Management of sepsis

New England Journal of Medicine

Volumn 355, Issue 16, 2006, Pages 1699-1713

  Russell, James A ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; ANTIOXIDANT; ANTITHROMBIN III; ANTITOXIN; BRADYKININ ANTAGONIST; CORTICOSTEROID; DOBUTAMINE; ELASTASE INHIBITOR; ERYTHROPOIETIN; EXOTOXIN; FLUDROCORTISONE; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HYDROCORTISONE; HYDROLASE; IBUPROFEN; IMMUNOGLOBULIN G; INSULIN; INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; INTERLEUKIN 10; NITRIC OXIDE SYNTHASE INHIBITOR; PROCOAGULANT; PROTEIN S; TISSUE FACTOR PATHWAY INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; TOXIC SHOCK SYNDROME TOXIN 1; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; TUMOR NECROSIS FACTOR ALPHA RECEPTOR; UNINDEXED DRUG; VASOPRESSIN;

ADRENAL INSUFFICIENCY; ANEMIA; ANTICOAGULATION; APOPTOSIS; BLOOD TRANSFUSION; CLINICAL TRIAL; DIALYSIS; DISEASE CONTROL; DRUG EFFECT; HOSPITAL INFECTION; HUMAN; HYPERGLYCEMIA; IMMUNE RESPONSE; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATION; INNATE IMMUNITY; INTENSIVE CARE; KIDNEY DISEASE; LACTIC ACIDOSIS; LUNG VENTILATION; MORTALITY; NEUROMUSCULAR DISEASE; NUTRITIONAL SUPPORT; OXYGEN THERAPY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SEPSIS; SEPTIC SHOCK; WOUND HEALING IMPAIRMENT;

ADRENAL CORTEX HORMONES; ANEMIA; ANTI-BACTERIAL AGENTS; BLOOD COAGULATION FACTORS; HUMANS; HYPERGLYCEMIA; HYPOGLYCEMIC AGENTS; IMMUNE TOLERANCE; INSULIN; PROTEIN C; RENAL REPLACEMENT THERAPY; RESPIRATION, ARTIFICIAL; SEPSIS; VASOPRESSINS;

EID: 33750047495     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMra043632     Document Type: Review

References (110)

1. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-8.
2. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
3. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644-55.
4. Russell JA, Singer J, Bernard GR, et al. Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 2000;28:3405-11.
5. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
6. Annane D, Aegerter P, Jars-Guincestre MC, Guidet B. Current epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med 2003;168:165-72.
7. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.
8. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138-50.
9. Ziegler EJ, Fisher CJ Jr, Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991;324:429-36.
10. Modlin RL, Brightbill HD, Godowski PJ. The toll of innate immunity on microbial pathogens. N Engl J Med 1999;340:1834-5.
11. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997;3:678-81.
12. Lyman GH. Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: a review of the evidence. J Natl Compr Canc Netw 2005;3:557-71.
13. Abraham E, Laterre PF, Garbino J, et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med 2001;29:503-10.
14. Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome: a randomized, controlled, double-blind, multicenter clinical trial. JAMA 1995;273:934-41.
15. Fisher CJ Jr, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized, double-blind, placebo-controlled trial. JAMA 1994;271:1836-43.
16. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997;336:912-8.
17. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653-8.
18. Fein AM, Bernard GR, Criner GJ, et al. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127): results of a randomized, double-blind, placebo-controlled trial. JAMA 1997;277:482-7.
19. Opal S, Laterre PF, Abraham E, et al. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med 2004;32:332-41.
20. Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. Chest 1997;112:164-72.
21. Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 2004;32:21-30.
22. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992;101:816-23.
23. Warren BL, Eid A, Singer P, et al. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-78. [Erratum, JAMA 2002;287:192.]
24. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003;290:238-47.
25. Carraway MS, Welty-Wolf KE, Miller DL, et al. Blockade of tissue factor: treatment for organ injury in established sepsis. Am J Respir Crit Care Med 2003;167:1200-9.
26. Corwin HL, Gettinger A, Rodriguez RM, et al. Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial. Crit Care Med 1999;27:2346-50.
27. Hotchkiss RS, Chang KC, Swanson PE, et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 2000;1:496-501.
28. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71.
29. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002;96:576-82.
30. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-61.
31. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67.
32. Brown MA, Jones WK. NF-kappaB action in sepsis: the innate immune system and the heart. Front Biosci 2004;9:1201-17.
33. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787-93.
34. Esmon CT. Structure and functions of the endothelial cell protein C receptor. Crit Care Med 2004;32:Suppl 5:S298-S301.
35. Walker FJ, Sexton PW, Esmon CT. The inhibition of blood coagulation by activated protein C through the selective inactivation of activated factor V. Biochim Biophys Acta 1979;571:333-42.
36. Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood 1984;63:486-9.
37. van Hinsbergh VW, Bertina RM, van Wijngaarden A, van Tilburg NH, Emeis JJ, Haverkate F. Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium. Blood 1985;65:444-51.
38. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001;276:11199-203.
39. Grinnell BW, Hermann RB, Yan SB. Human protein C inhibits selectin-mediated cell adhesion: role of unique fucosylated oligosaccharide. Glycobiology 1994;4:221-5.
40. Murakami K, Okajima K, Uchiba M, et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997;272:L197-L202.
41. Creasey AA, Reinhart K. Tissue factor pathway inhibitor activity in severe sepsis. Crit Care Med 2001;29:Suppl 7:S126-S129.
42. Liaw PC, Esmon CT, Kahnamoui K, et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood 2004;104:3958-64.
43. Lawson CA, Yan SD, Yan SF, et al. Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation. J Clin Invest 1997;99:1729-38.
44. Meakins JL, Pietsch JB, Bubenick O, et al. Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg 1977;186:241-50.
45. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001;166:6952-63.
46. Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 2001;16:83-96.
47. Ertel W, Kremer JP, Kenney J, et al. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 1995;85:1341-7.
48. 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;181:176-80.
49. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999;27:1230-51.
50. 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;3:259-67.
51. Crouser ED, Julian MW, Weinstein DM, Fahy RJ, Bauer JA. Endotoxin-induced ileal mucosal injury and nitric oxide dysregulation are temporally dissociated. Am J Respir Crit Care Med 2000;161:1705-12.
52. Herbertson MJ, Werner HA, Walley KR. Nitric oxide synthase inhibition partially prevents decreased LV contractility during endotoxemia. Am J Physiol 1996;270:H1979-H1984.
53. Herbertson MJ, Werner HA, Goddard CM, et al. Anti-tumor necrosis factor-alpha prevents decreased ventricular contractility in endotoxemic pigs. Am J Respir Crit Care Med 1995;152:480-8.
54. Cain BS, Meldrum DR, Dinarello CA, et al. Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Crit Care Med 1999;27:1309-18.
55. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004;351:159-69.
56. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-73. [Errata, Crit Care Med 2004;32:1448, 2169-70.]
57. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000;118:146-55.
58. Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med 1998;244:379-86.
59. Kietzmann T, Roth U, Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 1999;94:4177-85.
60. Eisner MD, Thompson T, Hudson LD, et al. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164:231-6.
61. Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282:54-61.
62. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-36.
63. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:1471-7.
64. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA 2003;289:2983-91.
65. Segredo V, Caldwell JE, Matthay MA, Sharma ML, Gruenke LD, Miller RD. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992;327:524-8.
66. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992-April 2000, issued June 2000. Am J Infect Control 2000;28:429-48.
67. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003;115:529-35.
68. Vincent JL, Angus DC, Artigas A, et al. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003;31:834-40.
69. Ely EW, Laterre PF, Angus DC, et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003;31:12-9.
70. Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332-41.
71. Opal SM, Garber GE, LaRosa SP, et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis 2003;37:50-8.
72. Bernard GR, Margolis BD, Shanies HM, et al. Extended Evaluation of Recombinant Human Activated Protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004;125:2206-16.
73. Manns BJ, Lee H, Doig CJ, Johnson D, Donaldson C. An economic evaluation of activated protein C treatment for severe sepsis. N Engl J Med 2002;347:993-1000.
74. Angus DC, Linde-Zwirble WT, Clermont G, et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003;31:1-11.
75. Whiting JF, Kiberd B, Kalo Z, Keown P, Roels L, Kjerulf M. Cost-effectiveness of organ donation: evaluating investment into donor action and other donor initiatives. Am J Transplant 2004;4:569-73.
76. Weintraub WS. Economics of sirolimus-eluting stents: drug-eluting stents have really arrived. Circulation 2004;110:472-4.
77. Dhainaut JF, Yan SB, Margolis BD, et al. Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis. Thromb Haemost 2003;90:642-53.
78. Derhaschnig U, Reiter R, Knobl P, Baumgartner M, Keen P, Jilma B. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 2003;102:2093-8.
79. Riewald M, Petrovan RJ, Donner A, Ruf W. Activated protein C signals through the thrombin receptor PAR1 in endothelial cells. J Endotoxin Res 2003;9:317-21.
80. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-17. [Erratum, N Engl J Med 1999;340:1056.]
81. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998;18:555-9.
82. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984;311:1137-43.
83. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004;329:480.
84. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723-32.
85. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727-34.
86. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000;355:1064-9.
87. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003;31:141-5.
88. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629-38.
89. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280:159-65.
90. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-84.
91. Fisher CJ Jr, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. N Engl J Med 1996;334:1697-702.
92. Grinevich V, Knepper MA, Verbalis J, Reyes I, Aguilera G. Acute endotoxemia in rats induces down-regulation of V2 vasopressin receptors and aquaporin-2 content in the kidney medulla. Kidney Int 2004;65:54-62.
93. Tamaki T, Kiyomoto K, He H, et al. Vasodilation induced by vasopressin V2 receptor stimulation in afferent arterioles. Kidney Int 1996;49:722-9.
94. Okamura T, Ayajiki K, Fujioka H, Toda N. Mechanisms underlying arginine vasopressin-induced relaxation in monkey isolated coronary arteries. J Hypertens 1999;17:673-8.
95. Holmes CL, Walley KR, Chittock DR, Lehman T, Russell JA. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001;27:1416-21.
96. van Haren FM, Rozendaal FW, van der Hoeven JG. The effect of vasopressin on gastric perfusion in catecholamine-dependent patients in septic shock. Chest 2003;124:2256-60.
97. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001;15:44-54.
98. Ortiz A, Ziyadeh FN, Neilson EG. Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. J Investig Med 1997;45:50-6.
99. Mesotten D, Swinnen JV, Vanderhoydonc F, Wouters PJ, Van den Berghe G. Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy. J Clin Endocrinol Metab 2004;89:219-26.
100. Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001;86:3257-65.
101. Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest 2005;115:2277-86.
102. Vanhorebeek I, Langouche L, Van den Berghe G. Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness? Curr Opin Crit Care 2005;11:304-11.
103. Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, De Wolf-Peeters C, Van den Berghe G. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005;365:53-9.
104. Cole L, Bellomo R, Hart G, et al. A phase II randomized, controlled trial of continuous hemofiltration in sepsis. Crit Care Med 2002;30:100-6.
105. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet 2000;356:2139-43.
106. Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: a prospective, controlled clinical study. Ann Intern Med 1990;112:492-8.
107. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999;341:793-800.
108. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 2001;29:2264-70. [Erratum, Crit Care Med 2001;29:2387-8.]
109. Cook D, Guyatt G, Marshall J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med 1998;338:791-7.
110. Eichacker PQ, Parent C, Kalil A, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002;166:1197-205.