago, IL ; Healthcare Facilit ies Accreditation Program, Donna Tiberi , RN, MHA , Chicago, IL; Infectious D isease Society of America, W. Charles Huskins, MD, MSc , Rochester, MN; National Association of County an d City Health Officials, Diana Gaviria MD, MPH , Martinsburg, WV ; Public Health Agency of Canada
, Kathleen Dunn , BScN, MN, RN , Ottawa, Ontario, Canada ; Society for Healthcar e Epidemiology of America, Mark E. Rupp , MD , Omaha, NE ; Society of Critical Care Med icine , Michael D. Howell , MD MPH , Chicago, IL ; Society of Hospital Medicine
, Sanjay Saint , MD, MPH , Ann Arbor, MI ; Surgical Infection Society (SIS)
, Robert, G. Sawyer , MD, FACS, FIDSA, FCCM , Charlottesville, VA; The Joint Commission
, Margaret Vanamringe , MHS , Washington , DC.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 3 

### Acknowledgement

We would like to thank the many individuals and organizations who provided valuable feedback on the guideline during the development process

. We would especially like to recognize and thank the HICPAC liaison organizations as well as those surgical societies (i.e., American College of Surgeons, Musculoskeletal Infection Society , and American Academy of Orthopaedic Surgeons ) who provided input throughout the development process.

We would like to especially thank the following experts for their input throughout the process : Rajender Aga r wal MD , MHP, J. William Costerton, PhD
, Thomas Hunt MD, Bernard Morrey MD, Lena M. Napolitano MD, FACS, FCCP, FCCM, Douglas Osmon MD , Robin Patel, MD (CM), FRCP(C), D(ABMM), FIDSA , FACP, and Mark Shirtliff, PhD

. The opinions of the reviewers might not be reflected in all of the recommendations contained in this document.



### Disclosures of Competing Interests

The authors S.I.B.T., E.F.B., J.B., R.D. E.S., J.S.S., and W.P.S. report no actual or potential conflicts of interest. G.A. reports lecturer fees for Ethicon and royalties from Wolters Kluwer Publishers as an author for Infection control for healthcare facilit ies. D.B. is a consultant for both the Oklahoma Foundation for Medical Quality, Telligen (a non

- profit Medicaid External Quality Review Organization); his institution received payment for his lectures including service on speakers’ bureaus from both Premie r and Janssen pharmaceuticals. E.P.D. reports received grants for clinical research from, served on an advisory board for, and/or lectu red for honoraria from, Merck, Baxter, Ortho

- McNeil, Targanta, Schering

- Plough, WebEx, Astellas, Care Fusion, Durata, Pfi zer, Applied Medical, Rib

- X, Affinium, and 3M. K.I. reports his institution receiving grants from Merck, Cubist and Trius for research trials; clinical advisory board membership at Forrest Pharmaceuticals; payment for development of educational presentatio ns for Med Direct and Avid Education; J.E.M. is a paid consultant for Forest Laboratories, MedImmune and Pfizer, and lecturer fees from Forest Laboratories, Merck/Merck Sharp and Dohme, and Pfizer; while his institution receives funding for his consultancy to Astra

- Zenca and grants from Astra

Zeneca, Merck/MSD and Tetraphase. J.P. reports his Institution receiving monies for his board membership of Journal of Arthroplasty, the Philadelphia Orthopedic Society, EOA, United Healthcare, Magnifi Group, 3M, and t he Journal of Bone and Joint Surgery

– America; consulting for Zimmer, Smith and Nephew, Convatech, TissueGene, Ceramtech, OsteoMEM, 3M and Cadence with money paid to his institution; grants to his institution from Orthopaedic Research and Education Founda tion, Stryker, Depuy, Zimmer, Baxter, 3M, Biomemetics, Ceramtec, and Smith and Nephew; royalties paid to his institution from SmarTech, Elsevier, Wolters Kluwer, Slack, Hip Innovations Technology, CD Diagnostics, Jaypee Publishers and Datatrace. J.S. repor ts lecture fees from Pfizer, Merck, and Forest; and stocks and/or stock options from Pfizer.
R.K., B.L., S.M., C.R., and C.A.U. all received funding from CDC to support the guideline development process. They report no other conflict of interest.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 4 

### Table of Contents
Abbreviations

................................ ................................ ................................ ................................ ................ 5 I. Executive Summary

................................ ................................ ................................ ................................ .... 6 II. Summary of Recommendations

................................ ................................ ................................ .............. 11

CORE SECTION

................................ ................................ ................................ ................................ ......... 11

PROSTHETIC JOINT ARTHROPLASTY SECTION

................................ ................................ ......................... 14 III. Background

................................ ................................ ................................ ................................ ............ 17 IV. Scope and Purpose

................................ ................................ ................................ ................................ 20
V. Methods

................................ ................................ ................................ ................................ .................. 23
VI. Evidence Review: Core section

................................ ................................ ................................ .............. 28 PARENTERAL ANTIMICROBIAL PROPHYLAXIS (AMP)

................................ ................................ .............. 28

NON

- PARENTERAL ANTIMICROBIALPROPHYLAXIS

................................ ................................ ................. 32

GLYCEMIC CONTROL

................................ ................................ ................................ ............................... 36

NORMOTHERMIA

................................ ................................ ................................ ................................ .... 38

OXYGENATION

................................ ................................ ................................ ................................ ........ 39

ANTISEPTIC PROPHYLAXIS

................................ ................................ ................................ ....................... 43
VII. Evidence Review

- Prosthetic Joint Arthroplasty section

................................ ................................ ...... 53

BLOOD TRANSFUSION

................................ ................................ ................................ ............................. 53

SYSTEM IC IMMUNOSUPPRESSIVE THERAPY

................................ ................................ ........................... 56

INTRA

- ARTICULAR CORTICOSTEROID INJECTIONS

................................ ................................ .................. 61

ANTICOAGULATION

................................ ................................ ................................ ................................ 63

ORTHOPAEDIC SPACE SUIT

................................ ................................ ................................ ..................... 68

POSTOP ERATIVE AMP DURATION IN PROSTHETIC JOINT ARTHROPLASTY WITH THE USE OF A DRAIN 69

BIOFILM

................................ ................................ ................................ ................................ ................... 70

REFERENCES

................................ ................................ ................................ ................................ ................ 73DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 5 

### Abbreviations
AMP Antimicrobial prophylaxis APRP Autologous platelet rich plasma ASA Acetylsalicylic acid (aspirin) ASEPSIS A dditional treatment, the presence of S erous discharge, E rythema, P urulent

exudate, and S eparation of the deep tissues, the I solation of bacteria, and the duration of inpatient Stay BMI Body mass index °C Celsius CABG Coronary artery bypass graft CDC Centers for Disease Control and Prevention CHG Chlorhexidine gluconate CMA Centers for Medicare & Medicaid Services DHQP Division of Healthcare Quality Promotion DMARD Disease Modifying Antirheumatic Drug FDA Food and Drug Administration FiO 2 Fraction of inspired oxygen GRADE Grading of Recommendations Assessment, Development, and Evaluation HICPAC Healthcare Infection Co ntrol Practices Advisory Committee ICD9

- CM International Classification of Diseases, 9th Revision, Clinical Modification INR International Normalized Ratio LMWH Low molecular weight heparin MRSA Methicillin

- resistant Staphylococcus aureus NICU Neonatal Intensive Care Unit NHSN National Healthcare Safety Network OBS Observational study OR Odds ratio P P value PJI P erip rosthetic joint infection RA Rheumatoid arthritis RCT Randomized control trial RR Relative risk SICU Surgical intensive care unit SD Standard deviation SR Systematic review SSI Surgical site infection THA Total hip arthroplasty TKA Total knee arthroplasty TNF Tumor Necrosis Factor VTE Veno us thrombo embolism WBC White blood cellDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 6 

### I. Executive Summary Surgical site infections (SSI) are infections of the incision or organ/space occurring after surgery.
1 , 2 Prevention of SSI is increasingly important as the number of surgical procedures performed continues to increase

. 3 , 4 S urgical patients present ing wit h more complex comorbidities 5 and the emergence of antimicrobial resistant pathogens increase the cost and challenge of treating SSIs

. 6

- 8 P ublic reporting of process, outcome
, and other quality improvement measures is now required
, 9 , 10 and reimbursements 11 for treating SSIs are being reduced or denied.

The Draft Guideline for Prevention of Surgical Site Infection addresses new and updated strategies for the prevention of SSI in healthcare setting s

. 12 This guideline does not provide comprehensive infect ion control recommendations for prevention of SSIs. The select areas of focus were informed by feedback received from clinical experts and input from the Healthcare Infection Control Practices Advisory Committee (HICPAC), a federal advisory committee to th e Centers for Disease Control and Prevention (CDC). The C ore section includes recommendations intended to be generalizable across surgical procedures. The P rosthetic J oint A rthroplasty section focuses on this frequently performed procedure with a high human and economic burden . This guideline does not specifically address SSI prevention issues unique to : burns, trauma, surgical incisions allowed to heal by secondary intention, transplant procedures, transmission of blood borne pathogens f rom healthcare personnel to the patient, pediatric surgical practice, minimally invasive procedures, procedures performed outside the operating room (e.g., endoscopic procedures )
, non

- surgical invasive procedures (e.g., cardiac catheterization, interventi onal radiology ), and other procedures or conditions not specifically mentioned

. In general, SSI prevention measures deemed effective in adults are also indicated in the pediatric population, and those effective in the operating room can be adapted or modi fied for other settings. In addition, this update does not address SSI surveillance or public reporting

. 1 , 2 Recommendations on infection control in healthcare personnel
, 13 environmental infection control
, 14 and disinfection and sterilization of medical devices 15 in health care settings all of which may have an impact on the incidence of SSI, are topics addressed by other guidelines.

This document is intended for use by surgeons, physician assistants, perio perative nurses and other allied perioperative assistive personnel, anesthesia providers, postoperative inpatient and clinic nurses, infection prevention staff, healthcare epidemiologists, healthcare administrators, other healthcare providers, and persons responsible for developing, implementing
, delivering, and evaluating infection prevention and control pr ograms for surgical procedures performed in an operating room (i npatient or ambulatory setting ) . The guideline can also be used as a resource for professional societies or organizations that wish to develop more detailed implementation guidance or to identify future research priorities where there are evidence gaps for the prevention of SSI

.
Our goal was to develop a guideline based on a targeted s ystematic review of the best available evidence, with explicit links between the evidence and recommendations. To accomplish thisDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 7 we used an adapted Grading of Recommendations, Assessment, Development, and Evaluation ( GRADE) system for evaluating quality of evidence and determining strength of recommendations

. 16

- 19 The methodology, structure, and components of this guideline were adopted by the Centers for Disease Control and Prevention (CDC) and Healthcare Infection Control Practices Advisory Committee ( HICPAC ) in 2009

. 20 , 21 A more detailed description of our approach is found in the Methods section. Evidence

- based recommendations were cross

checked with those from other guidelines identified in an initial systematic search.
The Key Questions, Evidenc e Review, and Summary of Recommendations, are each organized as follows:

CORE section To evaluate the evidence on SSI prevention across multiple surgical specialties and procedures, published material addressing ten key questions and related subquestions were examined:

Parenteral a ntimicrobial prophylaxis (AMP) Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI? A. W hat is the optimal timing of preoperative AMP ? B. What is the optimal t iming of AMP in cesarean section : prior to skin incision or at cord clamping ? C . How safe and effective is weight

- adjusted AMP dosing ? D

. How safe and effective is intra operative redosing of AMP ? E . How safe and effective is postop erative AMP and what is the optimal duration? Non

- parenteral a ntimicrobial prophylaxis Q2. What are the most effective strat egies for administering non

- parenteral antimicrobial prophylaxis at the surgical incision to reduce the risk of S SI ? A. How safe and effective is antimicrobial irrigation? B. How safe and effective are antimicrobial agents applied to the surgical incision ? C. How safe and effective are antimicrobial

- coated sutures ; when and how should they be used? D. How safe and effective are anti microbial dressings applied to surgical incision s following primary closure in the operating room ? Glycemic control Q3

. H ow do perioperative blood glucose and hemoglobin A1C levels impact the risk of SSI
, and what are the ir optimal perioperative t arget levels in diabetic and non

- diabetic patients ? Normothermia Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI? Q5. What are the most effective strategies for achieving and maintaining perioperative

no rmothermia? Oxygenation Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO 2 ) in reducing the risk of SSI ?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 8 Q7. What is the optimal target F i O 2 to reduce the risk of SSI ; h ow and when should it be administered? Antiseptic Prophylaxis Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI ? A. How safe and effective is preoperative an tiseptic bathing or showering? B. How safe and effective are antiseptic skin preparation agents individually and in combination? C. How safe and effective is the application of an antimicrobial sealant immediately following skin preparation ? D. How safe and effective are plastic adhesive drapes? Q9. How safe and effective is antiseptic i rrigation prior to closing the surgical incision ? Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision ?

PROSTHETIC JOINT ARTHROPLASTY Section To evaluate the evidence on SSI prevention in prosthetic joint arthroplasty procedures, published material addressing 1 0 key questions and related subquestions were examined:

Blood t ransfusion Q 11 . How do perioperative blood transfusion s impact the risk of SSI in prosthetic joint arthroplasty patients? A. Are specific blood products associated with a risk of SSI? B. If the risk of SSI is increased, can this effect be isolated from the risk associated with more complex cases ? C. How does the volume of transfused blood product impact the risk of SSI? D. How safe and effective is withholding blood transfusion to reduc e the risk of SSI ? Systemic i mmunosuppressive therapy Q 1 2 . How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients? A. Does the ty pe of agent impact the risk of SSI? B. Does the preoperative duration of the therapy impact the risk of SSI? C . Does the agent dose impact the risk of SSI? Q 1 3

. What are the most effective strategies in managing systemic corticosteroid or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients? A. How safe and effective is the discontinuation of these agents preoperatively, and when should they be resumed? B. Should the agent dos e be adjusted, and if so, for how long? Q 1 4 . What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients who are on systemic corticosteroid or other immunosuppressive therapy ? Intra

- articular corticosteroid injection sDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 9 Q 1 5 . How do preoperative intra

- articular corticosteroid injection s impact the risk of SSI in prosthetic joint arthroplasty patients? Q 1 6 . What are the most effective strategies for managing the preoperative use of intra

articular corticosteroid injections to reduce the risk of SSI in prosthetic j oint arthroplasty patients ? A. Does the length of time between intra

- articular corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? B. Does the corticosteroid injection dose impact the risk of SSI? Anticoagulation Q1 7 . What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI? A. Does the risk of SSI differ by individual VTE prophylaxis agent? B

. What is the optimal timing and duration of peri o perative VTE prophylaxis that also reduces t he risk of SSI? C

. How safe and effective is modifying the dose of the perioperative VTE prophylaxis agent to reduce the risk of SSI? Orthopaedic space suit Q 1 8 . How safe and effective are orthopaedic space suit s in reducing the risk of SSI in prosthetic joint arthroplasty patients , and wh ich healthcare personnel should wear them ? Antimicrobial prophylaxis duration with drain use Q 19

. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty in the presence of a drain? Biofilm Q 2 0 . What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty patients ? A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? B. How effective are prosthesis surface modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology)? C. How effective are vaccines? D. How effective are other biofilm c ontrol agents (e.g., biofilm dispersants, quorum

sensing inhibito rs, novel antimicrobial agents)?

Evidence addressing the key questions was used to formulate recommendations and explicit links between the evidence and recommendations are available in the Evidence Review in the body of the guideline and Evidence Tables and GRADE Tables in the Appendices

. Category I recommendations are ALL considered strong and should be equally implemented; only the quality of the evidence underlying the recommendation that distinguishes between levels A and B. Category IC recommendations are required by state or federal regulation and without regard to level of supporting evidence. Category II recommendation s are considere d weak recommendation s , discretionary for the individual institution, and not intended to be enforced

. The categorization scheme used in this guideline is presented in Table 1: Summary of Recommendations and described further in the Methods section.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 10 Readers who wish to examine the evidence underlying the recommendations are referred to the Evidence Review in the body of the guideline, and the Evidence Tables and GRADE Tables in the Appendices. The Evidence Review includes narrative summaries of the data presented in the Evidence Tables and GRADE Tables. The Evidence Tables include all study

- level data used in the guideline, and the GRADE Tables assess the overall quality of the evidence for each question and outc ome examined . The Appendices also contain a clearly delineated search strategy that can be used for periodic updates to ensure that the guideline remains a timely resource as new information becomes available

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 11 

### II. Summary of Recommendations Table 1. CD C and HICPAC Categorization Scheme for Recommendations * 20 , 21 Category IA A strong recommendation supported by high to moderate quality * 20
, 21 evidence suggesting net clinical benefits or harms. Category IB A strong recommendation supported by low

- quality evidence suggesting net clinical benefits or harms, or an accepted practice (e.g., aseptic technique) supported by low to very low

- quality evidence. Category IC A strong recommendation required by state or federal regulation

. Category II A weak recommendation supported by any quality evidence suggesting a tradeoff between clinical benefits and harms. No recommendation/ unresolved issue An unresolved issue for which there is either low to very low

- quality evidence with uncertain tradeoffs between benefits and harms or no published evidence on outcomes deemed critical to weighing the risks and benefits of a given intervention

.

* Please refer to Methods section and Umscheid et al., “Updati ng the Guideline Methodology of the Healthcare Infection Control Practices Advisory Committee” (HICPAC; http://www.cdc.gov/hicpac/pdf/guidelines/2009

- 10

- 29HICPAC_GuidelineMethodsFINAL.pdf ), for the process used to grade quality of evidence and formulate recommendations.



### CORE SECTION I. PARENTERAL ANTIMICROBIAL PROPHYLAXIS

1A. Administer preoperative antimicrobial agent only when indicated, based on published clinical practice guidelines and timed such that a bactericidal concentration of the agent is established in the serum and tissue s when the incision is made (Category IB) 12 (Key Question 1A)

 No further refinement of timing can be made for preoperative antimicrobial agent based on clinical outcomes. (No recommendation/unresolved issue) (Key Question 1A)

1B. Administer the appropriate parenteral prophylactic antimicrobial agent prior to skin incision in all cesarean sections. (Category IA) 22

- 25 (Key Question 1B)

1 C

. No recommendation can be made regarding the safety and effectiveness of weight

- adjusted dosin g of parenteral prophylactic antimicrobial agent s for the prevention of surgical site infection

. (No recommendation/unresolved issue) (Key Question 1C)

1 D

. No recommendation can be made regarding the safety and effectiveness of intraoperative redosing of parenteral prophylactic antimicrobial agent s for the prevention of surgical site infection

. (No recommendation/unresolved issue) 26 (Key Question 1D)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 12 1 E . In clean and clean

- contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in th e operating room , even in the presence of a drain

. (Category IA) 27

- 65 (Key Question 1E)

II. NON

- PARENTERAL ANTIMICROBIAL PROPHYLAXIS

2A .1. No recommendation can be made r egarding the safety and effectiveness of intraoperative antimicrobial irrigation (e.g., intra

- abdominal, deep or subcutaneous tissues) for the prevention of surgical site infection. (No recommendation/unresolved issue) (Key Question 2A)

2A. 2 . No recommendation can be made regarding the safety and effectiveness of soaking prosthetic devices in antimicrobial solutions prior to implantation for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key question 2A)

2B .1. Do not apply antimicrobial agents (i.e., ointments, solutions, powders) to the surgical incision for the prevention of surgical site infection (Category IB ) 66

- 72 (Key Question 2B)

2B. 2

. Application of a utologous platelet rich plasma is not necessary for the prevention of surgical site infection. (Category II ) 73

- 75 (Key Question 2B)

2C. Use of a ntimicrobial coated sutures is not necessary for the prevention of surgical site infection. (Category II ) 76

- 79 (Key Question 2C)

2D. No recommendation can be made regarding the safety and effectiveness of antimicrobial dressings applied to surgical incisions following primary closure in the operating room for the prevention of surgical site infection

. (No recommendation/ unresolved issue) (Key Question 2D)

III. GLYCEMIC CONTROL

3A. 1. Implement perioperative glycemic control and use blood glucose target levels <200mg/dL in diabetic and non

- diabetic patients. (Category IA) 80 , 81 (Key Question 3)

3A. 2 . No recommendation can be made regarding the safety and effectiveness of lower (<200mg/d L ) or narrower blood glucose target levels
, nor the optimal timing, duration
, or delivery method of perioperative glycemic control for the prevention of surgical site infection. (No recommendation/unresolved issue) (Key Question 3)

3B. No recommendation can be made regarding optimal hemoglobin A1C target levels for the prevention of surgical site infection in diabetic and non

- diabetic patients

. (No recommendation/unresolved issue) (Key Question 3)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 13 IV. NORMOTHERMIA

4. Maintain perioperative normothermia (Category IA) 82

- 84 (Key Question 4)

5. No recommendation can be made regarding the safety and effectiveness of strategies to achieve and maintain normothermia, the lower limit of normothermia, or the optimal timing and duration of normothermia for the prevention of surgical site infection. (No recommendation/unresolved issue) (Key Question 5)

V. OXYGENATION

6 A

. For patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation
, a dminister increased fraction of inspired oxygen (FiO 2 ) both intraoperatively and post

- extubation in the immediate postoperative period

. To o ptimize tissue oxygen delivery , maintain perioperative normothermia and adequate volume replacement. (Category IA) 85

- 90 (Key Question 6)

6 B . No recommendation can be made regarding the safety and effectiveness of administering perioperative increased fraction of inspired oxygen (F i O 2 ) for the prevention of surgical site infection in patients with normal pulmonary function undergoing either general anesthesia without endotracheal intubation or neuraxial anesthesia ( i.e. , spinal, epidural, or local nerve blocks). (No recommendation/unresolved issue) 91 (Key Question 6)

6 C . No recommendation can be made regarding the safety and effectiveness of administering increased fraction of inspired oxygen (F i O 2 ) via facemask or nasal cannula only during the postoperative pe riod for the prevention of surgical site infection in patients with normal pulmonary function. (No recommendation/unresolved issue) 92 , 93 (Key Question 6)

7. No recommendation can be made regarding the optimal target level, duration, and delivery method of the fraction of inspired oxygen (FiO 2 ) for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key Question 7)

VI. ANTISEPTIC PROPHYLAXIS

8A. Advise patients to shower or bathe (full body ) with either soap ( antimicrobial or non

antimicrobial ) or an antiseptic agent on at least the night before the operative day (Category IB) 94

- 102 (Key Question 8A)

8A.1. No recommendation can b e made regarding t he optimal timing of the preoperative shower or bath
, the total number of soap or antiseptic agent applications , or the use of chlorhexidine gluconate washcloths for the prevention of surgical site infection

. (No recommendation/ unresolved issue) (Key Question 8A)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 14 8B. Perform intraoperative skin preparation with an alcohol

- based antiseptic agent , unless contraindicated

. (Category IA) 103

- 116 (Key Question 8B)

8C. Application of an antimicrobial sealant immediately following intraoperative skin preparation is not necessary for the prevention of surgical site infection. (Category II ) 117

- 119 (Key Question 8C)

8D. Use of plastic adhesive drapes with or without antimicrobial properties, is not necessary for the prevention of surgical site infection

. (Category II) 104 , 120

- 124 (Key Question 8D)

9 A

. Consider intraoperative irrigation of deep or subcutaneous tissues with aqueous iodophor solution for the prevention of surgical site infection. Intra

- peritoneal lavage with aqueous iodophor solution in contaminated or dirty abdominal pro cedures is not necessary. (Category II) 125

- 131 (Key Question 9)

9 B

. No recommendation can be made regarding the safety and effectiveness of soaking prosthetic devices in antiseptic solutions prior to implantation for the prevention of surgical site infec tion. (No recommendation/unresolved issue) (Key Question 9)

10. No recommendation can be made regarding the safety and effectiveness of repeat

a pplication of antiseptic agents to the patient’s skin immediately prior to closing the surgical incision for the prevention of surgical site infection. ( No recommendation/unresolved issue ) 132 (Key Question 10)



### PROSTHETIC JOINT ARTHROPLASTY SECTION I. BLOOD TRANSFUSION

11 A . No recommendation can be made regarding the perioperative management of blood transfusion s for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) 133

- 141 (Key Question 11 A

- C )

11B. Do not withh old transfusion of necessary blood products from surgical patients as a means to prevent surgical site infection (Category IB) 12 (Key Question 11 D )

II. SYSTEMIC IMMUNOSUPPRESSIVE THERAPY

1 2 and 13

. No recommendation can be made regarding the perioperative management of systemic corticosteroid or other immunosuppr essive therapy for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/ unresolved issue) 142

- 148 (Key Question s 12 and 13)

1 4

. For prosthetic joint arthroplasty patients on systemic corticosteroid or other immunosuppressive therapy, Recommendation 1 E applies : In clean and clean

- contaminatedDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 15 procedures, do not administer additional prophylactic antimicrobial agent doses after the
surg ical incision is closed in the operating room, even in the presence of a drain. (Category IA) 27

- 65 (Key Question 14)

III. INTRA

- ARTICULAR CORTICOSTEROID INJECTION

1 5 and 16

. No recommendation can be made regarding the management of preoperative intra

articular corticosteroid injectio n for the prevention of surgical site infection in prosthetic joint arthroplasty

. (No recommendation/ unresolved issue) 149

- 153 (Key Question s 15 and 16 )

IV. ANTICOAGULATION

1 7 . No recommendation can be made regarding the perioperative management of venous thromboembolism prophylaxis for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) 154

- 167 (Key Question 1 7 )

V. ORTHOPAEDIC SPACE SUIT

1 8 . No recommendation can be made regarding the safety and effectiveness of orthopaedic
space suits or the health care personnel who should wear them for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolve d issue) 168

- 170 (Key Question 18 )

VI. POSTOPERATIVE AMP DURATION WITH DRAIN USE

1 9

. In prosthetic joint arthroplasty
, Recommendation 1E applies: In clean and clean

contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA) 27

- 65 (Key Question 19 )

VII. BIOFILM

20 A

. No recommendation can be made regarding the safety and effectiveness of cement modifications and the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplasty. (No recommendation/ unresolved issue ) 171,172 (K ey Question 20 A)

20 B. No recommendation can be made regarding the safety and effectiveness of prosthesis modifications for the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) (Key Question 20 B)

20 C

. No recommendation can be made regarding the safety and effectiveness of vaccines for the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplas ty

. (No recommendation/ unresolved issue) (Key Question 20 C)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 16 20 D. No recommendation can be made regarding the safety and effectiveness of biofilm control agents such as biofilm dispersants, quorum

- sensing inhibitors, or novel antimicrobial agents for the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) (Key Question 20 D)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 17 

### III . Background
In 2006, approximately 80 million surgical procedures wer e performed in U nited S tates (U.S.) inpatient hospital (46 million) 4 and ambulatory hospital

- affiliated or free

- standing (32million) setting s. 3 Between 2006 and 2009, SSIs complicated approximately 1.9% of surgical procedures in the U nited S tates

. 173 However, the number of SSIs is likely to be underestimated given that approximately 50% become evident after discharge

. 2 From January 2009 thr ough December 2010, SSIs accounted for 23% of 69,475 healthcare

- associated infections ( HAIs ) reported to the Centers for Disease Control and Prevention’s (CDC) National Healthcare Safety Network ( NHSN ) surveillance system by 2,039 hospitals

. 174 An attempt to establish a national surveillance definition for SSI 175 has not been widely adopted in the scientific literature
, which in combination wi th inconsistencies in coding and a lack of standardization of post

- discharge surveillance
, has made it challenging to evaluate or compare interventions and track SSIs over time

. 5

Multiple patient co

- morbidities and risk factors, in addition to procedure

- related risk factors
, can impact the risk of SSI

. 5 SSIs result in increased morbidity, mortality, and direct and indirect
cost s including increased hospital length of stay, readmission s for treatment including repeat surgical procedures, outpatient and emergency care visits, use of ancillary services, additional medications ( including prolonged antimicrobial therapy ) , lost productivity
, and temporary or permanent disability

. 176 Actual attributable cost s of SSIs are difficult to determine

. C ost estimates are commonly res tricted to hospital charges and vary according to surgical procedure, depth of infection, facility, region, country , publication year, study design, and accounting method

. 176

- 178 Estimate d average attributable cost s of SSIs range from $10,443 to $25,546 per infection (2005 and 2002 dollars, respectively)

. 6

- 8,179 Staphylococcus aureus and coagula se negative staphylococci are the organisms most commonly associated with SSIs , but pathogens can vary by procedure

. 174 C ost s can exceed $90,000 per infection when the SSI involves a prosthetic joint implant 180,181 or antimicrobial resistant organism

. 182

In 2002 CDC and Centers for Medicare & Medicaid Services (CMS) institut ed the Surgical Inf ection Prevention (SIP) project w ith the goal of reducing SSIs

. 183 In 2006, SIP became the Surgical Care Improvement Program (SCIP) and expanded to include patient hair removal at the surgical site , glyce mic control, and normothermia process measures

. 184 With t he Deficit Reduction Ac t of 2005
, the U

. S

. Congress set forth a mandate for hospital reporting of process, outcome, and othe r quality improvement measures and for making this info rmation available to the public and CMS

. 11 In addition, this act r equired CMS to adjust payments downward for H AIs that could have been prevented through the application of evidence

- based strategies

. In 2009 , the U

. S

. Department of Health and Human Services ' National Action Plan to Prevent Health Care

- Associated Infections: Road Map to Elimination set a 5

- year target goal of a 25% reduction in SSIs detected on admission and readmission or a 0.75 Standardized Infection Ratio (SIR)

. 9 Since January of 2012, CMS ’s Hospital Inpatient Quality Reporting Program has required facilities to report SSI outcome data through CDC’s NHSN

. 10 Between 2009 and 2010 improved prevention of deep incisional and organ/space SSI s detected on admission and readmission was documented for coronary artery bypass graft ( CABG )
, total knee arthroplasty ( TKA ) , and colonDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 18 surgical procedures (18%, 11%, and 9% relative risk reduction of SSI s , respectively)

. 185 Approximately 55% of SSIs are deemed preventable by application of e vidence

- based strategies

. 179

Prosthetic joint arthroplasty

Prevention efforts should target all surgical procedures, but especially those where both human and financial burden is greatest. In 2011 , p rimary TKAs account ed for over half of the 1.2 million prosthetic joint arthroplasty procedures (primary and revision) performed in the U nited S tates , followed by total hip arthroplasty ( THA )
, and hip hemi

- arthroplasties

. 186 P rimary shoulder
, elbow, and ankle arthroplasties are much less common

. By 2030, prosthetic joint arthroplasties are projected to increase to 3.8 million procedures per year. 187

- 189

Infection is the most common indication for revision in TKA 190 and the third most common indication in THA , 190 following instability/dislocation and mechanical loosening

. S

. aureus and coagulas e negative staphylococci are the most common pathogens associated with orthopaedic SSI

. 174 Between 2001 and 2009
, there was a significant increase in the risk of infection following hip and knee arthroplasties ( from 1.99% to 2.18% and from 2.05 % to 2.18 %
, respectively )

. 181 By 2030 the infection burden for hip and knee arthroplasty is expected to increase to 6.5% and 6.8%, respectively

. 191 Owing to both increasing risk and the number of individuals undergoing prosthetic joint arthroplasty procedures, b etween 2010 and 2020, t he total number of hip and knee prosthetic joint infection ( PJI ) cases is projected to increase from 25,000 to 70,000 and up to 221,500 cases per year by 2030

. 181,191 T reatment of PJI commonly inv olves a 2

- stage p rocedure , with 4 to 8 weeks of parenteral antimicrobial therapy between stages. When eradication of the infection i s not possible, treatment can include arthrodesis or even amputatio n. 192 In 2009 the average hospital cost for the revision of an infected hip or knee arthroplasty was $93,600 and $24,200, respectively

. 181 Between 2001 and 2009,

e stimated total hospital cost s for treating PJI increased from $320 million to $566 million
, and is projected to reach $1 billion by 2014 and $ 1.62 billion by 2020

. 181

Any indwelling medical device or prosthetic implant has the potential to becom e colonized by organisms embedded in biofilm

. 193,194 In the U nited S tates , as many as 13 million people experience a biofilm

- related infection every year

. 195 Biofilm is defined as “a microbially derived sessile community characterized by cells that are irreversibly attached to a substratum or interface or to each other, are embedded in a matrix of ext racellular polymeric substances that they have produced, and exhibit an altered phenotype with respect to growth rate and gene transcription”

. 194 Biofilm organisms exhibit significant resistance to antimicrobial agents (10 to 1000 times the minimum inhibit ory concentration [MIC]) as compared to their free floating, planktonic counterparts. 194 Mechanisms involved in this increased antimicrobial resistance may include: “...delayed penetration of the antimicrobial agent through the biofilm matrix, altered growt h rate of the biofilm organisms, and other physiologic changes due to the biofilm mode of growth”. 194 Between 7 % and 39% of PJIs are culture negative
, 196,197 which is often attributed toDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 19 previous antimicrobial therapy 198 or the presence of difficult to cul ture biofilm organisms , making diagnosis
, treatment , and the identification of prevention measures critical.

E vidence

- based guidelines have provided recommendations for the diagnosis of PJI using
convent ional testing techniques including serologic and synovial fluid markers
, tissue histopathology
, traditional culture

- based techniques , and imaging studies

. 199 Recently published studies further su pport or add to these recommendations

. 197,198,200

- 202 P otential future strategies for the diagnosis of PJI include the use of novel serologic 203

- 207 and synovial fluid 208 markers

. In addition
, novel strategies to improve the recovery of biofilm organisms may enhance detection of organisms present in lower numbers or species present as a minority

. 193
Sonicatio n of the explanted prosthesis 197,209

- 212 or cement spacer 211 produce s a diluent of released biofilm sonicate

. Culture of s onicate effluent may have improved culture sensitivity as compared to standard synovial fluid or tissue culture techniques

. Different growth media 197,213 and microscop ic 197,213

- 217 techniques to better grow and characterize biofilm and the embedded organisms are also being explored . Adjunct molecular techniques hold the potential to improve the sensitivity and specificity of t raditional culture

- based techniques

. 213

- 215,217

- 223 However, o nly culture

- based techniques provide information on antimicrobial susceptibility, which drives PJI treatment, t herefore exploring wa y s to enhance culturing technique s continues to be important

. 224 Multidisciplinary work to standardize the clinical diagnosis of PJI is ongoing

. 225DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 20 

### IV . Scope and Purpose This guideline provides update d and new recommendations for the prevention of SSI

. This guideline does not provide comprehensive infection control recommendations for prevention of SSIs. The select areas of focus were informed by feedback received from clinical experts and input from the Healthcare Infection Control Practices Advisory Committee (HICPAC), a federal advi sory committee to the Centers for Disease Control and Prevention (CDC). As in t he Guideline for Prevention of Surgical Site Infection
, 1999 t his guideline does not specifically address SSI prevention issues unique to: burns, trauma, surgical incisions all owed to heal by secondary intention, transplant procedures, transmission of blood borne pathogens from healthcare personnel to the patient, pediatric surgical practice, minimally invasive procedures, procedures performed outside of the operating room (e.g.
, endoscopic procedures )
, non

surgical invasive procedures (e.g., cardiac catheterization, interventional radiology ) and other procedures or conditions not specifically mentioned

. 12 In general, SSI prevention measures deemed effective in adults are also indicated in the pediatric surgical population, and those effective in the operating room can be adapted or modified for other settings. In addition, this update does not address SSI surveillance or public reporting

. 1 , 2 Recommendations on infection control in healthcare personnel
, 13 environmental infection control
, 14 and disinfection and sterilization of medical devices 15 in health care settings are topic s addressed by other guidelin es.

To evaluate the evidence on SSI prevention, key questions addressing 13 intervention categories were examined. Six topics evaluated the literature across all surgical procedures and comprise the Core s ection of the guideline: Parenteral a ntimicrobial p rophylaxis, Non

parenteral a ntimicrobial p rophylaxis , Glycemic c ontrol, Normothermia, Oxygenation, and Antiseptic prophylaxis

. Seven other topics e valuated the literature specific to P rosthetic J oint A rthroplasty and comprise the second section : Blood t ransfusion s , Systemic i mmunosuppressive t herapy
, I ntra

- articular corticosteroid injection s , Anticoagulation, Orthopaedic s pace s uit , Postoperative a ntimicrobial prophylaxis duration with drain use , and Biofilm. The specific key questions were:

CORE SECTION Parenteral a ntimicrobial prophylaxis (AMP) Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI?

Non

- parenteral A ntimicrobial prophylaxis Q2. What are the most effective strategies for administering non

- parenteral antimicrobial prophylaxis at the surgical incision to reduce the risk of SSI?

Glycemic control Q3. H ow do perioperative blood glucose and hemoglobin A1C levels impact the risk of SSI
, and what are the ir optimal perioperative target levels in diabetic and non

- diabetic patients ?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 21 Normothermia Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI? Q5. What are the most effective strategies for achieving and maintaining perioperative normothermia?

Oxygenation Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (Fi O 2 ) in reducing the risk of SSI? Q7. W hat is the optimal target F i O 2 to reduce the risk of SSI; how and when should it be administered?

Antiseptic prophylaxis Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI? Q9. How safe and effective is antiseptic irrigation prior to closing the surgical incision ? Q10. How safe and effective is repeat application of antiseptic skin preparation agent to the surgical site immediately prior to closing th e surgical incision ?

PROSTHETIC JOINT ARTHROPLASTY S ECTION Blood t ransfusion Q 11

. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients?

Systemic immunosuppressive therapy Q1 2

. How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients?

Q1 3

. What are the most effective strategies in managing systemic corticosteroid or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients?

Q1 4

. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients on systemic corticosteroid or other immunosuppressive therapy?

Intra

- articular corticosteroid injection s Q1 5

. How do preoperative intra

- articular corticosteroid injections impact the risk of SSI in prosthetic joint arthroplasty patients?

Q1 6 . What are the most effective strategies for man aging the preoperative use of intra

articular corticosteroid injections to reduce the risk of SSI in prosthetic joint arthroplasty patients?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 22 Anticoagulation

Q1 7 . What are the most effective strategies for managing perioperative venous thromboembolism ( VTE ) prophylaxis to reduce the risk of SSI?

Orthopaedic space suit Q1 8 . How safe and effective are orthopaedic space suit s in reducing the risk of SSI in prosthetic joint arthroplasty patients , and which healthcare personnel should wear them ?

Postopera tive a ntimicrobial prophylaxis duration with drain use Q 19

. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty in the presence of a drain? ?

Biofilm Q 20 . What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty?

Evidence

- based recommendations were cross

- checked with those from other guidelines identified in an initial systematic search.

This document is intended for use by surgeons, physician assistants, perioperative nurses and other allied perioperative assistive personnel, anesthesia providers, postoperative inpatient and clinic nurses, infection prevention staff, healthcare epidemiologists, healthcare administrators, other health care providers, and persons responsible for developing, implementing, delivering, and evaluating infection prevention and control programs for surgical procedures performed in an operating room (inpatient or ambulatory setting). The guideline can also be used as a resource for professional societies or organizations that wish to develop more detailed implementation guidance or to identify future research priorities where there are evidence gaps for the prevention of SSI.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 23 

### V . Methods This guideline was based on a systematic review of the best available evidence on SSI prevention. The Grading of Recommendations Assessme nt, Development and Evaluation (GRADE) approach was used to assess the quality of the available evidence, the strength of resulting the recommendations, and to provide explicit links between the m s

. 16

- 19 The guideline development process h as been previously described

. 21 Methods and details that were unique to this guideline are included below.

Development of Key Questions

A preliminary list of key questions was developed from a rev iew of the 1999 CDC SSI guideline

. 12 C ontent experts were surveyed to provide fe edback on the questions and identify additional topics of interest. Key questions were put in final form after vetting them with a panel of content experts and HICPAC members

.

Literature Search

Following the development of the key questions, search terms were developed for identifying literature most relevant to those questions. For the purposes of quality assurance, these terms were compared to those used in relevant seminal studies and guidelines. These search terms were then incorporated into search strategies for the r elevant databases

. Searches were performed in MEDLINE, EMBASE, CINAHL, and the Cochrane Library . All databases were searched from 1998
, when the previous guideline searches ended
, through June 2011 for the Core s ection and December 2011 for the Prosthetic J oint A rthroplasty Section. R eferences were imported into a reference manager where duplicates were resolved. The detailed search strategy and results for the Core section can be found in Appendix 1 and for the Prosthetic J oint A rthroplasty section in Appendix 2

.
Study Selection

Titles and abstracts were screened by one independent review er (S.I.B.T., R.K., or C.R.)

. A random sample of 10% of titles and abstracts had a second independent review to ensure consistency in screening. Kappa scores , used to measure agreement between the two independent reviewers beyond chance, ranged from 0.4

– 0.5, indicating “moderate agreement” between reviewers

. 226 Full text articles were retrieved if they were: 1) relevant to one or more key questions; 2) clinical pra ctice guidelines, systematic review (SRs) or primary study designs meeting the inclusion criteria (randomized control trial [ RCTs ] for the Core and Prosthetic J oint A rthroplasty s ections and observational [ OBS ] studies for the Prosthetic J oint A rthroplasty s ection because none of that section’s key questions were adequately addressed by results from the initial search); 3) written in English; and 4) available as full text studies (meeting abstracts were excluded). Animal studies and in vitro basic science studies were excluded from all topics except Biofilm

. P ediatric patient studies were included. Although the literature databases were searched from 1998 to 2011, studies published earlier than 1998DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 24 were eligible for inclusion (e.g., studies suggested by the expert panel
, included in the previous guideline or in published SRs).

Full

- text articles were screened by two independent reviewers (S.I.B.T and R.K. or S.I.B.T. and C.R.) and disagreements were resolved by discussion. Full

- text articles were excluded if: 1) SSI

was not reported as an outcome; 2) all patients included had “dirty” surgical procedures (except for Q2 addressing the use of aqueous iodophor irrigation) ; 3) the study only included oral medicine or dental hea lt h procedures; 4) the surgical procedures did not include primary closure of the incision in the operating room (e.g. orthopedic pin sites, thoracotomies , or percutaneous endoscopic gastrostomy ( PEG ) procedures
, or wounds healing by secondary intention ); or 5) the study evaluated wound protectors used post incision. For the Core s ection , Q1 Parenteral a ntimicrobial prophylaxis
, studies comparing the efficacy of antimicrobial prophylaxis to no prophylaxis ( placebo

- controlled studies ) and studies compari ng the efficacy of different prophylactic antimicrobial agents were excluded. Also for Q2 Non

- parenteral

a ntimicrobial prophylaxis
, use of gentamycin collagen sponge studies (not approved by the Food and Drug Administration [ FDA ] )were excluded

. For Q8

- 10 Antiseptic prophylaxis , studies evaluating vaginal antisepsis in combination with abdominal antisepsis were excluded. In addition, studies using electrolyzed ionized solution (not approved by the Food and Drug Administration [ FDA ] for intraoperative irrig ation of the surgical site) and dry povidone iodine powder spray studies were excluded. For the Prosthetic J oint A rthroplasty s ection , studies were excluded if they did not specifically examine prosthetic joint arthroplasties. Questions from four topics in the Prosthetic Joint Arthroplasty section were excluded from a targeted search when both: 1) the initial broad search identified very few or no RCTs or SRs that fit the inclusion criteria and 2) the content experts excluded them as priority topics and/ or key questions (i.e., Surgical attire

- gloves, Surgical technique s , Anesthesia, and Environmental factors )

. Also, q uestions and related studies addressing diagnosis of PJI or biofilm were excluded because they did not address SSI prevention. Special inclusion criteria for the Core

s ection were : for Q1, studies on the optimal timing of AMP in cesarean sections ; for Q2 autologous platelet rich plasma gel ; f or Q9 and Q10 aqueous iodophor solution irrigation or repeat application to skin prior to closing the surgical incision

. Special inclusion criteria for the Prosthetic J oint A rthroplasty s ection included: for Q1 1 Blood t ransfusion

- studies that evaluated the administration of epoetin alpha in combination with blood transfusion.

A draft bibliography was shared with a panel of content experts and a dditional suggested references then progressed through title/abstract and f ull text review as above. R esults of the entire study selection process are depicted in Figure 1

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 25 Figure 1. Results of the Study Selection Process

43 RCTs identified from excluded SRs

133 studies extracted into evidence
and GRADE tables 4,961 potentially relevant studies identified in literature searches 168 studies cited in 1999 CDC SSI guideline

5,233 title/abstracts screened

4,436 studies excluded

797 full text review

682 studies excluded

564: not relevant to key questions 108: study design 6: not available as full text article 4: not in English 25 clinical practice guidelines

14 additional clinical practice guidelines identified by writing group

23 clinical practice guidelines cited in current guideline

16 clinical practice guidelines excluded

104 studies suggested by content expertsDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 26 Data Extraction and Synthesis

For studies meeting the inclusion criteria, data on the study author, year, design, risk of bias, objective, population, setting, sample size, interventions, and results of clinically relevant outcomes were extracted into standardized evidence tables. From these, evidence table s were developed for each clinical topic represented by the key questions. Studies were extracted into the most relevant evidence table. Studies were organized by individual key questions and subquestion s . Data were extracted by a single author (S.I.B.T. , E.C.S., B. L ., or R.A.) and cross

checked by another author (S.I.B.T.)

. Disagreements were resolved by the remaining authors. Data and analyses were extracted as originally presented in the included studies. Meta

analyses were performed only where thei r use was deemed critical to a recommendation and only in circumstances in which multiple studies with sufficiently homogenous populations, interventions, and outcomes could be analyzed. The risk of bias associated with each study was assessed using scale s developed by the Penn Medicine Center for Evidence

- based Practice, and scores were recorded in the evidence tables. Appendices 1 and 2 include the questions used to assess the risk of bias of the included SRs, RCTs, and OBS for the Core and Prosthetic J oint A rthroplasty S ection s , respectively

.
Systematic reviews were included in this review if the individual studies in the review fit our inclusion criteria. To avoid duplication of data, primary studies identified by our search were excluded if they w ere also included in a systematic review captured in our search . The exception to this was 1) if the primary study also addressed a relevant question that was outside the scope of the included systematic review or 2) if it was one of a select number of
st udies in the systematic review that fit our inclusion criteria and was used to perform a new
meta

- analysis. Systematic reviews that analyzed primary studies that were fully captured in a more recent systematic review were excluded. The only exception t o this was if the older systematic review also addressed a relevant question that was outside the scope of the newer systematic review

. 227

To ensure that all relevant studies were captured in the search, the bibliography was vetted by a panel of content experts. Statistical analyses were performed using Review Manager 5.1. For the purposes of our review, statistical significance was define d as p≤0.05.

For all other methods (i.e., Grading of Evidence, Formulation of Recommendations, and Finalizing of the Guideline) please refer to the Guideline Methods supplement. 21

Reviewing and Finalizing the Guideline

The writing group completed a d ra ft of the guideline
, including evidence reviews, recommendations , evidence tables, and GRADE tables
, and shared it w ith the expert panel for in depth review

. B ased on the expert panel’s feedback , the writing group revised the guideline documents and prese nted draft recommendations to HICPAC at public meetings for their review and input

. Following further revisions, CDC then submitted the guideline for an initialDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 27 clearance at CDC and is p osting it in the Federal Register for a period of public comment. After this period of public comment, the co mments will be reviewed at a HICPAC meeting , revised accordingly , and the final guideline will be submitted to CDC for final clearance . Once cleared, the guideline will be posted to CDC’s website and published.

Updating the Guideline

R evisions to this guideline will be guided by new research and technological advancements for preventing SSIs

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 28 

### VI. Evidence Review : Core s ection

PARENTERAL ANTIMICROBIAL PROPHYLAXIS (AMP) 

### Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI?

To answer this question
, we focused on f ive subquestions: A) W hat is the optimal timing of preoperative AMP ? B) What is the optimal timing of AMP in cesare an section : prior to skin incision or at cord clamping ? C) How safe and effective is weight

- adjusted AMP dosing ? D ) How safe and effective is intra operative redosing of AMP ? and E ) How safe an d effective is postoperative AMP and what is the optimal duration?



### Q1A. W hat is the optimal timing of preoperative AMP ?

Our search did not identify RCTs or SRs that evaluated different timing s of preoperative AMP administration and its impact on the risk of SSI

.

Other Guidelines The 1999 CDC Guideline for Prevention of Surgical Site Infection and other c linical practice
g uidelines
, based on a review of the evidence and expert opinion
, recommend administering by the intravenous route a single dose of prophylactic antimicrobial agent only when indicated

. For most prophylactic agents, the 1999 CDC guideline recommended preoperative administration be timed such that a bactericidal concentration of the drug is established in the serum and tissues when the incision is made and now other clinical practice guidelines recommend that administration should be within 60 minutes prior to incision (vancomycin and fluoroquinolones within 60

- 120 minutes prior to incision)

. 12,183,228

- 232 None of the recommendations address whether it is necessary to admin ister a complete or a partial infusion of the parenteral AMP dose prior to surgical incision.



### Q1B. What is the optimal timing of AMP in cesarean section : prior to skin incision or at cord clamping ?

The available data on optimal timing of antimicrobial prophylactic agent administration in cesarean section examined AMP administered prior to skin incision versus at cord clamping.

For this comparison we considered post

- partum endometritis as the critical outcome. Incisional SSI, neonatal sepsis, neonatal sepsis workup, and neonatal intensive care unit ( NICU ) admission
outcomes were also evaluated. I n general, endometritis was defined as fever > 100.4 ○ F on two occasions with uterine tendernes s, purulent lochia, tachycardia or leukocytosis

. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 B

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 29 High

- quality evidence suggested a benefit of AMP administration prior to skin incision as compared to administration immediately after the umbilical cord is clamped in cesarean sections

. This was based on a SR 22 (low risk of bias) with a meta

- analysis (N=749) of 3 RCTs 23

- 25 suggesting a 53% reduction in post

- partum endometritis and no difference in proven neonatal sepsis or neonatal sepsis workups

. High

- quality evidence from a meta

- analysis (N=681 neonates) of 2 studies suggested no difference in NICU admissions

. 23 , 24 One study suggested significantly shorter NICU stays and no differenc e in neonatal sepsis causative organisms with administration of AMP prior to skin incision

. 23

Other Guidelines C linical practice guidelines based on a review of the evidence and expert opinion recommend administration of a single preoperative prophylactic antimicrobial agent by the intravenous route, based on the agent pharmacokinetics, commonly beginning within 60 minutes prior to skin incision in both elective and emergency cesarean section. 228

- 230,232 A dministration of AMP after cord clamping is no longer recommended

. 12



### Q1 C

. How safe and effective is weight

- adjusted AMP dosing ?

Our search did not identify RCTs or SRs that evaluated weight

- adjusted AMP dosing and its impact on the risk of SSI.

Other Guidelines C linical practice guidelines b ased on a review of the evidence and expert opinion recommend increasing the single preoperative prophylactic antimicrobial agent dose for select prophylactic antimicrobial agents in obese and morbidly obese p atients

. 228

- 232 For cefazolin
, recommendations are to administer 2g 229

- 231 for patients weighing >60

- 80k g and 3g 230 if >120kg

. For aminoglycosides, dosing is calculated using the patient’s ideal body weight plus 40% of the difference between the actual and ideal body weight

. 230,233 Vancomycin should be dosed at 15m g/kg

. 229

- 231



### Q1 D

. How safe and effective is intra operative redosing of AMP?

The available data examin ing intraoperative redosing of AMP compared one preoperative dose

v ersus one preoperative d ose plus an additional dose at 2 h ours intraoperatively

.
For this comparison we considered abdominal and perineal wound SSI and intra

- abdominal abscess as the outcomes of interest. Antimicrobial resistance outcome was also evaluated

. The evidenc e for this question consists of 1 RCT at moderate risk of bias in elective colorectal
surgery

. 26 The findings of the evidence review and the grades for all important outcomes are

s hown in Evidence Review Table 1 D

.

Moderate

- quality evidence suggested no benefit of intraoperative AMP redosing

. This was based on no difference in abdominal or perineal wound infection, intra

- abdominal abscess, orDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 30 antimicrobial res istance in 1 elective colorectal surgery study from 1991

. 26 However, p rocedure s with duration s >3 h ours had a significantly higher risk of SSI and 22% of patients with procedure duration s ≥2 h ours were not redosed. Fecal contamination almost doubled the SSI rate at every level of contamination ( of note, patients underwent mechanical bow e l prep alone). Pro cedure duration and fecal contamination were not reported by study group. Limited power of the study could result in a false negative finding.

Other Guidelines C linical practice guidelines b ased on a review of the evidence and expert opinion recommend
pr ophylactic antimicrobial agent redosing in cases of prolonged procedures (when the procedure exceeds the half

- life of the prophylactic antimicrobial agent or is longer than 3

- 4 hours) and in patients with major blood loss (>1500 ml) or extensive burns. 2 29

- 232,234 Redosing should also be performed at intervals of 1

- 2 times the prophylactic antimicrobial agent half

- life, starting at the beg inning of the preoperative dose

. 229

- 232,234 No recommendations are provided for optimal prophylactic antimicrobial age nt dosing in obese and morbidl y obese patients when redosing.



### Q1 E

. How safe and effective is postoperative AMP and what is the optimal duration ?

To answer this question
, we focused on studies that used the same prophylactic antimicrobial agent in both arms. We evaluated administration of postoperative AMP both with all surgical procedures combined a nd by select surgical specialties

. Studies that compared different
pr oph ylactic antimicrobial agents or those administering only oral AMP were excl uded . We defined postoperative AMP as any parenteral prophylac tic antimicrobial agent administered after intraoperative closure of the surgical incision . Therefore, postoperative AMP (in hour s or days), does not include any AMP administered a s a single preoperative dose, and/or any intraoperative redosing.

The available data examined the following comparisons for different postoperative AMP durations:

1. All surgeries

- None vs. ≤24 hours 2. Cardiac

a. None vs. ≤24 hours b. None vs. 72

- 96 hours 3. Thoracic

- None vs. 2 days 4. Vascular

a. None vs. ≤24 hours b. <24 hours vs. 3

- 5 days

c. None vs. 5 days 5. Ear, nose, and throat

- ≤24 hours vs. 3

- 5 days 6. GynecologicDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 31 a. None vs. ≤24 hours b. <24 h ours vs. <2.5 days 7. Orthopaedic

a. Fracture

- None vs. ≤24 hours b. Prosthetic Joint Arthroplasty

- None vs. ≤24 hours 8. Colorectal : Bowel preparation with oral antimicrobials

a. None vs. 3 days b. ≤24 hours vs. 5 days 9. Colorectal : Bowel preparation only

a. None vs. ≤24 hours b. None vs. <2

- 3 days 10. Colorectal : Bowel preparation not reported

a. None vs. ≤24 hours b. ≤24 hours vs. 2

- 3 days 11. Colorectal : No bowel preparation

a. None vs. ≤24 hours b. None vs. <2

- 3 days 12. Appendectomy

a. None vs. ≤24 hours b. None vs. 2 days 13. Rectal surgery

- None vs. ≤24 hours 14.Gastric surgery

a. None vs. ≤24 hours b. None vs. 4 days 15. Hepatectomy

– 2 days vs. 5 days

For all comparisons
, we considered SSI (superficial, deep incisi onal, and organ/space) and troc ar wound infection as the critical outcomes. Antimicrobial resistance, adverse events, length of stay, mortality, and pharyngocutaneous fistula outcomes were also evaluated

. The evidence for this question consists of 39 RCT s in cardiac
, 27

- 30 thoracic
, 31 vascular
, 32

- 34 ear, nose and throat
, 35 , 36 gynecologic
, 37

- 41 orthopaedic
, 42

- 47 and general surgical 48

- 65 procedures . Twenty

- eight (72%) studies were published between 1972 and 1998; 11 (28%) studies were published between 2003 and 2011. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 E

.

Q1 E .1. All sur geries

- None vs. ≤24 hours

High

- quality evidence suggested no benefit of continuing AMP after intraoperative closure of the surgical incisions . This was based on no difference in SSI in 1 large meta

- analysis (N=13,408) of 19 RCTs in cardiac, thoracic, vascular, ear, nose and throat, gynecologic, orthopaedic, and general surgical procedures

. 27 , 32 , 37

- 40 , 42

- 47 , 50

- 53 , 57 , 62 , 63 Fourteen (74%) studies were published between 1984 and 1995; 5 were published be tween 2005 and 2008. Results byDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 32 select surgical specialties or procedures and individual comparators are available in the GRADE table.

Q1

. R ecommendations

1A. Administer preoperative antimicrobial agent only when indicated, based on published clinical practice guidelines and timed such that a bactericidal concentration of the agent is established in the serum and tissues when the incision is made (Category IB) 12 (Key Question 1A)

 No further refinement of timing can be made for preoperative antimicrobial agent based on cl inical outcomes. (No recommendation/unresolved issue) (Key Question 1A)

1B. Administer the appropriate parenteral prophylactic antimicrobial agent prior to skin incision in all cesarean sections. (Category IA) 22

- 25 (Key Question 1B)

1C. No recommendation can be made regarding the safety and effectiveness of weight

- adjusted dosing of parenteral prophylactic antimicrobial agents for the prevention of surgical site infection. (No recommendation/unresolved issue) (Key Question 1C)

1D. No recommendation can be made regarding the safety and effectiveness of intraoperative redosing of parenteral prophylactic antimicrobial agents for the prevention of surgical site infection. (No recommendation/unresolved issue) 26 (Key Question 1D)

1 E. In clean and clean

- contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA) 27

- 65 (Key Question 1E)



### NON

- PA RENTERAL ANTIMICROBIAL PROPHYLAXIS 

### Q2. What are the most effective strat egies for administering non - parenteral antimicrobial prophylaxis at the surgical incision to reduce the risk of SSI ?

To answer this question we focused on four subquestions: A) How safe and effective is antimicrobial irrigation? B) How safe and effective are antimicrobial agents applied to the surgical incision ? C) How safe and effective are antimicrobial

- coated sutures, when and how should they be used? and D) How safe and effective are antimicrobial dressing s applied to the surgical incision following primary closure in the operating room?



### 2A. How safe and effective is antimicrobial irrigation?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 33 Our search did not identify RCTs or SRs that evaluated th e safety and effectiveness of antimicrobial irrigation or the soaking of surgical implants ( e.g., meshes, neurosurgical ventricular shunts) in antimicrobial solution prior to insertion ( in combination with parenteral AMP ) and its impact on SSI.

Other Guidelines One clinical practice guideline
, based on a review of the evidence
, recommends against antimicrobial wound irrigation or intra

- cavity lavage to reduce the risk of SSI. 234



### Q2B. How safe and effective are antimicrobial agents applied to the surgical incision ?

The available data examined the following comparisons:

1. Ampicillin vs. No topical antimicrobial agent 2. Chloramphenicol vs. No topical antimicrobial agent 3. Rifampin vs. No topical antimicrobial agent 4 . Autologous platelet rich plasma ( APRP ) (spray or gel ) vs. No APRP

For all comparisons
, we considered SSI the critical outcome. Wound dehiscence and wound closure outcomes were also evaluated

. The evidence for th e pharmacologic antimicrobial prophylactic agent comp arators consists of 1 SR 66 and 2 RCTs 67 , 68 and for the APRP comparator 3 RCTs 73

- 75

. APRP provides a platelet concentrate commonly used to enhance both, wound hemostasis (formation of a fibrin clot) and wound healing (clot provides a matrix for the migratio n of tissue

- forming cells and endothelial cells involved in angiogenesis and remodeling of the clot into repair tissue)

. 235,236 These characteristics have led to a significant increase in the use of APRP therapies for the treatment of chronic wounds and multiple orthopaedic conditions including bone repair, tendon, and soft tissue injuries

. 237,238 In addition, in vitro studies have demonstrated that APRP holds strong bactericidal activity, and suggested its potential value as an adjunct topical antimicrob ial prophylactic agent for use at the time of surgical incision closure

. 239,240 In all studies, both groups received parenteral AMP

. Our search did not identify RCTs or SRs that evaluated the safety and effectiveness of vancomycin powder for the prevention of SSI. The findings of the evidence review and grades for all important outcomes are shown in Evidence Review Table 2B.

Q2B.1. Ampicillin vs. n o topical antimicrobial agent

High

- quality evidence suggested no benefit of topical ampicillin solution or powder in combination with parenteral AMP. This was based on no difference in SSI in one SR’s 66 meta

analysis (N=699) of 4 older ( 1985

- 1994) RCTs in clean

- contaminated colorecta l 70 , 71 and appendectomy 69 , 72 procedures.

Q2B.2. Chloramphenicol v s

. n o topical antimicrobial agentDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 34 Moderate

- quality suggested no benefit of topical chloramphenicol ointment in combination with parenteral AMP. This was based on no difference in SSI in one small study at low risk of bias, in 92 hemi

- arthroplast y or dynamic hip screw fixation procedures for hip fracture s

. 67

Q2B.3. Rifampin vs

. n o topical antimicrobial agent

Low

- quality evidence suggested a benefit of topical rifampin in combination wit h parenteral AMP. This was based on a reduced risk of wound leakage, fewer local signs of inflammation, and reduced risk of wound dehiscence at the umbilical port site in one very small (N=48) laparoscopic cholecystectomy study at moderate risk of bias

. 6 8 Umbilical port

- site infection was defined as “purulent wound leakage”. Based on results reported in a histogram, 12 hours postoperatively, 71% of patients had purulent wound leakage including almost half of the rifampin and all of the control groups. By 24 hours the entire control group remained infected; a week later, only 2 infections remained . It is not clear if any of these were true infections.

Other Guidelines Clinical practice g uidelines b ased on a review of the evidence and expert opinion have recommendations both for 231 and against 234 the use of non

- parenteral antimicrobials in the prevention of SSI. There are also strong recommendations against the use of antimicrobial ointment s or creams on umbilical catheter insertion sites and other insert ion sites, except for dialysis catheters, because of their potential to promote fungal infections and antimicrobial resistance

. 241

Q2B. 4 . Autologous platelet rich plasma (spray or gel) vs

. nothing

Moderate

- quality evidence suggested no benefit of APRP spray or gel in combination with parenteral AMP. This was based on no difference in SSI in a meta

- analysis (N=257) of 3 small RCTs : 2 studies in cardiac procedures ( low 73 and moderate 74 risk of bias ) and 1 study in TKA procedures 75 ( low risk of bias ). Ea ch individual study found no difference. The cardiac studies applied APRP spray 73 or gel 74 (produced using the same type of commercial platelet concentrate system) to the saphenous vein harvest site 73 , 74 and/or the sternum 74

. The TKA study applied APRP s pray (produced using a different platelet concentrate system than the cardiac studies) to the femoral and tibial cut bone surfaces and joint capsule followed by platelet poor plasma sprayed on the subcutaneous tissue. Moderate

- quality evidence from this latter study suggested significantly increased risk of delayed total wound closure at 2 weeks postoperatively.



### Q2C. How safe and effective are antimicrobial

- coated sutures , when and how should they be used?

The available data examined a ntimicrobial

- coated suture s (absorbable) versus n on

antimicrobial

- coated suture s (absorbable and non

- absorbable) for the prevention of SSI.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 35 For this comparison we considered SSI the critical outcome. ASEPSIS score 2 42 , where points are given for “ A dditional treatment, the presence of S erous discharge, E rythema, P urulent exudate, and S eparation of the deep tissues, the I solation of bacteria, and the du ration of inpatient S tay”, and product related adverse event outcomes were also evaluated

.
The evidence for this question consists of 4 RCTs

. 76

- 79 The findings of the evidence review and grades for all important outcomes are shown in Evidence Review Table 2C.

High

- quality evidence suggested no benefit of using antimicrobial coated suture s . This was based on no difference in SSI in a meta

- analysis (N=42 0 ) of 4 RCTs and no product

- related adverse events

. 76

- 79 There was no difference in SSI among three small studies evaluating triclosan

- coated suture in modified r adical mastectomy (triclosan

- coated suture subcuticular skin closure vs. Chinese silk suture interrupted transcutaneous skin closure) 76 appendectomy for acute and ruptured appendicitis (abdominal sheath closure)
, 77 and pediatric general surgery (level of closure not specified) 79 procedu res . One study 79 at low risk for bias was designed to evaluate the surgeon’s assessment of intraoperative handling characteristics of the suture and another
, 76 the cosmetic outcome, but not SSI as a primary outco me . Only one very small study (N=86) in predominantly pediatric patients undergoing cerebrospinal fluid shunt implantation or revision procedures suggested a reduction in risk of shunt infections with triclosan

- coated suture closure of the galea and fasci a

. 78 This study also used plastic iodine

- impregnated adhesive drapes, antimicrobial irrigation, and soaked the silicone shunt component in aqueous iodophor solution prior to implantation in both groups

. Use of parenteral AMP was only reported for the appe ndicitis and cerebrospinal fluid shunt implantation studies.



### Q2D. How safe and effective are antimicrobial dressings applied to surgical incision s following primary closure in the operating room?

Our research did not identify RCTs or SRs that evaluated the safety and effectiveness of antimicrobial dressings (i.e., iodine, silver, or other antimicrobial ointment impregnated dressing) applied to surgical incisions closed primarily in the operating room (i.e., the skin edges

are re

- approximat ed at the end of the operation) and their impact on the risk of SSI

. 12 Our search identified a SR of 16 RCTs evaluating various non

- antimicrobial dressings

. 243 This SR found no evidence to suggest that either covering the wound was effective or that any one non

antimicrobial dressing was more effective than another in reducing the risk of SSI in surgical incisions that were closed primarily in the operating room

. T his guideline does not address prevention of SSI in trauma

- related procedures, in surgical incisions left open to heal by secondary intention (i.e., left open in the operating room to be closed later, left open to heal by granulation, or which break open postoperatively) or burns.

Q2. RecommendationsDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 36 2A.1. No recommendation can be made regarding the safety and effectiveness of intraoperative antimicrobial irrigation (e.g., intra

- abdominal, deep, or subcutaneous tissues) for the prevention of surgical site infection. (No recommendation/unresolved issue) (Key Question 2A)

2A. 2 . No recommendation can be made regarding the safety and effectiveness of soaking prosthetic devices in antimicrobial solutions prior to implantation for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key Question 2A)

2B .1. Do not apply antimicrobial agents (i.e., ointments, solutions, powders) to the surgical incision for the prevention of surgical site infection (Category IB) 66

- 72 (Key Question 2B)

2B. 2

. Application of a utologous platelet rich plasma is not necessary for the prevention of surgical site infection. (Category II ) 73

- 75 (Key Question 2B)

2C. Use of a ntimicrobial coated sutures is not necessary for the prevention of surgical site infection. (Category II ) 76

- 79 (Key Question 2C)

2D. No recommendation can b e made regarding the safety and effectiveness of antimicrobial dressings applied to surgical incisions following primary closure in the operating room for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key Question 2D)



### GLYCEMIC CONTROL 

### Q3

. How do perioperative blood glucose and hemoglobin A1C levels impact the risk of SSI , and what are the ir optimal perioperative target levels in diabetic and

non - diabetic patients ?

To answer this question we focused on two subtopics: A ) B lood glucose and B) Hemoglobin A1C , their optimal perioperative target level s and the risk of SSI

.
Q3A. B lood glucose and optimal perioperative target levels

The available data examined s trict v ersus standard blood glucose control in the prevention of SSI.

For this comparison we considered SSI and hypoglycemia as the critical outcomes. Each study reported a primary composite outcome variable that included SSI. Mortality and length of hospital stay , and surgical intensive care un it ( SICU ) stays were also evaluated in weighing the risks and benefits of perioperative glycemic control. The evidence for this question consists of 2 RCTs in cardiac surgery patients with glycemic control protocols (intravenous, intensive insulinDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 37 therapy) instituted intraoperatively and continued in the SICU for 24

- 36 hours. 80 , 81 Seventy to 80% of patients in both of these studies are non

- diabetic s , highlighting the importance of glycemic control in both diabetic and non

- diabetic surgical populatio ns

. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 3.

Moderate

- quality evidence suggested no benefit of strict (80

- 100mg/dL 80 or 80

- 130mm/dL 81 ) as compared to standard blood glucose target levels (<200mg/dL 80 or 160

- 200mg/dL 81 ) in diabetic and non

- diabetic cardiac patients. This was based on no differences between groups for both a composite outcome variable and SSI in both studies

. In Ghandi et al., 80 (N=371) the composite
outcome v ariable included: death, sternal wound infections, prolonged pulmonary ventilation, cardiac arrhythmias, heart block requiring pacemaker or cardiac arrest, stroke or acute renal failure within 30 days postop eratively

. In Chan et al., 81 (N=109) the composite outcome variable of infection included pneumonia, urinary tract infection, sepsis, septic shock, wound infection, bloodstream infection, and “ catheter ” infection (did not specify if venous or urinary)

.
High

- quality evidence suggested no increased risk of hypoglycemia with strict blood glucose target levels. This was based on no differences between groups for number of hypoglycemic episodes in the SICU 80 or ratio of hypoglycemic episodes per number of glucose
measurements

. 81 Hypoglyc emia definitions differed between studies: <60mg/dL in Ghandi and <50mg/dL in Chan. In Chan et al., while there was no difference between groups for the number of hypoglycemic episodes in the SICU, both groups reported a higher proportion of them there as compared to intraoperatively , suggesting the importance of continued close monitoring of glucose levels and the risk of hypoglycemic episodes in the postoperative period, even with standard glycemic control . No clinical complications resulting from hypog lycemia were reported at 30 day s of follow up.

Other guidelines While previous CDC guideline recommendations did not specify a perioperative blood glucose target level, they reported that in diabetics “increased glucose levels (>200mg/dL) in the immediate postoperative period ( ≤ 48 h ours ) were associated with increa sed risk of SSI”

. 12 Blood glucose target level of <200mg/dL became standard clinical practice. Both studies reviewed in this guideline used <200mg/dL as the upper blood glucose target level

. 80 , 81 Recently published professional society guidelines have recommended a slightly lower absolute serum blood glucose target level of <180mg/dL in diabetic 244,245 and non

- diabetic
, 244 non

- critically ill patients. In critically ill patients blood glucose ta rget levels <150

- 180mg/dL 246 and 140

- 200mg/dL 247 have been recommended. For terminally ill patients, those with limited life expectancy, or those at high risk for hypoglycemia, a blood glucose target level of 200mg/dL has been recommended. 245 Intensive i nsulin therapy (blood glucose target levels of 80

- 110mg/dl) to normalize blood glucose in the intensive care u nit setting (surgical and medical) is not recommended in either diabetic or non

- diabetic patients

. 247

Q3B. Perioperative h emoglobin A1C and optimal target levelsDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 38 Our search did not identify RCTs or SRs examining the association between hemoglobin A1C levels and risk of SSI.

Q3. Recommendations

3A. 1. Implement perioperative glycemic control and use blood glucose target levels <200mg/dL in d iabetic and non

- diabetic patients. (Category IA) 80 , 81 (Key Question 3)

3A. 2 . No recommendation can be made regarding the safety and effectiveness of lower (<200 mg/dL) or narrower blood glucose target levels , nor th e optimal timing, duration
, or delivery method of perioperative glycemic control for the prevention of surgical site infection. (No recommendation/unresolved issue) (Key Question 3)

3B. No recommendation can be made regarding optimal hemoglobin A1C target levels for the prevention of surgical site infection in diabetic and non

- diabetic patients. (No recommendation/unresolved issue) (Key Question 3)



### NORMOTHERMIA 

### Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI?

The available data examined the following comparisons:

1. Warming vs. no warming 2. Warming: perioperative vs. intraoperative only

For all comparisons, we considered SSI the critical outcome. ASEPSIS score, mortality, blood loss, core temperature, length o f hospital stay and duration of surgery outcomes were also evaluated

. The evidence for this question consists of 3 RCTs

. 82

- 84 The lower limit of normothermia has been inconsistently defined, ranging from a core temperature of 35.5 ○ C to 36 ○ C. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 4.

Q4A.1. Warming vs. no warming

High

- quality evidence suggested a benefit of patient warming over no warming. This was based on a reduced risk of SSI in a meta

- analysis (N=616) of 2 RCT s and reduced risk of ASEPSIS scores >20 with warming and maintenance of normothermia using various warming techniques in patients undergoing elective hernia repair, varicose vein surgery , and breast surgeryDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 39 (preoperative warming) 82 and elective colorectal surgery (intraoperative warming)

. 83 Normothermia was also associated with lower mean units of blood transfused per patient, fewer patients transfused
, and reduced hospital length of stay

. 83 No difference in mortality was observed

. 83

Q4A.2. Warming: perioperative vs. intraoperative only

Moderate

- quality evidence suggested a benefit of perioperative warming

. This was based on reduced incidence of SSI with perioperative warming in 1 RCT of 103 patients undergoing elective major abdominal surgery

. 84

Q4. Recommendation

4. Maintain perioperative normothermia (Category IA) 82

- 84 (Key Question 4)



### Q5. What are the most effective strategies for achieving and maintaining perioperative normothermia?

Our search did not identify RCTs or SRs that evaluated the most effective strategies for achieving and maintaining perioperative normothermia and their impact on the risk of SSI.

Other Guidelines Evidence

- based c linical practice guidelines provide recommendations on perioperative management of normothermia including risk factor assessment, temperature monitoring tools, and the safety and effectiveness of warming devices

. 248

- 250

Q5. Recommendation

5. No recomme ndation can be made regarding the safety and effectiveness of strategies to achieve and maintain normothermia, the lower limit of normothermia, or the optimal timing and duration of normothermia for the prevention of surgical site infection. (No

recommen dation/unresolved issue) (Key Question 5)



### OXYGENATION 

### Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO2) in reducing the risk of SSI?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 40 To answer this question we focused on three settings of oxygen delivery : A) General anesthesia: Intraoperative endo tracheal intubation and postoperative non

- rebreathing mask, B) Neuraxial anesthesia: Intraoperative and postoperative non

- rebreathing mask an d C) Postoperative only: Facemask and/or nasal cannula.

Q6A. General anesthesia: Intraoperative endo tracheal intubation and postoperative non

rebreathing mask

The available data examined the following comparisons:

1. 80% oxygen vs. 30% oxygen

- b oth without nitrous oxide 2. 80% oxygen/20% nitrous oxide vs. 35% oxygen/65% nitrous oxide

- b oth with nitrous oxide started 30 minutes after surgical incision

For all comparisons
, we considered SSI the critical outcome. ASEPSIS scores, mortality, respiratory failure, atelectasis, tissue oxygenation, and length of stay outcomes were also evaluated. The evidence for this question consists of 6 RCTs

. 85

- 90 One study 89 represents a

su banalysis of a larger study ; 88 therefore results in the GRADE table reflect solely those of the larger study. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 6.

Q6A.1. 80% oxygen vs. 30% ox ygen

- b oth without nitrous oxide

Moderate

- quality evidence suggested a benefit of supplemental 80% FiO 2 administered via end o tracheal intubation intraoperatively and non

- rebreathing mask for 2

- 6 hours postoperatively in patients under general anesthesia . This was based on a 40% reduction in SSI reported in 3 studies at low risk of bias (2 in 800 elective colorectal 85 , 87 and 1 in 210 elective open appendectomy 86 procedures), no difference in 1 multicenter, mixed surgical population 88 , 89 study at low risk of bias
, and no significant difference in adverse events.

The three studies reporting a significant SSI reduction all optimized perioperative tissue oxygen delivery by maintaining normothermia and avoiding hypo or hypervolemia

. 85

- 87 Greif e t al., 87 the larger colorectal study (N=500) actually confirmed optimized tissue oxygen delivery, measuring significantly higher intraoperative and postoperative subcutaneous tissue oxygen tension and higher muscle oxygen tension using 80% oxygen.

Meyhoff et al

. , 88 , 89 the large (N=1400), multicenter, mixed population study of emergency or elective laparotomy for a variety of general and gynecologic surgical conditions, found no difference in overall, organ/space, deep, or superficial SSI . However, due to a number of factors, the study failed to optimize tissue oxygen delivery. While the target core temperatures were 36 ○ C

- 37 ○ C, the minimum reported temperatures were 35.0 ○ C and 35.1 in each group, respectively. Most potentially limiting to the optimization of oxygen delivery was the intentional restriction of fluid replacement, limiting postoperative weight gain to less than 1kg.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 41 Mortality at 14

- 30 days was rare, there was no difference between groups, and it was not associated with use of increased oxygenation

. 85 , 87 In a recent follow

- up study (median 2.3 years, range 1.3

- 3.4) , administration of 80% oxygen was associated with significantly increased long

- term mortality only in patients undergoing cancer surgery. The only gynecologic pa tients included in this study were those with ovarian cancer

. 251 It is not clear what other cancer patients were included.

Q6A.2. 80% oxygen/20% nitrous oxide vs

. 35% oxygen/65% nitrous oxide

– b oth groups nitrous oxide started 30 minutes after incision

Moderate

- quality evidence suggested no benefit of supplemental 80% FiO 2 (20% nitrous oxide added 30 minutes after incision) administered via endo tracheal intubation intraoperatively and

non

- rebreathing mask for 2

- 6 hours postoperatively in patients under g eneral anesthesia. This was based on increased risk of SSI (all combined) in one small (N=160) , mixed surgical population study

. 90 Several factors may account for the increased incidence of total SSIs in the intervention group. Patients in the 80% FiO 2 group had significantly increased body mass index ( BMI ) , higher blood loss, and more crystalloid infused . O n multivariate logistic regression analysis
, 80% oxygen and remaining intubated postoperatively r emain ed predictive of SSI

. Mortality was rare in either group and unrelated to increased supplemental oxygenation.

Q6B. Neuraxial anesthesia: Intraoperative and postoperative non

- rebreathing mask

The available data on the impact of different levels of supplemental increased fraction of inspired oxygen on SSI in patients under regional anesthesia examined 80% oxygen versus 30% oxygen

.
For this comparison we considered SSI the critical outcome. Length of stay outcome was also evaluated. The evidence for this question consists of 1 RCT

. 91 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 6.

Moderate quality evidence suggested no benefit of supplemental 80% FiO 2 administered via

non

- rebreathing mask intra and postoperatively in patients under neuraxial anesthesia. This was based on no difference in risk of SSI in study (N=143) in cesarean section s, at low risk of bias

. 91 Despite no difference in blood loss between groups, it was the only factor predictive of SSI in an associat ed regression analysis . The study d id not note a ny protocol used during the study to optimiz e tissue oxygenation.

Q6C. Postoperative only: Facemask and/or nasal cannula

The data available on the impact of different levels of supplemental increased fraction of inspired oxygen used in the postoperative period only examined 28

- 30% oxygen v ersus room air

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 42 For this comparison we considered SSI as the critical outcome. SSI type (organ/space, superficial and deep SSI)
, ASEPSIS scor es, mortality, adverse events, tissue oxygenation, and length of stay
outcomes were also evaluated

. The evidence for this question consists of 2 RCTs

. 92 , 93 The findings of the evidence review and the grades for all important outcomes are shown in Eviden ce Review Table 6.

High

- quality evidence suggested no benefit of supplemental 28

- 30% FiO 2 administered via facemask and/or nasal cannula solely in the postoperative period. This was based on no difference in SSIs from two studies

. 92 , 93 Turtiainen et al., 92 a lower limb vascular surgery study (N=143) at low risk of bias used 30% oxygen via facemask in the recovery room and on the first postoperative day on the ward (~36 hours), followed by constant oxygen flow of 5L/min via nasal cannula during the se cond postoperative day. A significant reduction in SSI was seen only in isolated groin incisions. Subcutaneous tissue oxygen tension (measured hourly for the first four hours, then at 18 and 36 hours) was significantly higher in the supplemental oxygenati on group. Whitney et al., 93 a second, smaller, study at high risk of bias, in 24 cervical spine procedures, reported no wound complications in either group with supplemental 28% oxygen administered at 2L/min via nasal cannula for 36 hours after discharge from the post

- anesthesia care unit as compared to the room air group. Mortality 92 and adverse events 92 , 93 were rare, did not differ between groups
, and were unrelated to use of supplemental oxygenation.

Q6. Recommendations

6 A

. For patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation , administer increased fraction of inspired oxygen (FiO 2 ) both intraoperatively and post

- extubation in the immediate postoperative period. To optimize tissu e oxygen delivery, maintain perioperative normothermia and adequate volume replacement. (Category IA) 85

- 90 (Key Question 6)

6 B . No recommendation can be made regarding the safety and effectiveness of administering perioperative increased fraction of inspired oxygen (F i O 2 ) for the prevention of surgical site infection in patients with normal pulmonary function undergoing either general anesthesia without endotracheal intubation or neuraxial anesthesia ( i.e. , spinal, epidural, or local nerve blocks). (N o recommendation/unresolved issue) 91 (Key Question 6)

6 C . No recommendation can be made regarding the safety and effectiveness of administering increased fraction of inspired oxygen (F i O 2 ) via facemask or nasal cannula only during the postoperative perio d for the prevention of surgical site infection in patients with normal pulmonary function. (No recommendation/unresolved issue) 92 , 93 (Key Question 6)



### Q7. What is the optimal target F i O 2 

### to reduce the risk of SSI; how and when should it be administered?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 43 Our search did not identify RCTs or SRs that both evaluated the optimal fraction of inspired oxygen, how and when it should be administered, and included SSI as an outcome. All studies

e valuating the use of supplemental increased oxygenation both intraoperative and postoperatively used 80% F i O 2 as the target level.

Other Guidelines Evidence

- based clinic al practice guidelines recommend maintain ing patient homeostasis, by optimizing oxygenation during major surgery and in the recovery period (maintain ing a >95% hemoglobin satura tion)
, in concert with maintaining both patient temperature to avoid hypothermia and adequate perfusion during surgery

. 234

Q7. Recommendation

7. No recommendation can be made regarding the optimal target level, duration, and delivery method of the fraction of inspired oxygen (FiO 2 ) for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key Question 7)



### ANTISEPTIC PROPHYLAXIS 

### Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI ?

To answer this question we focused on four subquestions: A) How saf e and effective is preoperative antiseptic bathing or s howering? B) How safe and effective are antiseptic skin preparation agents individually and in combination ? C) How safe and eff ective is the application of an antimicrobial sealant immediately following intraoperative skin preparation ? a nd D) How safe and effective are plastic adhesive drapes?


### Q8A. How safe and effective is preoperative antiseptic bathing or showering?

The available data examined the following comparisons :

1. C hlorhexidine gluconate (C HG ) solution vs. p lacebo solution 2. CHG solution vs. u n

- medicated bar soap 3. CHG solution vs. n o wash 4. CHG whole body wash vs. partial body wash 5. Aqueous iodophor solution vs. control (“ routine personal hygiene”)

For all comparisons we considered SSI as the critical outcome. Product

- related adverse reaction outcomes were also evaluated

. The evidence for this question consists of 1 SR 94 ( 7DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 44 RCTs 95

- 101 ) evaluating CHG solution and 1 RCT 102 e valuat ing povidone iodine solution . The RCTs span a 26 year period with 6 published between 1983 and 1992 and 2 between 2008 102 and 2009

. 100 Our search did not identify RCTs or SRs that evaluated optimal preoperative ti ming, number of showers/baths, number of product applications at each shower/bathing episode, or CHG

- washcloths
, and the ir impact on the risk of SSI. The findings of the evidence review and grades for all important outcomes are shown in Evidence Review Table 8A.

Q8A.1. CHG solution vs. p lacebo solution

High

- quality evidence suggested no benefit of preoperative bathing or showering with 4% CHG solution as compared to placebo. This was based no difference in SSI in both a meta

- analysis (N=7791) of 4 RCTs 94 , 95 , 97 , 99 , 100 and a meta

- analysis (N=6302) restricted to only the 2 higher quality studies

. 94 , 95 , 99 Each individual tri al found no difference. Five months into 1 large study
, the placebo solution was found to have antimicrobial properties and was changed ; however, the study did not stratify by or exclude that data. 97 Procedures included in the studies were elective or pot entially contaminated surgery
, 95 elective inpatient surgery
, 97 elective clean mixed surgical procedures including thyroidectomy, inguinal herniorrhaphy, hip and knee surgery, laminectomy, mastectomy, vascular surgery , 99 and elective plastic surgery of the trunk

. 100 Number of preoperative showers/baths, amount of antiseptic used per bath, bathing instructions to each group, intraoperative antiseptic skin preparation agent, use of AMP, and follow up varied between studies. Three studies instructed patients to shower 95 , 99 , 100 and one instructed them to shower or bathe

. 97 Product

- related adverse reactions (irritation, itching, reddening of the skin) were rare and did not differ between groups

. 94 , 95 , 99 , 100

Q8A.2. CHG soluti on vs. u n

- medicated bar soap

High

- quality evidence suggested no benefit of preoperative bathing or showering with 4% CHG solution as co mpared to un

- medicated bar soap. This was based on no difference in SSI in a
meta

- analysis (N=1443) of 3 RCTs

. 94 , 96

- 98 Heterogeneity for this comparison was high. Only the largest study (N=1315) reported a reduction in SSI with 4% CHG ; however, no special showering/bathing instructions were given to the un

- medicated bar soap group whereas “great care was taken to ensure t hat the patients using [CHG] ...complied with the instructions.” 97 For the two smaller, lesser quality studies, one study 96 suggested a higher rate of SSI with CHG while the other 98 suggested no difference. Number of preoperative baths, bathing instructions, intraoperative antiseptic skin preparation agent, AMP use , procedures, and follow up varied between studies. One study instructed patients to bathe
, 96 one to shower
, 98 and one to shower or bathe

. 97

Q8A.3. CHG solution vs. n o wash

Moderate

- quality evidence suggested no benefit of preoperative showering with 4% CHG solution as compared to no wash . This was based on no difference in a meta

- analysis (N=1142) of 3 RCTs

. 94 , 98 , 100 , 101 Despite instructions not to shower, it is un clear if the “no wash” groupsDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 45 showered. T he largest study 101 favored 4% CHG, while the other two 98 , 100 suggested no difference

. Heterogeneity for this comparison was significant. Studies included outpatient and inpatient procedures, patients undergoing vasectomy , 98 plastic surgery of the trunk
, 100 and elective, clean biliary tract, inguinal hernia or breast cancer 101 procedures. There were also differences in SSI definitions between studies

.
Q8A.4. CHG whole body vs. partial body wash

Moderate

- quality evidence suggested a benefit of a CHG shower (i.e., a whole body wash including the scalp ) as compared to a partial body wash (restricted to the proposed surgical site) . This was based on reduced risk of SSI with whole body washing (1 time, 2 application s on the afternoon before surgery) in one large RCT (N=1093) of elective clean biliary tract, inguinal hernia, and breast cancer procedures

. 94 , 101

Q8A.5. Aqueous iodophor solution vs. control (“ routine personal hygiene”)

Very l ow

- quality evidence suggested no benefit of preoperative shower with 10% aqueous iodophor s olution as compared to routine personal hygiene. This was based on no infections reported in either group in 1 small RCT (N=114) in elective, clean plastic surgical pro cedures (thorax or abdomen) designed to evaluate the product ’ s efficacy in reducing skin contamination, not SSI

. 102

Other Guidelines C linical practice guidelines recommend that patients shower or bathe with an antiseptic agent or soap on at least the night before surgery

. 12,234 They do not favor the use of one antiseptic agent in preference of another. There may be contraindications for specific antiseptic

- agent

use in some patients or surgical procedures

.


### Q8B. How safe and effective are antisept ic skin preparation agents individually and in combination?

The available data examined the following comparisons :

1. Aqueous iodophor: 1

- step vs. 2

- step 2. Aqueous iodophor (1 or 2

- step) vs. i odophor in alcohol (1

- step with or without adhesive drape) 3. CHG

- alcohol (1 or 2

- step) vs. a queous iodophor (1 or 2

- step) 4. CHG

- alcohol (1 or 2

- step) vs. i odophor

- alcohol (1 or 2

- step)

a. CHG

- alcohol (2

- step) vs. i odophor

- alcohol (2

- step) b. CHG

- alcohol (1

- step) vs. i odophor

- alcohol (1

- step)

For all comparisons
, we considered SSI the critical outcome. Product

- related adverse event
outcomes were also evaluated

. The evidence for this question consists of 14 RCTs

. 103

- 116 TheDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 46 findings of the evidence review and the grades for all important outcomes are shown in Evi dence Review Table 8B.

Q8B.1. Aqueous iodophor: 1

- step vs. 2

- step

High

- quality evidence suggested no benefit of using 2

- step as comp ared to 1

- step aqueous iodophor for skin preparation of the surgical site

. This was based on no difference in SSI in 2 RC Ts at moderate risk of bias

. 103 , 104 One study in 234 clean (30%) and clean

- contaminated (70%) oncologic, non

- laparoscopic abdominal procedures compared povidone iodine paint (1% iodine) to a 5 minute povidone iodine scrub (0.75% iodine) followed by povidone iodine paint (1% iodine). 103 Another study in 108 CABG procedures did not report the product

co ncentration or scrub duration. 104 In the latter study, patients were also instructed to take antimicrobial showers (unspecified product) the evening be fore and the morning of surgery.

Q8B.2. Aqueous iodophor (1 or 2

- step) vs. i odophor in alcohol (1

- step with or without adhesive drape)

Moderate

- quality evidence suggested no benefit of iodophor in alcohol as compared to aqueous iodophor. This was based o n no difference in SSI in a m eta

- analysis (N=626) of 5 RCTs including 4 RCTs at moderate risk 104

- 107 and 1 at low risk 108 of bias . Only one study at moderate risk of bias in CABG procedures showed a reduced risk of sternal SSI with iodophor in alcohol (with or without plastic adhesive drape)

. 104 A second study ( low risk of bias ) in CABG procedures using iodophor impregnated plastic adhesive drape at the sternal site showed no difference between groups

. 108 The three remaining studies ( moderate risk of bi as ) in THA and TKA , 106 shoulder
, 107 and foot and ankle 105 procedures reported no infections, however, each was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI.

Q8B.3. CHG

- alcohol (1 or 2

- step) vs. a queous iodophor (1 o r 2

- step)

High

- quality evidence suggested a benefit of CHG

- alcohol as compared to aqueous iodophor. This was based on a reduced risk of SSI in a meta

- analysis (N=1976) of 5 RCTs ( two low risk
, 109 , 110 one moderate risk
, 107 and two high risk 111 , 112 of bias ) and no difference in product

related adverse events. Only one large study showed a reduced risk of SSI in multiple mixed clean

- contaminated abdominal and non

- abdominal (thoracic, gynecologic, and urologic) procedures. 110 CHG

- alcohol was specifi cally associated with reduced risk of superficial and deep incisional SSI , but not organ space SSI or sepsis. The study in clean hernia repairs (herniotomy, herniorraphy, or hernioplasty) showed no difference between groups

. 109 In both of these studies, a uthors reported receiving funds from and/or being employed by the manufacturer of the CHG

- alcohol product. Of the three studies at moderate or high risk of bias
, one in clean, clean

- contaminated or contaminated general surgery 112 procedures showed no diff erence , and the studies in clean elective shoulder 107 and foot and ankle 111 procedures reported no infections ; however, each was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 47 High

- q uality evidence from 2 studies suggested no difference in product

- related adverse events including skin irritation or pruritis or erythema around the wound

. 110 , 112

Q8B.4. CHG

- alcohol (1 or 2

- step) vs. i odophor

- alcohol (1 or 2

- step)

High

- quality evidence suggested no benefit of CHG

- a lcohol (1 or 2

- step) as compared to iodophor alcohol (1

- or 2 step). This was based on no difference in SSI in a m eta

- analysis (N=1223) of 5 RCTs

. 107 , 113

- 116 Three studies (one low risk
, 115 one moderate risk
, 113 and one high risk 114 of bias ) compared 2

- step application
, and two studies 107 , 116 (moderate risk of bias ) compared 1 step product application. There was no difference in SSI in individual meta

analyses of “2

- step” or “1

- step” product application. Details are available under the individual

com parators below.

Q8B.4.a. CHG

- alcohol (2

- step) vs. i odophor

- alcohol (2

- step)

High

- quality evidence suggested no benefit of 2

- step CHG

- alcohol as compared to 2

- step iodophor

- alcohol. This was based on no difference in SSI in 3 studies comparing 0. 5% chlorhexidine gluconate and alcohol with 10% povidone

- iodine (1% available iodine) and 23% isopropyl alcohol. 113

- 115 No preoperative antiseptic shower protocol was reported in the studies. The large, moderate risk of bias study in a mixed general surge ry population reported no difference. 115 CHG

- alcohol was associated with a significant reduction in SSI in biliary and “other clean procedures”. One study ( high risk of bias ) in elective, clean, plastic surgery breast procedures reported no difference bet ween groups. 114 The smallest study ( moderat e risk of bias ) in foot procedures reported no infections in either group. 113 However, the study was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI.

Q8B.4.b. CHG

- alcohol (1

- step) vs

. i odophor

- alcohol (1

- step)

High

- quality evidence suggested no benefit of 1

- step CHG

- alcohol as compared to 1 step iodophor

- alcohol. This was based on no difference in SSI in two studies at moderate risk of bias

c omparing 2% chlorhexidine glu conate with 70% alcohol (water insoluble film) to 0.7% iodine with 74% alcohol (water insoluble film). 107 , 116 One study in shoulder procedures (96 arthroscopies and 4 arthroplasties) reported no infections in either group

. 107 Patients were instructed to s hower the evening prior to surgery (product not reported). Iodophor

impregnated plastic adhesive drapes were applied to the shoulder arthroplasties’ operative site. The second study reported only one wound infection following 80 foot and ankle procedures

. 116 Patients were not instructed to take an antiseptic shower prior to surgery. Both studies were designed to evaluate the products’ efficacy in reducing skin contamination, not SSI , and both received funding by one or both product manufacturers.

Other GuidelinesDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 48 Clinical practice guidelines recommend skin preparation with an antiseptic agent, but do not favor one antiseptic agent over another

. 12,234 There may be contraindications to use of specific antiseptic skin preparation agents

.


### Q8C. How safe and effective is the application of an antimicrobial sealant immediately following intraoperative skin preparation?

The available data examined the application of a c yanoacrylate

- based anti

- microbial skin sealant immediately after skin preparation as compared to no sealant

.
For this comparison we considered SSI as the critical outcome. Product

- related adverse event
outcomes were also evaluated

. The evidence for this question consists of 3 RCTs

. 117

- 119 The findings of the evidence review and the g rades for all important outcomes are shown in Evidence Review Table 8C.

High

- quality evidence suggested no benefit of cyanoacrylate

- based antimicrobial skin sealant applied immediately following skin preparation . This was based on no difference in SSI i n a meta

- analysis (N=553) of 3 RCTs evaluating surgical site skin preparation with povidone iodine

alcohol 117 , 118 or aqueous povidone iodine 118 , 119 solution followed by application of cyanoacrylate

- based skin sealant before skin incision (1 CABG sternal and/or venous harvest site , 118 1 CABG leg saphenous vein harvest site
, 117 1 open inguinal hernia repair 119 ). The two CABG studies also followed skin sealant application with plastic adhesive drape application. Two studies at low risk of bias suggested no difference between groups. 118 , 119 However, due to the low number of events in the latter study
, superiority of the antimicrobial sealant could not be established and study enrollment ceased once the cyanoacrylate sealant was granted regulatory approval by the FDA (based on porcine data on skin contamination

. 119 Both studies were funded by and/or authors had a financial relationship with the skin seal ant manufacturer. Only one small study 117 ( low risk of bias ) suggested a reduced risk of SSI ; however, authors acknowledged that the apparent increased risk of SSI in the control legs could be explained by their use of a grading system 252 whose stringent criteria included minimal erythema or discharge as SSI. High

- quality evidence suggested no significant product

- related sensitivity or other adverse events

. 117

- 119 In the inguinal hernia repair study surgeons reported difficulty incising through the clear film (4/166 patients) and one reported visible “flaking” of the film at the time of procedure (no report of plastic adhesive drape use )

. 119



### Q8D. How safe and effective are plastic adhesive drapes?

The available data examined the following comparisons :

1. Non

- iodophor impregnated adhesive drape vs. n o drape 2. Iodophor

- impregnated adhesive drape vs. n o drapeDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 49 For all comparisons
, we considered SSI as the critical outcome. The evidence for this que stion consists of 6 RCTs

. 104 , 120

- 124 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 8D.

Q8D.1. Non

- iodophor impregnated drape vs. n o drape

High

- quality evidence suggested no benefit of non

- iodophor impregnated plastic adhesive drapes in addition to skin preparation as compared to skin preparation alone. This was based on no difference in SSI in a meta

- analysis (N=1742) of 4 RCTs spanning a 30 yea r period (1971

- 2001), each reporting no difference

. 120

- 123 The two most recent studies 120 , 121 used polyurethane adhesive drapes; drape material informatio n was not reported in the older 122 , 123 studies

. The

s urgical skin preparation agent applied prior to the application of the adhesive drape s varied between studies and may have impacted drape adhesion. Studies included general
surgery , 122 , 123 cesarean section , 120 and hip fracture 121 surgery.

Q8D.2. Iodophor

- impregnated drape vs. n o drape

High

- quality e vidence suggested no benefit of iodophor

- impregnated plastic adhesive drapes in addition to skin preparation as compared to skin preparation alone. This was based on no difference in SSI in a meta

- analysis (N=1113) of 2 RCTs, spanning a 15 year period (198 7

- 2002) each reporting no difference

. 104 , 124 Both studies used povidone iodine

– alcohol skin preparation (2

- step application in the study at low risk of bias in abdominal procedures 124 and one

- step application in the study at moderate risk of bias in CABG 104 procedures ).

Other guidelines One evidence

- based clinical practice guideline recommends against the routine use of non

iodophor impregnated plastic adhesive drapes and recommends that if a plastic adhesive drape is required, then an iodophor

- impregnat ed one should be used (unless the patient has an iodine allergy)

. 234

Q8. Recommendations

8A. Advise patients to shower or bathe (full body) with either soap (antimicrobial or non

antimicrobial) or an antiseptic agent on at least the night before the operative day (Category IB) 94

- 102 (Key Question 8A)

8A.1. No recommendation can be made regarding the op timal timing of the preoperative shower or bath
, the total number of soap or antiseptic agent applications , or the use of chlorhexidine gluconate washcloths for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key Question 8A)

8B. Perform intraoperative skin preparation with an alcohol

- based antiseptic agent, unlessDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 50 contraindicated. (Category IA) 103

- 116 (Key Question 8B)

8C. Application of an a ntimicrobial sealant immediately following intraoperative skin preparation is not necessary for the prevention of surgical site infection. (Category IA) 117

- 119 (Key Question 8C)

8D. Use of plastic adhesive drapes with or without antimicrobial properties, is not necessary for the prevention of surgical site infection. (Category II) 104 , 120

- 124 (Key Question 8D)



### Q9. How safe and effective is antiseptic irrigation prior to closing the surgical incision ?

Our search did not identify RCTs or SRs that evaluated the safety and e ffectiveness of soaking surgical implants (e.g., meshes, neurosurgical ventricu lar shunts) in antiseptic solution prior to insertion (in combination with parenteral AMP) and its impact on SSI.

The available data examined a queous iodophor irrigation versus n ormal saline for the prevention of surgical site infection.

For this comparison, we considered superficial and deep SSIs and organ/space abscess as the critical outcomes. Product related adverse events including wound healing and iodine toxicity
outcomes were also evaluated. The evidence for this question consists of 7 RCTs. 125

- 131 In all studies, both groups received parenteral AMP, but the specific protocol was not necessarily described in all. The findings of the evidence review and the grades for all important outcomes

are shown in Evidence Review Table 9

.

Moderate

- quality evidence suggested a benefit of intraoperative aqueous iodophor irrigation of the deep incision, in combination with parenteral AMP, for clean spine procedures. This was based on m oderate

- quality evidence from a meta

- analysis (N=660) of 2 RCTs suggesting a reduced risk of deep SSI when the deep tissues were irrigated and allowed to soak for 3 minutes with 0.35% povidone iodine solution, then irrigated with an additional 2L of normal saline prior to bone grafting and spinal instrumentation. 125 , 126 All procedures in both studies were performed by the same surgeon. Perioperative AMP included preoperative parenteral dose, postoperative parenteral dosing for 2 days followed by oral proph ylaxis for an additional 3 days. Over 80% of the SSIs were MRSA SSIs.

High

- quality evidence suggested a benefit of aqueous iodophor irrigation of the subcutaneous tissue, in combination with parenteral AMP, for clean

- contaminated, contaminated, and dirt y open abdominal procedures. This was based on reduced risk of superficial SSI on meta

- analysis (N=329) of 2 RCTS that performed 60 seconds of subcutaneous tissue irrigation with 10% aqueous iodophor solution prior to wound closure. 127 , 128 The larger 12 7 study administered parenteral AMP preoperatively and for 48 hours postoperatively, while the smaller 128 studyDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 51 only reports administering perioperative parenteral AMP. Individual meta

- analyses of clean

contaminated (N=149) and dirty (N=90) procedures bot h showed reduced risk of superficial SSI.

Moderate

- quality evidence suggested no benefit of aqueous iodophor peritoneal lavage in contaminated and dirty general surgical abdominal cases. This was based on no difference in organ/space abscess formation in meta

- analysis (N=268) of 3 RCTs. 129

- 131 Aqueous iodophor solution amount, concentration, application, and perioperative AMP regimen varied between studies.

High

- quality evidence from 3 studies suggested no increased risk of product

- related adverse
event s 126 , 128 , 129 or iodine toxicity. 128 , 129 , 131 Moderate

- quality evidence from 2 studies suggested no wound healing problems. 125 , 128

Q9. Recommendation

9 A

. Consider intraoperative irrigation of deep or subcutaneous tissues with aqueous iodophor solution for the prevention of surgical site infection. Intra

- peritoneal lavage with aqueous iodophor solution in contaminated or dirty abdominal procedures is not nec essary. (Category II) 125

- 131 (Key Question 9)

9B

. No recommendation can be made regarding the safety and effectiveness of soaking prosthetic devices in anti septic solutions prior to implantation for the prevention of surgical site infection. (No recommendation/ unresolved issue) (Key Question 9)



### Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision ?

The available data examined the repeat application of aqueous iodophor solution to the patient’s skin immediately prior to closing the surgical incision v ersus no additional application of topical antiseptic agent for the prevention of surgical site infection. Our search did not identify RCTs or SRs that evaluated repeat application of chlorhexidine, chlorhexidine

- alcohol, iodophor alcohol or other topical antiseptic agent The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 10

.

Low

- quality evidence suggested no benefit of application of aqueous iodophor solution to the patient’s skin immediately prior to closing the surgical incision, in combination with parenteral AMP. This was based on no difference in SSI (combined or indivi dual incisional or organ/space SSI) in a small study at high risk of bias, in 107 gastric and colorectal procedures. 132DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 52 Q10. Recommendation

10. No recommendation can be made regarding the safety and effectiveness of repeat

a pplication of antiseptic agents to the patient’s skin immediately prior to closing the surgical incision for the prevention of surgical site infection. ( No recommendation/unresolved issue ) 132 (Key question 10)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 53 

### VII. Evidence Review

- Prosthetic J oint A rthroplasty s ection

BLOOD TRANSFUSION 

### Q 11

. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients ?

To answer this question we first addressed the general question of any blood transfusion and its impact on the risk of SSI. We then focused on four subquestions: A) Are specific blood products associated with a risk of SSI? B) If the risk of SSI in increased, can this effect be isolated from the risk associated with more complex c ases ? C) How does the volume of transfused blood product impact the risk of SSI? and D) How safe and effective is withh olding blood transfusion to reduce the risk of SSI?

For the general question of risk of any blood transfusion on SSI, we considered SSI as the critical
outcome. The evidence for this question consists of 2 RCTs 133 , 134 and 4 OBS 135

- 138 studies

. All of the studies reflect European transfusion practices between 1999 and 2007. Studies were published between 2001 and 2008 ; however
, only 2 report the study periods (1998

- 2000)

. 137 , 138 All studies were at low risk of bias. When reported, hemoglobin thresholds for blood transfusion ranged between 8 and 11g/dL. The findings of the evidence review and the grades for all important outcom es are shown in Evidence Review Table 11

.
High

- quality evidence suggested blood transfusion s increased the risk of SSI. This was based on increased risk of SSI in a meta

- analysis (N=8493) of 6 studies
, 2 RCTs 133 , 134 and 4 OBS studies
, 135

-
138 and a separa te meta

- analysis (N=7484) of the 4 OBS studies. Analysis combined allogeneic, autologous, and autologous plus allogeneic blood transfusion data. Data in both of these

me ta

- analyses may be driven by 2 OBS studie s with a large number of patients who received allogeneic only blood transfusion and the possibility of selection bias inherent in observational studies. 136 , 138 In contrast, meta

- analysis (N=1009) of the 2 RCTs (N=1009) does not suggest an increased risk of SSI with autologous and autologous p lus additional allogeneic blood transfusion s

.


### Q 11 A. Are specific blood products associated with a risk of SSI?

The available data examined the following comparisons :

1. Allogeneic blood (any) vs. n o transfusion a. Allogeneic not WBC depleted vs. n o transfusion b. Allogeneic WBC depleted vs. n o transfusion c. Allogeneic “buffy coat depleted” vs. n o Transfusion d. Allogeneic WBC filtered vs. n o transfusion e. Allogeneic “lower WBC content” vs. a llogeneic “higher WBC content” 2. Autologous blood (any) vs. n o transfusion a. Autologous ±WBC filtration vs. n o transfusionDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 54 b. Autologous whole blood vs. n o transfusion c. Autologous “not WBC depleted” vs. n o transfusion d. Autologous buffy coat depleted vs. n o transfusion e. Autologous “lower WBC conten t” vs. a utologous “higher WBC content” f. Post

- operative salvage only vs. a utologous donated blood 3. Allogeneic blood (any) vs. a utologous blood (any) a. Allogeneic WBC± WBC depleted vs. a utologous not WBC depleted b. Allogeneic WBC filtered vs. a utolog ous buffy coat depleted. 4. Combined autologous and allogeneic (any) vs. n o transfusion

a. Combined a utologous and a llogeneic vs. a utologous only

For all comparisons
, we considered SSI, PJI, or reoperation due to wound infection as the critical outcome s

. Wound disturbance outcome was also evaluated

. The evidence for this question consists of 2 RCTs 133 , 134 and 7 OBS 135

- 141 studies. There were differences between studies including: surgical procedures, definition of SSI, blood product WBC content
, length of blood product storage, hemoglobin transfusion trigger levels and other criteria for transfusion, as well as follow up. In several studies
, missing data resulted in discrepancies in the numbers. The findings of the evidence review and the grade s for all important outcomes are shown in Evidence Review and GRADE Table 11 A.

1

. Allogeneic b lood t ransfusion s

Q 11 A.1. Allogeneic blood (any) v s. n o transfusion

Low

- quality evidence suggested that allogeneic blood transfusion s increased the risk of SSI. This was based on increased risk of SSI in a meta

- analysis (N=5737) of 4 OBS 135

- 138 studies in primary and revision THA and TKA and no difference in reoperation due to wound infection in another OBS 139 study . See individual comparators in GRADE table 9A for specific study findings.

2

. Autologous b lood t ransfusion s

Q 11 A.2 Autologous b lood (any) vs. n o transfusion

Moderate

- quality evidence suggested that autologous blood transfusion s did not increase the risk of SSI. This was based on no difference in a meta

- analysis (N=970) of 2 RCTs

. 133 , 134 One large RCT in THA suggested no difference at 90 day s of follow up

. 133 T he second small RCT in THA reported no infections in either group ; however, this study was designed to evaluate transfusion induced immunomodulation, not SSI
, and follow up was limited to 7 days

. 134 In contrast, 1 large 136 (N=912) prospective OBS study in primary and revision THA and TKA suggested reduced risk of SSI and a smaller 135 study in primary THA and TKA reported only 1 infection in the transfused group. See individual comparators in GRADE table 11 A for specific study findings.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 55 3

. Allogeneic vs. Autologous b lood t ransfusions

Q 11 A.3. Allogeneic blood (any) v s. a utologous blood (any)

Moderate

- quality evidence suggested that allogeneic blood transfusion s increased the risk of SSI. This was based on a greater than 4 fold increase in risk in a meta

- analysis (N=2592) of 3 OBS studies

. 135 , 136 , 140 Allogeneic blood products included whole blood, WBC depleted, WBC filtered and not filtered; autologous included whole blood, buffy coat depleted, and perioperative cell salvage

- washed blood. See individual comparators in GRADE table 11 A for specific s tudy findings.

4. Combined Autologous and Allogeneic b lood t ransfusion s

Q 11 A.4. Combined autologous and allogeneic blood (any) v s. n o transfusion

Moderate

- quality evidence suggested that combined autologous and additional allogeneic blood transfusion s did not increase the risk of SSI . This was based on no difference in subanalysis in 1 RCT 133 (N=470) and 2 OBS 135 , 136 studies (N=1632)

. In each study, patients received allogeneic blood transfusion only after all (2

- 3 units) of the autologous donated b lood (with or without additional salvage blood) had been transfused. Autologous blood products included autologous blood donation whole blood, packed red blood cells, salvage blood
, 136 “buffy coat depleted”
, 135 or “WBC filtered” 133 . Allogeneic blood produ cts included “WBC depleted or not depleted”
, 136 or “WBC filtered (WBCF)”

. 135 , 138 Transfusion triggers included: hemoglobin level s of 8

- 9g/dL
, 133 , 136 <11g/dL for autologous transfusions and <6g/dL for allogeneic transfusions or < 10g/dL in patients with cardiovascular or cerebrovascular disease, or symptomatic anemia in another 141 study. See individual comparators in GRADE table 11A for specific study findings.

Other Guidelines R ecent blood transfusion practice guidelines recomme nd more restrictive transfusion strategies than those used in these studies

. 253 In hemodynamically stable postoperative surgical patients, transfusion is recommended for hemoglobin levels of 8g/dL or less for symptoms (e.g., chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart fai lure). In adult and pediatric intensive care unit patients, the recommended hemoglobin level for transfusion is 7g/dL or less.



### Q 11 B. If the risk of SSI is increased, can this effect be isolated from the risk associated with more complex cases ?

Our se arch did not identify data that directly evaluated the association between increasing blood transfusion requirements, more complex cases , and the risk of SSI in prosthetic joint arthroplasty patients. However, data from 3 OBS 136 , 138 , 141 studies stratified blood transfusionDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 56 requirement s and 1 OBS 136 study reported blood loss , both by procedure type. See individual comparators in GRADE table 11B for specific study findings.



### Q 11 C. How does the volume of transfused blood product impact the risk of SSI?

Our search did not identify data that evaluated differences in the volume of transfused blood product and their impact on the risk of SSI in prosthetic joint arthroplasty patients.



### Q 11 D. How safe and effective is withholding blood transfusion s to reduce t he risk of SSI?

Our search did not identify data that both evaluated the safety and effectiveness of withholding blood transfusions and its impact on the risk of SSI in prosthetic joint arthroplasty patients.

Other Guidelines Clinical practice guidelines recommend against withholding transfusion of necessary blood product s from surgical patients as a means to prevent SSI

. 12

Q 11 . Recommendation

11 A. No recommendation can be made regarding the perioperative management of blood transfusions for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) 133

- 141 (Key Question 11 A

- C )
11B. Do not withhold transfusion of necessary blood products from surgical patients as a means to prevent surgical site infection. (Category IB) 12 (Key Question 11 D )



### SYSTEMIC I MMUNOSUPPRESSIVE THERAPY 

### Q1 2

. How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients?

Immunosuppressive therapy agents used to treat rheumatoid arthritis ( RA ) are divided into disease modifying antirheumatic drugs (DMARDs) and biologic agents. The most common DMARD is methotrexate, but can also include hydroxychloriquine, leflunomide, minocycline, sulfasazaline, azathioprine, cyclosporine and gold. DMARD comb ination therapy includes 2 or 3 drugs, most of which are methotrexate based. Biologic agents are commonly divided into “non

tumor necrosis factor (TNF)” agents (e.g., anakinra, abatacept, rituximab, and tocilizumab) and “anti

- TNF” agents (e.g., adalimumab , etanercept, infliximab, certolizumab pegol, and golimumab). In the treatment of both early ( < 6 months) and established ( > 6 months) RA , progression from DMARD monotherapy, to DMARD double or triple therapy, to use of biologic agents is indicative of prog ression from low to high disease activity with or without poorDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 57 prognostic features (e.g., functional limitation, extra

- articular disease, positive rheumatoid factor or anti

- cyclic citrullinated peptide antibodies
, and bony erosion by radiographs). 254 Syst emic corticosteroids most commonly refer to oral prednisone use.

To answer this question
, we focused on two subquestions: A) Does the type of agent impact the risk of SSI? B) Does the preoperative duration of therapy impact the risk of SSI? and C) Does the agent dose impact the risk of SSI?



### Q12A. Does the type of agent impact the risk of SSI?

The available data examined the following comparisons :
1. Biologic agents (non

- TNF and anti

- TNF) vs. d isease modifying antirheumatic drugs (DMARDs) 2. DMARDs: methotrexate vs. n o DMARD therapy

For all comparisons we considered SSI, PJI, superficial SSI, deep wound abscess, and infected hematoma as the critical outcomes. Drug

- related a dverse events , as well as adverse events of the surgical wound ne crotic eschar, and serous drainage outcomes were also evaluated. “Adverse events of surgical wound” was a composite variable that included: wound dehiscence (not completely healed 14 days after surgery or needs secondary closure), continued discharge
, and culture

- positive infection. The evidence for this question consists of 4 OBS studies in RA patients

. 142

- 145 All studies were at low risk of bias. The findings of the evidence review and the grades for all important outcomes are s hown in Evidence Review T able 1 2 A

.

Q1 2 .1. Biologic a gents (

non

- TNF and anti

- TNF) vs. DMARDs

Very low

- quality evidence suggested biologic agent therapy (non

- TNF and anti

- TNF) increased the risk of SSI. This was based on greater than 5

- fold increase in risk of SSI and superficial SSI, but no difference in PJI in 3 separate meta

- analys e s (N=528) of 2 OBS studies

. 142,143 Multivariate logistic regression analyses in both studies identified biologic agents as a significant risk factor for infection
, and in one study 142 they were also a risk factor for deep venous thrombosis ( DVT ) . Very

- low quality evidence also suggested no difference in other adverse events of the surgical wound

. 144 For superficial SSI, the large 143 study in primary or revision THA or T KA RA patients (superficial SSI rate 18.8%) reported a significantly incr eased risk with biologic agents while the smaller 142 study (superficial SSI rate of 7.4%) reported no difference . The large and small studies each reported no difference in PJI, howe ver the number of events in both groups (n=3 and 1, respectively) and the number of patients in the smaller

one (N=108) limited the power of the analyses

.
Biologic agents included anti

- TNFs (etane r cept, infliximab, adalimumab) and non

- TNFs (anakinra, abatacept and rituximab). In each study patients had established RA (on average > 10 years). All patients on biologic agent therapy also received prednisone 3

- 5mg/ day , and the majority also received methotrexate (88% 142 to 92% 144 ) and/or another DMARD 142 (13% )

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 58 DMARD patients in all three studies were on single or multiple DMARD therapy in addition to daily prednisone (average, 3mg/ day). The most common DMARD was methotrexate but none of the studies reported average weekly doses and only one reported t he DMARD perioperative administration protocol ( it was administered continuously). 143

Q1 2 .2. DMARDs: methotrexate vs. n o DMARD therapy

Very low

- quality evidence suggested methotrexate therapy did not increase the risk of SSI. This was based on no difference in PJI, deep wound abscess, infected hematoma, necrotic eschar, or serous drainage at 6 month s of follow up in 1 OBS study

. 145 Both the study size and the total number of events for each outcome were limited

. This 1991 study utilized data collected between 1978 and 1987 with patients on a mean weekly methotrexate dose of 8.7mg (range: 7.5

- 12.5 mg ) and could be consi dered sub

- therapeutic in current clinical practice

. 255 T he methotrexate group included both patients who had continued and patients who had stopped methotrexate within 4 weeks of surgery. While patients in the no therapy group had never taken methotrexate, some were on daily prednisone (study does not report h ow many).



### Q1 2 B . Does the preoperative duration of the therapy impact the risk of SSI?

Our search did not identify data that directly evaluated length of time that immunosuppressive therapy was used preoperatively and its impact on the risk of SSI in pr osthetic joint arthroplasty patients. Thus, w e evaluated disease duration as a proxy. We considered SSI as the critical outcome. The evidence for this question consists of 2 OBS studies

. 142,143 Our search did not reveal data that evaluated patients with early RA (<6 months). The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 2 B

.

Low

- quality evidence suggested that in patients with established RA (>6 months), years of disease duration was a risk factor for SSI. This was based on increased risk in 2 OBS studies that performed multivariate logistic regression analyses comparing infected to non

- infected patients on biologic (anti

- TNF) agents and DMARDs

. 142,143



### Q1 2 C . Does the agent dose impact the risk of SSI?

Our search did not identify data that directly evaluated different doses of biologic agent s or DMARD s and their impact on the risk of SSI in arthroplasty patients. The available data examined dos es of prednisone and risk of SSI in patients on biologic agents (anti

- TNF) as compared to those on DMARDs.

For this comparison
, we considered SSI as the critical outcome . The evidence for this question consists of 2 OBS studies in RA patients. 142,143 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 2 C

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 59 Very low

- quality evidence suggested higher prednisone dose increased the risk of SSI. This was based on increased risk of SSI on multivariate logistic regression analyses comparing infected and non

- infected patients in 2 OBS studies

. 142,143 The small study, with the majority of patients on combination biolo gic/DMARD or dual DMARD therapy, suggested that increasing prednisone dose was a risk factor for SSI

. 142 Patients in the biologic agent group were on significantly higher daily prednisone doses (5mg/day; range 2

- 7) tha n those in the DMARD group (3mg/ day ; r ange 0

- 5). The larger study, where none of the patients were on combination biologic and DMARD therapy
, suggested prednisone dose was not a risk factor for SSI. Patient in bot h groups were

on an average prednisone dose of 3mg/ day (range, 0

- 5)

. 143 Result s were not stratified by immunosuppressive therapy agent.



### Q1 3

. What are the most effective strategies in managing systemic corticosteroids or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients?

To answer this question we focused on two subquestions: A) How safe and effective is the discontinuation of these agents preoperatively and when should they be resumed? and B) Should the agent dose be adjusted, and if so, for how long?



### Q1 3 A. Ho w safe and effective is the discontinuation of these agents preoperatively and when should they be resumed?

The available data examined the following comparisons:

1. DMARDs: methotrexate stopped vs. continued perioperatively 2. Biologic agents: a nti

- TNF stopped vs. continued perioperatively

The evidence for this question consists of 4 OBS studies examining DMARDs 145

- 148 and 1 OBS study examining biologic agents 148 in RA patients. All studies were at low risk of bias. For all comparisons we considered PJI the critical outcome. RA flares, infected hematomas, necrotic eschar, and non

- communicating serous drainage outcomes were also evaluated

. The findings of the evidence review and the grades for all important outcomes a re shown in Evidence Review Table 1 3 A.

Q1 3 A.1. DMARDs: methotrexate stopped v s. continued perioperatively

Low

- quality evidence suggested no increased risk of PJI with methotrexate continued throughout the perioperative period. This was based on no diffe rence in PJI in a meta

- analysis of 3 small 145

- 147 OBS studies and a separate 148 OBS study

. In the meta

- analysis
, both the number of patients (N=135) and events (n=6) were small. The studies were performed between 1991 and 1996 and the methotrexate doses could be considered subtherapeutic in current practice

. 255 Procedures followed and length of time during which th erapy was stoppedDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 60 varied. In a larger study, stopping DMARD therapy at the time of surgery (not defined) reduced the incidence of subsequent PJI. 148

Q1 3 A.2. Biologic agents: a nti

- TNF stopped vs. continued perioperatively

Very low

- quality evidence suggested no difference in risk of PJI with continuation of biologic (anti

- TNF) therapy perioperatively. This was based on no difference in risk of PJI in a small

s ubanalysis in 1 OBS study in THA and TKA patients

. 148 Both the n umber of patients ( N =50) and events (n=3 ) , all in the group continuing biologic agent therapy perioperatively
, were very small.



### Q1 3 B. Should the agent dose be adjusted , and if so, for how long?

Our search did not identify data that evaluated perioperative immunosuppressive therapy dose adjustment and its impact on the risk of SSI in prosthetic joint arthroplasty patients.

Other Guidelines Clinical practice guidelines provide conflicting recommendations regarding the perio perative management of immunosuppressive therapy. In 2008 the American College of Rheumatology provided no recommendation for the perioperative management of DMARDs due to the “absence of consistent evidence”

. 256 The following year, a multinational guidel ine suggested that methotrexate could be safely continued in the perioperative period in RA patients undergoing elective orthopaedic surgery

. 255 Their recommendation was based on studies with low methotrexate dosing (4

- 13mg/week). For biologic agents
, the British Society for Rheumatology recommended in 2005 that treatment with anti

- TNF agents be withheld for 2

- 4 weeks prior to major surgical procedures and restarted postoperatively if there was no evidence of infection and wound healing was satisfactory

. 25 7 Recommendations were based solely on information provided by pharmaceutical companies. In 2008, the American College of Rheumatology (ACR) recommended that biologic agents not be used for at least one week prior to and one week following surgery (based on the pharmacokinetic properties of a given agent)

. 256 The 2012 ACR update does not address perioperative management of immunosuppressive therapy

. 254

Q 12 and Q 1 3 . Recommendation

1 2 and 13

. No recommendation can be made regarding the perioperative management of systemic corticosteroid or other immunosuppressive therapy for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/ unresolved issue) 142

- 148 (Key Question s 12 and 13)DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 61 

### Q1 4

. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients who are on systemic corticosteroid or other immunosuppressive therapy?

Our search did not identify data that specifically evaluated diffe rences in duration of postoperative AMP in prosthetic joint arthroplasty patients who were on systemic corticosteroids or other immunosuppressive agents and its impact on the risk of SSI

. However, multiple procedures examined in the Core s ection, Q1. E : Postoperative AMP duration that included patients on immunosuppressive therapy showed no benefit of continuing AMP after closing the surgical incision in the operating room. Therefore, the broader recommendation for duration of postoperative AMP should be applied to prosthetic joint arthroplasty procedures irrespective of use if systemic corticosteroid or other i mmunos uppre s sive therapy.

Q1 4 . Recommendation

1 4

. For prosthetic joint arthroplasty patients on systemic corticosteroid or other immunosuppressive therapy, Recommendation 1E applies: In clean and clean

- contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the
surg ical incision is closed in the operating room, even in the presence of a drain. (Category IA) 27

- 65 (Key question 14)



### INTRA

- ARTICULAR CORTICOSTEROID INJECTIONS 

### Q1 5

. How do preoperative intra

- articular corticosteroid injection s impact the risk of SSI in prosthetic joint arthroplasty patients?

The available data examined the following comparisons:

1. History of corticosteroid i njection vs. n o i njection a. TKA: Injection vs. no injection b. THA: Injection vs. n o i njection

For all comparisons we considere d any SSI, PJI, and superficial SSI as the critical outcomes. The evidence for this question consists of 2 OBS studies in TKA 149,150 and 3 OBS studies in THA 151

- 153 patients. All studies were at low risk of bias. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 5

.

Low

- quality evidence suggested that preoperative intra

- articular corticosteroid injection did not increase the risk of SSI following total joint arthroplasty . This was based on no difference in aDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 62 meta

- analysis (N=1146) of 5 OBS studies in TKA 149,150 and THA

. 151

- 153 See individual comparators below and in the GRADE table for individual TKA and THA findings.

Q1 5 .1.a. TKA: Injection vs. n o i njection

Very low

- quality evidence suggested that preoperative intra

- articul ar corticosteroid injection did not increase the risk of SSI following TKA. This was based on no difference in SSI, PJI, or superficial SSI in meta

- analyses (N=414) of 2 OBS studies

. 149,15 0 Both the total number of patients and events was small. One study in 144 patients 149 suggested that a history of preoperative intra

- articular injection was significantly associated with PJI after TKA (3 infections, all in the injection group) while anot her study in 270 TKAs 150 reported no PJIs in either group . B oth studies had 1 year of follow up. The majority of infections were superficial SSIs and no difference was reported at 30 day s of follow up. In the smaller study
, patient s received injection s in the orthopaedic clinic, rheumatology clinic
, or general practice setting
, while those in the larger study all received their injections in the operating room using strict aseptic technique. Patients had been injected within 11 149 and 12 150 months of s urgery.

Q1 5 .1.b. THA: Injection vs. n o Injection

Very low

- quality evidence suggested that a preoperative intra

- articul ar corticosteroid injection did not i ncrease the risk of infection following THA. This was based on no difference in SSI, PJI,

or su perficial SSI on separate meta

- analyses of 3 OBS studies

. 151

- 153 No difference in PJI or superficial SSI was reported in each individual study. In 2 studies
, both the number of patients and events was small

. 151,153 Corticosteroid doses and follow up periods varied. In each study
, corticosteroid injection was administered in a radiology suite using standard protocols for aseptic technique and one study also indicated that the radiologists wore sterile masks and
gowns. 153



### Q 1 6 . What are the most effective strategies for managing the preoperative use of intra

- articular corticosteroid injections to reduce the risk of SSI in prosthetic joint arthroplasty patients ?

Our search did not identify data that evaluated different intra

- articular corticosteroid injection agents and their impact on risk of SSI. To answer this question we focused on 2 subquestions: A) Does the length of time between corticosteroid injection an d prosthetic joint arthroplasty impact the risk of SSI? and B) Does the corticosteroid injection dose impact the risk of SSI?



### Q1 6 A. Does the length of time between intra

- articular corticosteroid injection

an d prosthetic joint arthroplasty impact the risk of SSI?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 63 The available data evaluated different lengths of time between preoperative intra

- articular corticosteroid injection and prosthetic joint arthroplasty and the impact on the risk of SSI in THA only, not TKA

.
For all comparisons we considered SSI as the critical outcome. The evidence for this question consists of 2 OBS studies. 152,153 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 6

.

Low

- quality evidence suggested no association between the length of time between intra

articular corticosteroid injection and THA and the development of SSI. This was based on no difference in the length of time between injection and surgery and the devel opment of SSI in 2 OBS studies. 152,153 The smaller, underpowered study, also reported no association between the number of injections and SSI. 153 In the larger study, while there was no difference in PJI or superficial SSI (mean time between injection and THA was 112 days), the mean time from injection to surgery for those diagnosed with PJI was less than half as long those diagnosed with superficial SSI (44 vs. 112 days). 152



### Q1 6 B. Does the corticosteroid injection dose impact the risk of SSI?

Our sear ch did not identify data that evaluated different doses of preoperative intra

- articular corticosteroid injections and their impact on the risk of SSI.

Other Guidelines While clinical practice guidelines include intra

- articular corticosteroid injections among their pharmacologic recommendations for the initial management of knee and hip osteoarthritis, they do not provide recommendations on management strategies with regard to SSI prevention

. 258 Safe injection practices apply to the administration of intra

- articular corticosteroid injections. 259

Q 15 and Q 1 6 . Recommendation

1 5 and 16

. No recommendation can be made regarding the management of preoperative intra

articular corticosteroid injections for the prevention of surgical site infection in pros thetic joint arthroplasty. (No recommendation/ unresolved issue) 149

- 153 (Key question s 15 and 16)



### ANTICOAGULATION 

### Q1 7 . What are the most effective strategies for managing perioperative venous thromboembolism ( VTE ) prophylaxis to reduce the risk of SSI in prosthetic joint arthroplasty patients?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 64 To answer this question we focused on two subquestions: A) Does the risk of SSI differ by individual VTE prophylaxis agent? B) What is the optimal timing and duration of perioperative VTE prophylaxis that also reduces the risk of SSI in prosthetic joint arthroplasty patients? and C ) How safe and effective is modifying the dose of the perioperative VTE prophylaxis a gent to reduce t he risk of SSI?



### Q 1 7 A . Does the risk of SSI differ by individual VTE prophylaxis agent?

The available data examined the following comparisons between different anticoagulation agents:

1. E noxaparin vs. fondaparinux 2. E noxaparin vs. rivaroxaban 3. E noxaparin vs. aspirin ( ASA ) and mechanical prophylaxis 4. E noxaparin vs. bemiparin vs. fraxiparin vs. fondaparinux 5. LMWHs or fondaparinux vs. ASA 6. W arfarin vs. n o pharmacologic or mechanical prophylaxis 7. W arfarin vs. ASA ± mechanical prophylaxis 8. Higher vs. l ower mean INR

For all comparisons we considered SSI and PJI as the critical outcomes. Hemorrhagic wound complications, time until wound was dry or persistent wound drainage, drug related adverse events, and wound hematoma outcomes were also e valuated

. The evidence fo r this question consists of 1 SR, 154 4 RCTs , 159

- 162 and 5 OBS 163

- 167 studies in primary and revision, unilateral, THA, TKA, and hip fracture procedures. Injectable agents included LMWHs (Factor Xa and some thrombin inhibition), m ost commonly enoxaparin or the indirect Factor Xa inhibitor fondaparinux. Oral agents included rivaroxaban (direct Factor Xa inhibitor), warfarin (Vitamin K antagonist, Factor II, VII, IX, X inhibitor) and ASA ( cyclooxygenase inhibitor). N o reversing agents currently exist for fondaparinux or rivaroxaban. Our search did not identif y studies that evaluated warfarin as compared to enoxaparin or the impact of unfractionated heparin, or clopidogrel on the risk of SSI. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 7 A.

Q1 7 A.1. E noxaparin vs. fondaparinux

Low

- quality evidence suggested no difference between perioperative injectable VTE prophylaxis with enoxaparin or fondaparinux and risk of SSI . This was based on no difference in SSI and no drug related adverse events at the end of VTE prophylaxis (11 days) in a large meta

analysis ( N=7237) of 4 RCTs (in primary and revision THA, TKA, and hip fracture procedures (osteosynthesis and hemi

- arthroplasties). 154

- 158 The studies were large, international, multi

center studies evaluating the safety and effectiveness of these agents in reducing the risk of postoperative VTE, not SSI. Wh ile fondaparinux administration was standard ized (2.5mg once aDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 65 day starting postoperatively , except in hip fractures where it was started preoperatively if the case was delayed for > 24 hours), enoxaparin dose and timing of administration varied between studies (30mg twice a day starting p ostoperatively 15 5,158 or 40 mg once a day starting preoperatively 156,157 )

. In all four studies
, prophylaxis was scheduled to last 5

- 9 days postoperatively. SSI was a secondary outcome and follow up was limited ( up to 11 days postoperatively). The 4 individual RCTs and the SR meta

- analysis were all sponsored by the manufacturer of fondaparinux and authored by the same investigators, in which the lead, senior, and multiple co

- authors reported serving as scientific consultants to the manufacturers of both agents evaluated in the studies. Turpie et al., indicated that the sponsor was responsible for data collection and final statistical analysis. 158

Q1 7 A.2. E noxaparin vs. rivaroxaban

High

- quality evidence suggested no difference between injectable enoxaparin and oral rivaroxaban , and risk of SSI . This was based on no difference in SSI in a large meta

- analysis (N=12,383) of 4 RCTs in elective primary or revision THA or TKA, and no diff erence in hemorrhagic wound complications or drug related adverse events

. 159

- 162 These studies were large, international, multi

- center studies at low risk of bias, evaluating the safety and effectiveness of once daily dosing with enoxaparin or rivaroxaban in reducing the risk of postoperative VTE, not SSI. Eriksson et al., 159 and Kakkar et al., 160 compared enoxaparin 40mg once a day start ed preoperatively to rivaro xaban 10mg once a day start ed postoperatively in elective unilateral primary (95%) or revision THA. R ivaroxaban was administered for 35 days in both studies ; e noxaparin was administered for 35 days in one 159 and 10

- 14 days in the other 160

. Follow up was approximately 2 months

. Two other studies evaluated these agents in elective unilateral primary (97%) or revision TKA , administered over 10

- 14 days

. 161,162 While r ivaroxaban administration was standardized (10mg once a day, started preoperatively)
, enoxaparin dose and timing varied between studies ( 40mg once a day, started preoperatively 161 or 30mg twice a day started postoperatively SSI was a secondary outcome and follow up was approximately 6 weeks. All studies were sponsored by the manufacturer of rivaroxaban and authored by investigators who were employees of the manufacturer or who served as scientific consultants to the manufacturers of both agents evaluated in the studies.

Q1 7 A.3 E noxaparin vs. ASA and mechanical prophylaxis

Very low

- quality evidence suggested no difference between injectable enoxaparin and combined oral ASA and mechanical prophylaxis , and risk of SSI . This was based on no increased risk of SSI on logistic regression analysis in one large study in primary THA or TKA

. 163 Enoxaparin was associated with a longer time until wound was dry in THA, but not TKA. Enoxaparin was started 12

- 24 hours postoperatively. ASA 325mg along with pneumatic compression devices was started on the morning after surgery. Analysis w as limited to patients with a closed suction drain and normal coagulation profile. Duration of VTE prophylaxis and follow up period were not reported.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 66 Q1 7 A.4. E noxaparin vs. bemiparin vs. fraxiparin vs. fondaparinux

Very low

- quality evidence suggested no difference between perioperative injectable LMWH, ultra LMWH and fondaparinux and risk of SSI . This was based on no difference in PJI at 6 months of follow up in a small nested, case control study within a larger European multicenter prospective study investigating the independent effects of VTE prophylaxis timing on the risk of PJI in TKA ( low risk of bias ). 164 L ogistic regression analysis suggested that hematoma formation increased the risk of PJI four fold.

Q1 7 A.5. E noxaparin, dalterparin, tinzaparin or fondaparinux vs. ASA ± mechanical prophylaxis

Very low

- quality evidence suggested no difference between perioperative injectable LMWH, fondaparinux, and combined oral ASA (with or without mechanical VTE prophylaxis ) , and risk of SSI . This was based on no difference in SSI in a subanalysis (n=41,917) of a very large retrospective OBS study (low risk of bias) using administrative data from a national sample of primary TKAs

. 165 Data were collected from 307 facilities over a 2 year peri od and compared the risk of V TE, bleeding, SSI, and mortality in primary TKA patients 4719 (5.0%) of whom were on ASA, 51,923 (55.3%) on oral warfarin, and 37,198 (39.6%) on injectable agents (LMWHs and fondaparinux were combined in the analysis ). Pneumati c compression devices were used on the day of surgery or on the first postoperative day in 1795 (38%), 28,757 (55%), and 17,756 (48%) of the populations , respectively. Patients on ASA had fewer baseline comorbidities, lower baseline risk of venous thrombo emboli sm, and received care in hospitals with shorter average length of stay that more commonly discharged to the patient’s home after surgery. The study included SSIs detected at the time of admission or upon readmission to the hospital within 30 days of the index procedure using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD

- 9

- CM) wound infection codes. Authors indicated that subtherapeutic dosing and/or inappropriate dose timing of the LMWHs or synthetic Factor Xa inhibitor may have impacted the results.

Q1 7 A.6. Warfarin vs. n o pharmacologic or mechanical prophylaxis

Very low

- quality evidence suggested no difference between oral warfarin VTE prophylaxis and no pharmacologic or mechanical prophylaxis , and risk of SSI . This was based on no difference in SSI (deep or superficial) in one large retrospective OBS study in primary unilateral TKA at 3 month s of follow up ( low risk of bias ). 166 History of anticoagulation prophylaxis for cardiac (arrhythmia or prosthetic valve) or thromboembolic event was not associated with increased risk of SSI or gastrointestinal bleed in patients on 6 weeks of postoperative warfarin VTE prophylaxis. I NR level s (target INR : 1.6

- 2.2) were monitored and medication adjusted twice weekly. Standardized postoperative protocol s in both groups included continuous passive motion, physical therapy, weight bearing, and similar pain and nausea medications.

Q1 7 A.7. Warfa rin vs. ASA ± mechanical prophylaxisDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 67 Low

- quality evidence suggested no difference between perioperative oral warfarin and ASA (with or without mechanical VTE prophylaxis) , and risk of SSI . This was based on no difference in SSI in two large retrospective studies at low risk of bias

. 163,165 In one large single institution study, l ogistic regression analysis suggested that in THA and TKA, warfarin (target INR=2) started on the day of surgery was not associated with an increased risk of SSI or longer time

un til wound was dry, as compared to ASA 325mg with pneumatic compression devices started on the morning after surgery

. 163 Duration of VTE prophylaxis and follow up period were not reported. Analysis was limited to patients with a closed suction drain and normal coagulation profile . A second, large study using administrative data collected from 307 facilities over a 2 year period suggested no difference in SSI in primary TKAs

. 165 Target INR was not reported. Pneumatic compression devices were used on the day of surgery or on the first postoperative day in 55% of patients on warfarin and 38% of patients on ASA. SSIs were detected on admission or readmission to the hospital within 30 days of the index procedure using International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD

- 9

- CM ) wound infection codes . Authors indicated that subtherapeutic dosing or inappropriate timing may have impacted results.

Q1 7 A.8. Higher vs

. lower INR

Very low

- quality evidence suggested no difference between higher and lower oral warfarin INR s , and risk of SSI . This was based on no difference in PJI in a small (N=154) 1:2 case control study in primary and revision THA and TKAs ( low risk of bias ). 167 Low dose warfarin (target INR=1.5) was administered on the day of surgery and continued for 6 weeks. Thirteen patients on anticoagulation therapy preoperatively for a chronic condition , were heparinized postoperatively until fully anticoagulated on warfarin with a higher target INR=2

- 3 . A ll of these patients were in the infected cohort. The INR was also significantly higher in patients with wound

- related problems who later developed infection. I n addition, i nfected patients and those with woun d complications were more likely to have INR > 1.5 at the time of hospital discharge. Infected patients also had a significantly higher incidence of wound hematomas. On multivariate logistic regres sion analysis, wound hematomas and persistent wound draina ge were significant risk factors for PJI. Nine (69%) of the heparinized patients developed wound complications including: hematomas, persistent wound drainage, or delayed wound healing.



### Q1 7 B . What is the optimal timing and duration of perioperative VTE prophylaxis that also reduces the risk of SSI?

The available data examined VTE prophylaxis started preoperatively as compared to postoperatively in patients receiving injectable LMWHs (enoxapa rin, bemiparin, or fraxiparin)

or fondaparinux.

For this comparison we considered PJI as the critical outcome. The evidence for this question consists of 1 OBS study in TKA , at low risk of bias

. 164 Our search did not identify data that evaluated optimal timing in THA or in patients taking oral agents. Our search did not identifyDISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 68 data that evaluated optimal duration of perioperative anticoagulation prophylaxis and its impact on SSI. The findings of the evidence review and the grades for all important out comes are shown in Evidence Review and GRADE table 1 7 B

.
Very low

- quality evidence suggested that close perioperative administration of injectable LMWHs or fondaparinux VTE prophylaxis agents did not increase the risk of PJI. This was based

on no difference in PJI at 6 month s of follow up, in a small
, nested, multicenter, case control study in TKAs. 164

Other Guidelines Clinical practice guidelines, on prevention of VTE in patients undergoing THA, TKA, or hip fracture procedures provide recommenda tions on choice, timing, and duration of VTE prophylaxis

. 260 , 261



### Q 1 7 C .How safe and effective is modifying the dose of perioperative VTE prophylaxis agent to reduce the risk of SSI ?

Our search did not identify data that evaluated the safety and effectiveness of modifying the dose of perioperative VTE prophylaxis agent and its impact on the risk of SSI.

Q1 7 . Recommendation

1 7

. No recommendation can be made regarding perioperative management of venous thromboembolism prophylaxis for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) 154

- 167 (Key Question 1 7 )



### ORTHOPAEDIC SPACE SUIT 

### Q1 8 . How safe and effective are orthopaedic space suit s in reducing the risk of SSI in prosthetic joint arthroplasty patients , and which healthcare personnel should wear them ?

The available data evaluated the use of a space suit as compared to no space suit

.
For this comparison we considered deep SSI r equiring reoperation, deep SSI requiring revision
, and deep SSI as the critical outcomes. Superficial SSI outcome was also evaluated

. The evidence for this question consists of 3 OBS studies at low risk of bias

. 168

- 170 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1 8

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 69 Very

- low quality evidence suggested no benefit to using an orthopaedic space suit to reduce the risk of SSI . This was based on no differe nce in deep SSI requiring reoperation
, 168 deep SSI requiring revision surgery , 169 or deep or superficial SSI 170 in 3 OBS studies. The number of events for each of these studies was low. The largest national joint registry study with multiple subgroup ana lyses suggested that use of a space suit was associated with an increased number of deep SSIs requiring revision surgery within 6 months of THA or TKA
, but this evidence was limited in size

. 169 Results did not differ based on the presence or absence of lam inar flow. A large multicenter study using administrative data from patients undergoing TKA suggested no difference in deep SSIs requiring reoperation within 90 days

. 168 Reoperations included incision and drainage and implant removal . The definition of d eep SSI in this study may have included PJI. Space suit and laminar flow use varied between groups. A third small study in THA and hip hemiarthroplasties reported only 1 deep SSI in the space suit group and 1 superficial SSI in each group at 24 month s of follow up

. 170 High

- efficiency particulate air ( HEPA ) /mixed turbulent filtration was used in both groups.

Our search did not identify data that quantified potential complications associated with the use of space suit s . In one large national joint regis try study (N=88,311) comments by surgeons completing a questionnaire (n=35) included “ limited spatial awareness and ease of contamination due to an apparent false sense of security ” with the use of a space suit. 169 We did not evaluate the efficacy of the s pace suit as per sonal protective equipment

.
Also, o ur search did not identify data that evaluated the association between specific health

care personnel wearing a space suit and SSI. One retrospective control led study included a surgeon questionnaire rep orting that the surgeon, assistant, and scrub nurse were the team members wearing a full space suit. 169 One prospective control led study reported those same team members wearing the space suit in the intervention group. 170

Q1 8 . Recommendation

1 8 . No recommendation can be made regarding the safety and effectiveness of orthopaedic space suits or the health care personnel who should wear them for the prevention of surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresol ved issue) 168

- 170 (Key question 18 )



### POSTOPERATIVE AMP DURATION IN PROSTHETIC JOINT ARTHROPLASTY WITH THE USE OF A DRAIN 

### Q 19

. What is the optimal duration of postoperative AMP to reduce the risk of SSI i n prosthetic joint arthroplasty in the presence of a drain?DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 70 Our search did not identify data that directly evaluated optimal postoperative AMP duration in the presence of a drain and its impact on the risk of SSI in prosthetic joint arthroplasty patients

. However, multiple procedures examined in the Core s ection , Q1. E : P ostoperative AMP duration that included use of a drain (including prosthetic joint arthroplasty procedures) showed no benefit of continuing AMP after closing the incision in the operating room. Therefore, the broader r ecommendation for postoperative AMP duration should be applied to prosthetic joint arthroplasty procedures irrespective of drain use.

Q 19 . Recommendation

1 9 . In prosthetic joint arthroplasty, Recommendation 1E applies: In clean and clean

contaminated pr ocedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA) 27

- 65 (Key question 19 )



### BIOFILM 

### Q 2 0 . What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty patients ?

To answer this question we focused on four subquestions: A) How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? B) How effectiv e are prosthesis modification s (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology ) ? C) How effective are vaccines? and D) How effective are other biofilm control agents (e. g., biofilm dispersants, quorum

- sensing inhibitors, novel antimicrobial agents )?



### Q 20 A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)?

Our search did not identify data that evaluated the safety and effectiveness of cement modifications in THA and the risk of SSI

. In vitro studies and s tudies that evaluated antimicrobial loaded cement in the absence of perioperati ve parenteral antimicrobial prophylaxis were excluded from our analysis. The available data examined ce furoxime loaded cement vs. plain cement in primary TKA patient receiving perioperative AMP.

For this comparison we considered deep SSI as the critical outcome. In these studies, deep SSI likely refers to or includes PJI. The evidence for this question consists of 2 RCTs

. 171,172 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2 0 A

.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 71 Moderate

- quality evidence suggested a benefit of cefuroxime loaded cement. This was based

on a reduced risk of deep SSI in a meta

- analysi s (N=428) of 2 RCTs : 1 large study in non

diabetic 171 patients and 1 small study (N=78) in diabetic 172 patients

. Both studies were at moderate risk of bias. There were no deep SSIs in the cefuroxime loaded cement groups at an average 49 month s of follow up. A single surgeon performed all TKAs in an operating room without ultraviolet lights, laminar flow, or use of a n orthopaedic space suit . Only the tibial and patellar components were cemented. Cefuroxime 2g in 40g polyme thylmethacrylate cement was used in the study groups. AMP included parenteral cefazolin and gentamycin preoperatively then every 6 and 12 hours, respectively
, postoperatively for 36 hours followed by cefazolin orally for 7 more days. Data on organisms iso lated from the SSIs and antimicrobial resistance were not reported.



### Q 2 0 B. How effective are prosthesis surface modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology) ?

Our search did not identify in vivo studies that evaluated the safety and effectiveness of prosthesis modifications and their impact on biofilm formation and the risk of SSI.



### Q 20 C. How effective are vaccines?

Our search did not identify in vivo studies that evaluated the safety and effectiveness of vaccines and their impact on biofilm formation and the risk of SSI.



### Q 20 D. How effective are other biofilm control agents (e.g., biofilm dispersants,
quorum - sensing inhibitor s, novel antimicrobial agents)?

Ou r search did not identify in vivo studies that evaluated the safety and effectiveness of biofilm control agents and their impact on biofilm formation and the risk of SSI.

Q 20 . Recommendations

20 A. No recommendation can be made regarding the safety and effectiveness of cement modifications and the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplasty. (No recommendation/ unresolved issue ) 171,172 (Key Question 20 A )

20 B. No recommendation can be made regarding the safety and effectiveness of prosthesis modifications for the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplasty. (No recommendation/unresolved issue) (Key Question 2 0 B )

20 C. No recommendation can be made regarding the safety and effectiveness of vaccines for the prevention of biofilm formation or surgical site infection in prosthetic joint arthroplasty.DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 72 (No recommendation/unresolved issue) (Key Question 20 C )

20 D. No recommendation can be made regarding the safety and effectiveness of biofilm control agents such as biofilm dispersants, quorum

- sensing inhibitors, or novel antimicrobial agents for the prevention of biofilm formation or surgical site infection in prost hetic joint arthroplasty. (No recommendation/unresolved issue) (Key Question 20 D )DISCLAIMER: This document is a DRAFT. The findings and conclusions in this draft guideline have not been formally disseminated by the

Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy

. 73 

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