Clinical trial NCT00395161: The CRISIS Prevention Study
Official title: The Critical Illness Stress-induced Immune Suppression Prevention Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Sepsis
Keywords: sepsis
prevention
mineral supplementation
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Seattle Children's Hospital
name: Children's Hospital Los Angeles
name: Arkansas Children's Hospital Research Institute
name: Children's Hospital of Michigan
name: University of Pittsburgh
name: Children's National Research Institute
name: University of California, Los Angeles
name: Harborview Injury Prevention and Research Center
First posted: 2006-11-02
Enrollment: 293
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Despite strict hand washing, sterile technique, and antibiotic-coated catheters, nosocomial infection and sepsis remain the leading acquired causes of morbidity and mortality in critically ill children. Subsequent use of antibiotics to treat nosocomial infection and sepsis is considered a major attributable factor in the rise of antibiotic-resistant organisms in this population of children. This study will use a double-blind, randomized, controlled trial design to test the hypothesis that daily prophylaxis with metoclopramide, zinc, selenium and glutamine will reduce nosocomial infection and sepsis in critically ill children.

Detailed description: Despite strict hand washing, sterile technique, and antibiotic-coated catheters, nosocomial infection and sepsis remain the leading acquired causes of morbidity and mortality in critically ill children. Subsequent use of antibiotics to treat nosocomial infection and sepsis is considered a major attributable factor in the rise of antibiotic-resistant organisms in this population of children. Presently, "prophylaxis" strategies are used to prevent stress-induced gastrointestinal bleeding; however, no "prophylaxis" strategy is used to prevent stress-induced nosocomial infection and sepsis. When left unopposed, the stress hormone, cortisol, induces lymphocyte apoptosis, lymphopenia, and immune insufficiency. Prolactin is the counter-regulatory stress hormone that prevents cortisol-induced apoptosis and immunosuppression. Zinc, selenium, and glutamine are also important in maintenance of lymphocyte health. Critically ill patients commonly develop hypoprolactinemia secondary to increased central nervous system dopaminergic activity, as well as zinc, selenium, and glutamine deficiency caused by increased utilization and decreased supply. Hypoprolactinemia can be prevented by metoclopramide, a dopamine 2 receptor antagonist commonly used as a prokinetic in children, and zinc, selenium, and glutamine deficiency can be prevented with enteral supplementation. This study will use a double-blind randomized controlled trial design to test the hypothesis that daily prophylaxis with metoclopramide, zinc, selenium and glutamine will reduce nosocomial infection and sepsis in critically ill children.

Eligibility criteria: Inclusion Criteria:

During the initial accrual period for this study, prior to the first interim analysis, patients will be eligible for enrollment if they:

* are between 12 months and less than 18 years; AND
* are within the first 48 hours of the PICU admission; AND
* have an endotracheal tube, central venous catheter (new or old, tunneled or not tunneled), or Foley catheter; AND
* are anticipated to have an indwelling arterial or central venous catheter for blood sampling during the first three days of study enrollment.

After the Data Safety Monitoring Board (DSMB) conducts its first interim evaluation, after enrollment of approximately 200 subjects, a decision will be made by the DSMB concerning enrollment of subjects between 40 weeks gestational age and 12 months. If the DSMB approves enrollment of infants after the first interim analysis, then patients will be eligible for enrollment if they:

* are between 40 weeks gestational age and less than 18 years; AND
* are within the first 48 hours of the PICU admission; AND
* have an endotracheal tube, central venous catheter (new or old, tunneled or not tunneled), or Foley catheter; AND
* are anticipated to have an indwelling arterial or central venous catheter for blood sampling during the first three days of study enrollment.

Exclusion Criteria:

During the initial accrual period for this study, prior to the first interim analysis, patients will be ineligible for enrollment if ANY of the following is true or anticipated:

* are less than 1 year age; OR
* are greater than or equal to 18 years of age; OR
* have a known allergy to metoclopramide; OR
* planned removal of endotracheal tube, central venous catheter, AND Foley catheters, within 72 hours of study enrollment, OR
* suspected intestinal obstruction, OR
* intestinal surgery or bowel disruption, OR
* chronic metoclopramide therapy prior to enrollment, OR
* failure to enroll within 48 hours of PICU admission, OR
* readmission to PICU in the previous 28 days, OR
* previously enrolled in this study, OR
* lack of commitment to aggressive intensive care therapies.

After the Data Safety Monitoring Board (DSMB) conducts its first interim evaluation, after enrollment of approximately 200 subjects, a decision will be made by the DSMB concerning enrollment of subjects between 40 weeks gestational age and 12 months. If the DSMB approves enrollment of infants after the first interim analysis, then patients will be ineligible for enrollment if ANY of the following is true or anticipated:

* are less than 40 weeks gestational age; OR
* are greater than or equal to 18 years of age; OR
* have a known allergy to metoclopramide; OR
* planned removal of endotracheal tube, central venous catheter, AND Foley catheters, within 72 hours of study enrollment, OR
* suspected intestinal obstruction

Primary outcomes:
measure: The Primary Endpoint of This Study is the Median Time Between Admission to the PICU and Occurrence of Nosocomial Infection or Clinical Sepsis in PICU Patients Who Have Endotracheal Tubes, Central Venous Catheters, or Urinary Catheters.
timeFrame: 48 hours after admission until 5 days after discharged from the PICU
Secondary outcomes:
measure: Rate of Nosocomial Infection or Clinical Sepsis Per 100 Study Days
timeFrame: 48 hours after PICU admission till discharge from PICU
measure: Antibiotic-free Days
timeFrame: 48 hours after admission until PICU discharge
measure: Incidence of Prolonged Lymphopenia (Absolute Lymphocyte Count Less Than or Equal to 1,000/mm³ for > or Equal to 7 Days)
timeFrame: from time of PICU admission till discharge from PICU
measure: All-cause 28-day Mortality Rate.
timeFrame: 28 days after admission to the PICU
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Childrens Hospital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: University of Pittsburgh Medical Center
name: Joseph Carcillo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003 Mar 1;167(5):695-701. doi: 10.1164/rccm.200207-682OC. Epub 2002 Nov 14.
citation: Brown RB, Stechenberg B, Sands M, Hosmer D, Ryczak M. Infections in a pediatric intensive care unit. Am J Dis Child. 1987 Mar;141(3):267-70. doi: 10.1001/archpedi.1987.04460030045021.
citation: Stein F, Trevino R. Nosocomial infections in the pediatric intensive care unit. Pediatr Clin North Am. 1994 Dec;41(6):1245-57. doi: 10.1016/s0031-3955(16)38871-x.
citation: Ford-Jones EL, Mindorff CM, Pollock E, Milner R, Bohn D, Edmonds J, Barker G, Gold R. Evaluation of a new method of detection of nosocomial infection in the pediatric intensive care unit: the Infection Control Sentinel Sheet System. Infect Control Hosp Epidemiol. 1989 Nov;10(11):515-20. doi: 10.1086/645938.
citation: Milliken J, Tait GA, Ford-Jones EL, Mindorff CM, Gold R, Mullins G. Nosocomial infections in a pediatric intensive care unit. Crit Care Med. 1988 Mar;16(3):233-7. doi: 10.1097/00003246-198803000-00005.
citation: Allen U, Ford-Jones EL. Nosocomial infections in the pediatric patient: an update. Am J Infect Control. 1990 Jun;18(3):176-93. doi: 10.1016/0196-6553(90)90183-s.
citation: Donowitz LG. High risk of nosocomial infection in the pediatric critical care patient. Crit Care Med. 1986 Jan;14(1):26-8. doi: 10.1097/00003246-198601000-00006.
citation: Meakins JL, Pietsch JB, Bubenick O, Kelly R, Rode H, Gordon J, MacLean LD. Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg. 1977 Sep;186(3):241-50. doi: 10.1097/00000658-197709000-00002.
citation: Pellegrini JD, De AK, Kodys K, Puyana JC, Furse RK, Miller-Graziano C. Relationships between T lymphocyte apoptosis and anergy following trauma. J Surg Res. 2000 Feb;88(2):200-6. doi: 10.1006/jsre.1999.5797.
citation: O'Sullivan ST, Lederer JA, Horgan AF, Chin DH, Mannick JA, Rodrick ML. Major injury leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection. Ann Surg. 1995 Oct;222(4):482-90; discussion 490-2. doi: 10.1097/00000658-199522240-00006.
citation: Menges T, Engel J, Welters I, Wagner RM, Little S, Ruwoldt R, Wollbrueck M, Hempelmann G. Changes in blood lymphocyte populations after multiple trauma: association with posttraumatic complications. Crit Care Med. 1999 Apr;27(4):733-40. doi: 10.1097/00003246-199904000-00026.
citation: Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis. 2000 Jan;181(1):176-80. doi: 10.1086/315214.
citation: Rathmell JC, Thompson CB. Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell. 2002 Apr;109 Suppl:S97-107. doi: 10.1016/s0092-8674(02)00704-3.
citation: Fletcher-Chiappini SE, Compton MM, LaVoie HA, Day EB, Witorsch RJ. Glucocorticoid-prolactin interactions in Nb2 lymphoma cells: antiproliferative versus anticytolytic effects. Proc Soc Exp Biol Med. 1993 Mar;202(3):345-52. doi: 10.3181/00379727-202-43545.
citation: Ayala A, Herdon CD, Lehman DL, DeMaso CM, Ayala CA, Chaudry IH. The induction of accelerated thymic programmed cell death during polymicrobial sepsis: control by corticosteroids but not tumor necrosis factor. Shock. 1995 Apr;3(4):259-67. doi: 10.1097/00024382-199504000-00003.
citation: Tarcic N, Ovadia H, Weiss DW, Weidenfeld J. Restraint stress-induced thymic involution and cell apoptosis are dependent on endogenous glucocorticoids. J Neuroimmunol. 1998 Feb;82(1):40-46. doi: 10.1016/S0165-5728(97)00186-0.
citation: Noel GL, Suh HK, Stone JG, Frantz AG. Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab. 1972 Dec;35(6):840-51. doi: 10.1210/jcem-35-6-840. No abstract available.
citation: Yu-Lee LY. Molecular actions of prolactin in the immune system. Proc Soc Exp Biol Med. 1997 May;215(1):35-52. doi: 10.3181/00379727-215-44111.
citation: Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000 Oct;80(4):1523-631. doi: 10.1152/physrev.2000.80.4.1523.
citation: L Vankrieken. Immulite reproductive hormone assays: multicenter reference range data, 2000.
citation: HG Friesen. Human prolactin. Ann Rev Coll Phys Surg Can, 11:275- 281, 1978.
citation: Buckley AR, Buckley DJ. Prolactin regulation of apoptosis-associated gene expression in T cells. Ann N Y Acad Sci. 2000;917:522-33. doi: 10.1111/j.1749-6632.2000.tb05417.x.
citation: Krishnan N, Thellin O, Buckley DJ, Horseman ND, Buckley AR. Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo. Endocrinology. 2003 May;144(5):2102-10. doi: 10.1210/en.2003-0053.
citation: Leff MA, Buckley DJ, Krumenacker JS, Reed JC, Miyashita T, Buckley AR. Rapid modulation of the apoptosis regulatory genes, bcl-2 and bax by prolactin in rat Nb2 lymphoma cells. Endocrinology. 1996 Dec;137(12):5456-62. doi: 10.1210/endo.137.12.8940371.
citation: Buckley AR, Buckley DJ, Leff MA, Hoover DS, Magnuson NS. Rapid induction of pim-1 expression by prolactin and interleukin-2 in rat Nb2 lymphoma cells. Endocrinology. 1995 Dec;136(12):5252-9. doi: 10.1210/endo.136.12.7588268.
citation: Hotchkiss RS, Swanson PE, Knudson CM, Chang KC, Cobb JP, Osborne DF, Zollner KM, Buchman TG, Korsmeyer SJ, Karl IE. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol. 1999 Apr 1;162(7):4148-56.
citation: Matera L. Endocrine, paracrine and autocrine actions of prolactin on immune cells. Life Sci. 1996;59(8):599-614. doi: 10.1016/0024-3205(96)00225-1.
citation: Berczi I. Pituitary hormones and immune function. Acta Paediatr Suppl. 1997 Nov;423:70-5. doi: 10.1111/j.1651-2227.1997.tb18376.x.
citation: Buckley AR. Prolactin, a lymphocyte growth and survival factor. Lupus. 2001;10(10):684-90. doi: 10.1191/096120301717164912.
citation: Chikanza IC. Prolactin and neuroimmunomodulation: in vitro and in vivo observations. Ann N Y Acad Sci. 1999 Jun 22;876:119-30. doi: 10.1111/j.1749-6632.1999.tb07629.x.
citation: Fraker PJ, King LE, Laakko T, Vollmer TL. The dynamic link between the integrity of the immune system and zinc status. J Nutr. 2000 May;130(5S Suppl):1399S-406S. doi: 10.1093/jn/130.5.1399S.
citation: Newsholme P, Curi R, Pithon Curi TC, Murphy CJ, Garcia C, Pires de Melo M. Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease. J Nutr Biochem. 1999 Jun;10(6):316-24. doi: 10.1016/s0955-2863(99)00022-4.
citation: King LE, Osati-Ashtiani F, Fraker PJ. Apoptosis plays a distinct role in the loss of precursor lymphocytes during zinc deficiency in mice. J Nutr. 2002 May;132(5):974-9. doi: 10.1093/jn/132.5.974.
citation: Aleksandrowicz J, Starek A, Moszczynski P. [Effect of selenium on peripheral blood in rats chronically exposed to benzene]. Med Pr. 1977;28(6):453-9. Polish.
citation: Szondy Z. The effects of cell number, concentrations of mitogen and glutamine and time of culture on [3H]thymidine incorporation into cervical lymph node lymphocytes stimulated by concanavalin-A. Immunol Lett. 1995 Mar;45(3):167-71. doi: 10.1016/0165-2478(94)00256-q.
citation: Devins SS, Miller A, Herndon BL, O'Toole L, Reisz G. Effects of dopamine on T-lymphocyte proliferative responses and serum prolactin concentrations in critically ill patients. Crit Care Med. 1992 Dec;20(12):1644-9. doi: 10.1097/00003246-199212000-00007.
citation: Van den Berghe G, de Zegher F, Lauwers P. Dopamine suppresses pituitary function in infants and children. Crit Care Med. 1994 Nov;22(11):1747-53.
citation: Van den Berghe G, de Zegher F. Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med. 1996 Sep;24(9):1580-90. doi: 10.1097/00003246-199609000-00024.
citation: Le Saux NM, Sekla L, McLeod J, Parker S, Rush D, Jeffery JR, Brunham RC. Epidemic of nosocomial Legionnaires' disease in renal transplant recipients: a case-control and environmental study. CMAJ. 1989 May 1;140(9):1047-53.
citation: Parra A, Ramirez-Peredo J, Larrea F, Cabrera V, Coutino B, Torres I, Angeles A, Perez-Romano B, Ruiz-Arguelles G, Ruiz-Arguelles A. Decreased dopaminergic tone and increased basal bioactive prolactin in men with human immunodeficiency virus infection. Clin Endocrinol (Oxf). 2001 Jun;54(6):731-8. doi: 10.1046/j.1365-2265.2001.01262.x.
citation: Parra A, Ramirez-Peredo J. The uncoupled couple? Prolactin and CD4 lymphocytes in HIV infection. Med Hypotheses. 1999 Nov;53(5):425-8. doi: 10.1054/mehy.1999.0930.
citation: Ijaiya K, Roth B, Schwenk A. The effects of arginine, insulin and metoclopramide on growth hormone, prolactin and cortisol release in children. Clin Endocrinol (Oxf). 1980 Jun;12(6):589-94. doi: 10.1111/j.1365-2265.1980.tb01380.x.
citation: LL Brunton. Agents affecting gastrointestinal water flux and motility. In Limbird LE Hardman JG, editor, Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 931-933. McGraw-Hill, New York, 9th edition, 1996.
citation: F Shann, editor. Drug Doses. Collective Pty Ltd., Melbourne, 12th edition, 2003.
citation: PR Dallman. White blood cells: developmental changes in numbers. In Ruolph CD Rudolph AM, Hoffman JIE, editor, Pediatrics, page 1061. Appleton and Lange, Norwalk CT, 19th edition, 1987.
citation: Anonymous. Immunization in special clinical circumstances. In LK Pickering, editor, 2000 Redbook: Report of the Committee of Infectious Diseases, page 59. Academy of Pediatrics, Elk Grove Village, IL, 25th edition, 2000.
citation: E.R. Stiehm. Immunologic disorders in infants and children. W.B. Saunders, Philadelphia, PA, 1989.
citation: Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG, Karl IE. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol. 2001 Jun 1;166(11):6952-63. doi: 10.4049/jimmunol.166.11.6952.
citation: Gurevich P, Ben-Hur H, Czernobilsky B, Nyska A, Zuckerman A, Zusman I. Pathology of lymphoid organs in low birth weight infants subjected to antigen-related diseases: a morphological and morphometric study. Pathology. 1995 Apr;27(2):121-6. doi: 10.1080/00313029500169702.
citation: Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson DW, Karl IE. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol. 2000 Dec;1(6):496-501. doi: 10.1038/82741.
citation: Zellweger R, Wichmann MW, Ayala A, Chaudry IH. Metoclopramide: a novel and safe immunomodulating agent for restoring the depressed macrophage immune function after hemorrhage. J Trauma. 1998 Jan;44(1):70-7. doi: 10.1097/00005373-199801000-00006.
citation: Zellweger R, Zhu XH, Wichmann MW, Ayala A, DeMaso CM, Chaudry IH. Prolactin administration following hemorrhagic shock improves macrophage cytokine release capacity and decreases mortality from subsequent sepsis. J Immunol. 1996 Dec 15;157(12):5748-54.
citation: Knoferl MW, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Insight into the mechanism by which metoclopramide improves immune functions after trauma-hemorrhage. Am J Physiol Cell Physiol. 2000 Jul;279(1):C72-80. doi: 10.1152/ajpcell.2000.279.1.C72.
citation: Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol. 2005 Mar 15;174(6):3765-72. doi: 10.4049/jimmunol.174.6.3765.
citation: Yavagal DR, Karnad DR, Oak JL. Metoclopramide for preventing pneumonia in critically ill patients receiving enteral tube feeding: a randomized controlled trial. Crit Care Med. 2000 May;28(5):1408-11. doi: 10.1097/00003246-200005000-00025.
citation: Brooks WA, Yunus M, Santosham M, Wahed MA, Nahar K, Yeasmin S, Black RE. Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial. Lancet. 2004 May 22;363(9422):1683-8. doi: 10.1016/S0140-6736(04)16252-1.
citation: Fischer Walker C, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr. 2004;24:255-75. doi: 10.1146/annurev.nutr.23.011702.073054.
citation: Baqui AH, Black RE, El Arifeen S, Yunus M, Zaman K, Begum N, Roess AA, Santosham M. Zinc therapy for diarrhoea increased the use of oral rehydration therapy and reduced the use of antibiotics in Bangladeshi children. J Health Popul Nutr. 2004 Dec;22(4):440-2.
citation: Raqib R, Roy SK, Rahman MJ, Azim T, Ameer SS, Chisti J, Andersson J. Effect of zinc supplementation on immune and inflammatory responses in pediatric patients with shigellosis. Am J Clin Nutr. 2004 Mar;79(3):444-50. doi: 10.1093/ajcn/79.3.444.
citation: Bhatnagar S, Bahl R, Sharma PK, Kumar GT, Saxena SK, Bhan MK. Zinc with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children: a randomized controlled trial. J Pediatr Gastroenterol Nutr. 2004 Jan;38(1):34-40. doi: 10.1097/00005176-200401000-00010.
citation: Sazawal S, Black RE, Menon VP, Dinghra P, Caulfield LE, Dhingra U, Bagati A. Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. Pediatrics. 2001 Dec;108(6):1280-6. doi: 10.1542/peds.108.6.1280.
citation: Darlow BA, Austin NC. Selenium supplementation to prevent short-term morbidity in preterm neonates. Cochrane Database Syst Rev. 2003;2003(4):CD003312. doi: 10.1002/14651858.CD003312.
citation: van den Berg A, van Elburg RM, Westerbeek EA, Twisk JW, Fetter WP. Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. Am J Clin Nutr. 2005 Jun;81(6):1397-404. doi: 10.1093/ajcn/81.6.1397.
citation: Boelens PG, Houdijk AP, Fonk JC, Puyana JC, Haarman HJ, von Blomberg-van der Flier ME, van Leeuwen PA. Glutamine-enriched enteral nutrition increases in vitro interferon-gamma production but does not influence the in vivo specific antibody response to KLH after severe trauma. A prospective, double blind, randomized clinical study. Clin Nutr. 2004 Jun;23(3):391-400. doi: 10.1016/j.clnu.2003.09.002.
citation: Yalcin SS, Yurdakok K, Tezcan I, Oner L. Effect of glutamine supplementation on diarrhea, interleukin-8 and secretory immunoglobulin A in children with acute diarrhea. J Pediatr Gastroenterol Nutr. 2004 May;38(5):494-501. doi: 10.1097/00005176-200405000-00007.
citation: Leteurtre S, Martinot A, Duhamel A, Gauvin F, Grandbastien B, Nam TV, Proulx F, Lacroix J, Leclerc F. Development of a pediatric multiple organ dysfunction score: use of two strategies. Med Decis Making. 1999 Oct-Dec;19(4):399-410. doi: 10.1177/0272989X9901900408.
citation: Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, Lacroix J, Leclerc F. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet. 2003 Jul 19;362(9379):192-7. doi: 10.1016/S0140-6736(03)13908-6. Erratum In: Lancet. 2006 Mar 18;367(9514):902. Lancet. 2006 Mar 18;367(9514):897; author reply 900-2. doi: 10.1016/S0140-6736(06)68371-2.
citation: Doughty LA, Kaplan SS, Carcillo JA. Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure. Crit Care Med. 1996 Jul;24(7):1137-43. doi: 10.1097/00003246-199607000-00012.
citation: Pollack MM, Patel KM, Ruttimann UE. The Pediatric Risk of Mortality III--Acute Physiology Score (PRISM III-APS): a method of assessing physiologic instability for pediatric intensive care unit patients. J Pediatr. 1997 Oct;131(4):575-81. doi: 10.1016/s0022-3476(97)70065-9.
citation: Slota M, Green M, Farley A, Janosky J, Carcillo J. The role of gown and glove isolation and strict handwashing in the reduction of nosocomial infection in children with solid organ transplantation. Crit Care Med. 2001 Feb;29(2):405-12. doi: 10.1097/00003246-200102000-00034.
citation: Leclerc F, Leteurtre S, Duhamel A, Grandbastien B, Proulx F, Martinot A, Gauvin F, Hubert P, Lacroix J. Cumulative influence of organ dysfunctions and septic state on mortality of critically ill children. Am J Respir Crit Care Med. 2005 Feb 15;171(4):348-53. doi: 10.1164/rccm.200405-630OC. Epub 2004 Oct 29.
citation: Klein BS, Perloff WH, Maki DG. Reduction of nosocomial infection during pediatric intensive care by protective isolation. N Engl J Med. 1989 Jun 29;320(26):1714-21. doi: 10.1056/NEJM198906293202603.
citation: Carcillo J, Holubkov R, Dean JM, Berger J, Meert KL, Anand KJ, Zimmerman J, Newth CJ, Harrison R, Willson DF, Nicholson C; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Rationale and design of the pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial. JPEN J Parenter Enteral Nutr. 2009 Jul-Aug;33(4):368-74. doi: 10.1177/0148607108327392. Epub 2009 Apr 14.
citation: Carcillo JA, Dean JM, Holubkov R, Berger J, Meert KL, Anand KJ, Zimmerman J, Newth CJ, Harrison R, Burr J, Willson DF, Nicholson C; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN). The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial. Pediatr Crit Care Med. 2012 Mar;13(2):165-73. doi: 10.1097/PCC.0b013e31823896ae.