Risk and the efficacy of antiinflammatory agents: Retrospective and confirmatory studies of sepsis

American Journal of Respiratory and Critical Care Medicine

Volumn 166, Issue 9, 2002, Pages 1197-1205

  Eichacker, Peter Q ^a   Parent, Chantal ^a   Kalil, Andre ^a   Esposito, Claire ^a   Cui, Xizhong ^a   Banks, Steven M ^a   Gerstenberger, Eric P ^a   Fitz, Yvonne ^a   Danner, Robert L ^a   Natanson, Charles ^a  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

Author keywords

Antiinflammatory therapies; Metaregression analysis; Preclinical and clinical trials; Septic shock

Indexed keywords

ANTIINFLAMMATORY AGENT; BAYX 1351; BRADYKININ ANTAGONIST; CPO 127; GINKGOLIDE B; IBUPROFEN; INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; MAK 195F; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; TUMOR NECROSIS FACTOR ANTIBODY; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; DISEASE ASSOCIATION; DRUG EFFICACY; INFLAMMATION; MORTALITY; NONHUMAN; PRIORITY JOURNAL; RAT; RISK FACTOR; SEPSIS; SEPTIC SHOCK; SURVIVAL; TREATMENT OUTCOME; TREATMENT PLANNING;

EID: 0036840629     PISSN: 1073449X     EISSN: None     Source Type: Journal    
DOI: 10.1164/rccm.200204-302OC     Document Type: Article

References (87)

1. Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985;229:869-871.
2. Suitters AJ, Foulkes R, Opal SM, Palardy JE, Emtage JS, Rolfe M, Stephens S, Morgan A, Holt AR, Chaplin LC, et al. Differential effect of isotype on efficacy of anti-tumor necrosis factor alpha chimeric antibodies in experimental septic shock. J Exp Med 1994;179:849-856.
3. Bagby GJ, Plessala KJ, Wilson LA, Thompson JJ, Nelson S. Divergent efficacy of antibody to tumor necrosis factor-alpha in intravascular and peritonitis models of sepsis. J Infect Dis 1991;163:83-88.
4. Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988;81:1925-1937.
5. Fiedler VB, Loof I, Sander E, Voehringer V, Galanos C, Fournel MA. Monoclonal antibody to tumor necrosis factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab Clin Med 1992;120:574-588.
6. Opal SM, Cross AS, Sadoff JC, Collins HH, Kelly NM, Victor GH, Palardy JE, Bodmer WM. Efficacy of antilipopolysaccharide and antitumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis. J Clin Invest 1991;88:885-890.
7. Stack AM, Saladino RA, Thompson C, Sattler F, Weiner DL, Parsonnet J, Nariuchi H, Siber GR, Fleisher GR. Failure of prophylactic and therapeutic use of a murine anti-tumor necrosis factor monoclonal antibody in Escherichia coli sepsis in the rabbit. Crit Care Med 1995;23:1512-1518.
8. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662-664.
9. Cross AS, Opal SM, Palardy JE, Bodmer MW, Sadoff JC. The efficacy of combination immunotherapy in experimental Pseudomonas sepsis. J Infect Dis 1993;167:112-118.
10. Opal SM, Cross AS, Kelly NM, Sadoff JC, Bodmer MW, Palardy JE, Victor GH. Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa. J Infect Dis 1990;161:1148-1152.
11. Hinshaw LB, Emerson TE Jr, Taylor FB Jr, Chang AC, Duerr M, Peer GT, Flournoy DJ, White GL, Kosanke SD, Murray CK, et al. Lethal Staphylococcus aureus-induced shock in primates: Prevention of death with anti-TNF antibody. J Trauma 1992;33:568-573.
12. Hinshaw LB, Tekamp-Olson P, Chang AC, Lee PA, Taylor FB Jr, Murray CK, Peer GT, Emerson TE Jr, Passey RB, Kuo GC. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock 1990;30:279-292.
13. Jesmok G, Lindsey C, Duerr M, Fournel M, Emerson T Jr. Efficacy of monoclonal antibody against human recombinant tumor necrosis factor in E. coli-challenged swine. Am J Pathol 1992;141:1197-1207.
14. Silva AT, Bayston KF, Cohen J. Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative shock. J Infect Dis 1990;162:421-427.
15. Eskandari MK, Bolgos G, Miller C, Nguyen DT, DeForge LE, Remick DG. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J Immunol 1992;148:2724-2730.
16. Jin H, Yang R, Marsters SA, Bunting SA, Wurm FM, Chamow SM, Ashkenazi A. Protection against rat endotoxic shock by p55 tumor necrosis factor (TNF) receptor immunoadhesion: Comparison with anti-TNF monoclonal antibody. J Infect Dis 1994;170:1323-1326.
17. Echtenacher B, Falk W, Mannel DN, Krammer PH. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 1990;145:3762-3766.
18. Mastroeni P, Arena A, Costa GB, Liberto MC, Bonina L, Hormaeche CE. Serum TNF alpha in mouse typhoid and enhancement of a Salmonella infection by anti-TNF alpha antibodies. Microb Pathog 1991;11:33-38.
19. Ashkenazi A, Marsters SA, Capon DJ, Chamow SM, Figari IS, Pennica D, Goeddel DV, Palladino MA, Smith DH. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesion. Proc Natl Acad Sci USA 1991;88:10535-10539.
20. Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA 1992;89:4845-4849.
21. Lesslauer W, Tabuchi H, Gentz R, Brockhaus M, Schlaeger EJ, Grau G, Piguet PF, Pointaire P, Vassalli P, Loetscher H. Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. Eur J Immunol 1991;21:2883-2886.
22. Russell DA, Tucker KK, Chinookoswong N, Thompson RC, Kohno T. Combined inhibition of interleukin-1 and tumor necrosis factor in rodent endotoxemia: Improved survival and organ function. J Infect Dis 1995;171:1528-1538.
23. Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993;151:1548-1561.
24. Evans TJ, Moyes D, Carpenter A, Martin R, Loetscher H, Lesslauer W, Cohen J. Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram-negative sepsis. J Exp Med 1994;180:2173-2179.
25. Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 1990;348:550-552.
26. Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J 1991;5:338-343.
27. Fischer E, Marano MA, Van Zee KJ, Rock CS, Hawes AS, Thompson WA, DeForge L, Kenney JS, Remick DG, Bloedow DC, et al. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 1992;89:1551-1557.
28. Myers AK, Robey JW, Price RM. Relationships between tumour necrosis factor, eicosanoids and platelet-activating factor as mediators of endotoxin-induced shock in mice. Br J Pharmacol 1990;99:499-502.
29. Chang SW, Feddersen CO, Henson PM, Voelkel NF. Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. J Clin Invest 1987;79:1498-1509.
30. Etienne A, Hecquet F, Guilmard C, Soulard C, Braquet P. Inhibition of rat endotoxin-induced lethality by BN 52021 and BN 52063, compounds with PAF antagonistic effect and protease-inhibitory activity. Int J Tissue React 1987;9:19-26.
31. Rabinovici R, Yue TL, Farhat M, Smith EF III, Esser KM, Slivjak M, Feuerstein G. Platelet activating factor (PAF) and tumor necrosis factor-alpha (TNF alpha) interactions in endotoxemic shock: Studies with BN 50739, a novel PAF antagonist. J Pharmacol Exp Ther 1990;255:256-263.
32. Feuerstein G, Leader P, Siren AL, Braquet P. Protective effect of a PAF-acether antagonist, BN 52021, in trichothecene toxicosis. Toxicol Lett 1987;38:271-274.
33. Whalley ET, Solomon JA, Modafferi DM, Bonham KA, Cheronis JC. CP-0127, a novel potent bradykinin antagonist, increases survival in rat and rabbit models of endotoxin shock. Agents Actions Suppl 1992;38:413-420.
34. Fletcher JR, Ramwell PW. Indomethacin improves survival after endotoxin in baboons. Adv Prostaglandin Thromboxane Res 1980;7:821-828.
35. Parratt JR, Sturgess RM. E. coli endotoxin shock in the cat: Treatment with indomethacin. Br J Pharmacol 1975;53:485-488.
36. Wise WC, Cook JA, Eller T, Halushka PV. Ibuprofen improves survival from endotoxic shock in the rat. J Pharmacol Exp Ther 1980;215:160-164.
37. Jacobs ER, Soulsby ME, Bone RC, Wilson FJ Jr, Hiller FC. Ibuprofen in canine endotoxin shock. J Clin Invest 1982;70:536-541.
38. Fletcher JR, Ramwell PW. Modification, by aspirin and indomethacin, of the haemodynamic and prostaglandin releasing effects of E. coli endotoxin in the dog. Br J Pharmacol 1977;61:175-181.
39. Kay CA. Reducing mortality to patients and suppliers. Paper presented at: Cambridge Health Institute's Designing Better Drugs and Clinical Trials for Sepsis/SIRS; 1996; Washington, DC.
40. Dhainaut JF, Vincent JL, Richard C, Lejeune P, Martin C, Fierobe L, Stephens S, Ney UM, Sopwith M. CDP571, a humanized antibody to human tumor necrosis factor-alpha: Safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock: CPD571 Sepsis Study Group. Crit Care Med 1995;23:1461-1469.
41. Fisher CJ Jr, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RM, Panacek EA, Vincent JL, et al. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis: The CB0006 Sepsis Syndrome Study Group. Crit Care Med 1993;21:318-327.
42. Reinhart K, Wiegand-Lohnert C, Grimminger F, Kaul M, Withington S, Treacher D, Eckart J, Willatts S, Bonza C, Krausch D, et al. Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: A multicenter, randomized, placebo-controlled, dose-ranging study. Crit Care Med 1996;24:733-742.
43. Cohen J, Carlet J. INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis: International Sepsis Trial Study Group. Crit Care Med 1996;24:1431-1440.
44. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R, 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: TNF-alpha MAb Sepsis Study Group. JAMA 1995;273:934-941.
45. Clark MA, Plank LD, Connolly AB, Streat SJ, Hill AA, Gupta R, Monk DN, Shenkin A, Hill GL. Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis: A randomized, clinical trial. Crit Care Med 1998;26:1650-1659.
46. Reinhart K, Menges T, Gardlund B, Harm Zwaveling J, Smithes M, Vincent JL, Tellado JM, Salgado-Remigio A, Zimlichman R, Withington S, et al. Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomabin hyperinflammatory response during sepsis: The RAMSES Study. Crit Care Med 2001;29:765-769.
47. Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, Dal Nogare A, Nasraway S, Berman S, Cooney R, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock: NORASEPT II Study Group. Lancet 1998;351:929-933.
48. Fisher CJ Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein: The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334:1697-1702.
49. Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, Kudsk K, Bruining HA, Otto C, Tobin E, et al. p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: A randomized controlled multicenter trial: Ro 45-2081 Study Group. JAMA 1997;277:1531-1538.
50. Abraham E, Laterre P-F, Garbino J, Pingleton S, Butler T, Dugernier T, Margolis B, Kudsk K, Zimmerli W, Anderson P, 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;39:503-510.
51. Fisher CJ Jr, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open-label, placebo-controlled multicenter trial: The IL-1RA Sepsis Syndrome Study Group. Crit Care Med 1994;22:12-21.
52. Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial: The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997;25:1115-1124.
53. Fisher CJ Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL, 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: Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994;271:1836-1843.
54. Dhainaut JF, Tenaillon A, Le Tulzo Y, Schlemmer B, Solet JP, Wolff M, Holzapfel L, Zeni F, Dreyfuss D, Mira JP, et al. Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: A randomized, double-blind, placebo-controlled, multicenter clinical trial: BN 52021 Sepsis Study Group. Crit Care Med 1994;22:1720-1728.
55. Dhainaut JF, Tenaillon A, Hemmer M, Damas P, Le Tulzo Y, Radermacher P, Schaller MD, Sollet JP, Wolff M, Holzapfel L, et al. Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial: BN 52021 Sepsis Investigator Group. Crit Care Med 1998;26:1963-1971.
56. Bernard GR, Reines HD, Halushka PV, Higgins SB, Metz CA, Swindell BB, Wright PE, Watts FL, Vrbanac JJ. Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome: Effects of cyclooxygenase inhibition. Am Rev Respir Dis 1991;144:1095-1101.
57. Haupt MT, Jastremski MS, Clemmer TP, Metz CA, Goris GB. Effect of ibuprofen in patients with severe sepsis: A randomized, double-blind, multicenter study: The Ibuprofen Study Group. Crit Care Med 1991;19:1339-1347.
58. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis: The Ibuprofen in Sepsis Study Group. N Engl J Med 1995;336:912-918.
59. Rodell TC, Scharschmidt LA, Knaus WA. CP-0127 SIRS and Sepsis Study Group: Results of a multi-center randomized, placebo-controlled trial of CP-0127, a novel bradykinin antagonist, in patients with SIRS and sepsis. Shock 1995;3:60.
60. Fein AM, Bernard GR, Criner GJ, Fletcher EC, Good JT Jr, Knaus WA, Levy H, Matuschak GM, Shaines HM, Taylor RW, 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. CP-0127 SIRS and Sepsis Study Group. JAMA 1997;277:482-487.
61. Stephenson J. Reflecting and regrouping after failed trials, sepsis researchers forge on. JAMA 1996;275:823-824.
62. Piper RD, Cook DJ, Bone RC, Sibbald WJ. Introducing critical appraisal to studies of animal models investigating novel therapies in sepsis. Crit Care Med 1996;24:2059-2070.
63. Heumann D, Glauser MP. Anticytokine strategies for the treatment of septic shock: Relevance of animal models. Curr Top Microbiol Immunol 1996;216:299-311.
64. From the bench to the bedside: The future of sepsis research: Executive summary of an American College of Chest Physicians, National Institute of Allergy and Infectious Disease, and National Heart, Lung, and Blood Institute Workshop. Chest 1997;111:744-753.
65. Opal SM, Cross AS. Clinical trials for severe sepsis: Past failures and future hopes. Infect Dis Clin North Am 1999;13:285-297.
66. Knaus WA, Harrell FE, LaBrecque JF, Wagner DP, Pribble JP, Draper EA, Fisher CJ Jr, Soll L. Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis: The rhIL-1ra Phase III Sepsis Syndrome Study Group. Crit Care Med 1996;24:46-56.
67. Schmid CH, Lau J, McIntosh MW, Cappelleri JC. An empirical study of the effect of the control rates a predictor of treatment efficacy in meta-analysis of clinical trials. Stat Med 1998;17:1923-1942.
68. Boissel JP, Collet JP, Lievre M, Girard P. An effect model for the assessment of drug benefit: Example of antiarrhythmic drugs in postmyocardial infarction patients. J Cardiovasc Pharmacol 1993;22:356-363.
69. Antman EM, Seelig MS, Fleischmann K, Lau J, Kuntz K, Berkey CS, McIntosh WM. Magnesium in acute myocardial infarction: Scientific, statistical, and economic rationale for its use. Cardiovasc Drugs Ther 1996;10:297-301.
70. Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: The importance of considering initial level of risk. BMJ 1993;306:1367-1373.
71. Brand R, Kragt H. Importance of trends in the interpretation of an overall odds ratio in the meta-analysis of clinical trials. Stat Med 1992;11:2077-2082.
72. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment. Crit Care Med 1997;25:1095-1100.
73. Cox DR, Snell EJ. Analysis of Binary Data. London: New York: Chapman and Hall, CRC Press; 1989.
74. Breslow NE, Day NE. Statistical Methods in Cancer Research, Volume II: The Design and Analysis of Cohort Studies. New York: Oxford University Press; 1994.
75. Yaish P, Gazit A, Gilon C, Levitzki A. Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 1988;242:933-935.
76. Glaser KB, Asmis R, Dennis EA. Bacterial lipopolysaccharide priming of P388D1 macrophage-like cells for enhanced arachidonic acid metabolism. Platelet-activating factor receptor activation and regulation of phospholipase A2. J Biol Chem 1990;265:8658-8664.
77. Dong Z, O'Brian CA, Fidler IJ. Activation of tumoricidal properties in macrophages by lipopolysaccharide requires protein-tyrosine kinase activity. J Leukoc Biol 1993;53:53-60.
78. Guy GR, Chua SP, Wong NS, Ng SB, Tan YH. Interleukin 1 and tumor necrosis factor activate common multiple protein kinases in human fibroblasts. J Biol Chem 1991;266:14343-14352.
79. Novogrodsky A, Vanichkin A, Patya M, Gazit A, Osherov N, Levitzki A. Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors. Science 1994;264:1319-1322.
80. Vanichkin A, Patya M, Gazit A, Levitzki A, Novogrodsky A. Late administration of a lipophilic tyrosine kinase inhibitor prevents lipopolysaccharide and Escherichia coli-induced lethal toxicity. J Infect Dis 1996;173:927-933.
81. Sevransky JE, Shaked G, Novogrodsky A, Levitzki A, Gazit A, Hoffman A, Elin RJ, Quezado ZM, Freeman BD, Eichacker PQ, et al. Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. J Clin Invest 1997;99:1966-1973.
82. Natanson C, Danner RL, Reilly JM, Doerfler ML, Hoffman WD, Akin GL, Hosseini JM, Banks SM, Elin RJ, MacVittie TJ, et al. Antibiotics versus cardiovascular support in a canine model of human septic shock. Am J Physiol 1990;259:H1440-H1447.
83. Freeman BD, Correa R, Karzai W, Natanson C, Patterson M, Banks S, Fitz Y, Danner RL, Wilson L, Eichacker PQ. Controlled trials of rGCSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats. J Appl Physiol 1996;80:2066-2076.
84. Hedges LV, Olkin I. Statistical Methods for Meta-analysis. Orlando: Academic Press; 1985.
85. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
86. Taylor FB, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli in the baboon. J Clin Invest 1987;79:918-925.
87. Anonymous. FDA Briefing Document: Anti Infective Advisory Committee Drotrecogin Alfa (Activated) [Recombinant Human Activated Protein C (rhAPC)]. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_02_FDAbriefing.doc 1 A.D.