New insights into the pathogenesis and therapy of sepsis and septic shock

Current Clinical Topics in Infectious Diseases

Volumn , Issue 21, 2001, Pages 148-171

  Llewelyn, M ^a   Cohen, J ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; ANTIINFECTIVE AGENT; CYTOKINE; LIPOPOLYSACCHARIDE;

ANIMAL; BLOOD CLOTTING; DRUG ANTAGONISM; DRUG EFFECT; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HUMAN; METABOLISM; MICROBIOLOGY; MORTALITY; PATHOGENICITY; PHASE 3 CLINICAL TRIAL; REVIEW; SEPSIS; SEPTIC SHOCK;

ANIMALS; ANTI-BACTERIAL AGENTS; ANTICOAGULANTS; BLOOD COAGULATION; CLINICAL TRIALS, PHASE III; CYTOKINES; GRAM-NEGATIVE BACTERIA; GRAM-POSITIVE BACTERIA; HUMANS; LIPOPOLYSACCHARIDES; SEPSIS; SHOCK, SEPTIC;

EID: 0035233215     PISSN: 01953842     EISSN: None     Source Type: Book Series    
DOI: None     Document Type: Article

References (172)

1. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993;328:1471-1477.
2. Glauser MP, Heumann D, Baumgartner JD, Cohen J. Pathogenesis and potential strategies for prevention and treatment of septic shock: an update. Clin Infect Dis 1994;18:S205-S216.
3. Raetz CR, Ulevitch RJ, Wright SD, et al. Gram-negative endotoxin: an extraordinary lipid with profound effects on eukaryotic signal transduction. Faseb J 1991;5:2652-2660.
4. Rietschel ET, Brade H, Holst O, et al. Bacterial endotoxin: chemical constitution, biological recognition, host response, and immunological detoxification. Curr Topic Microbiol Immunol 1996;216:39-81.
5. Seydel U, Schromm AB, Blunck R, Brandenburg K. Chemical structure, molecular conformation, and bioactivity of endotoxins. Chem Immunol 2000;74:5-24.
6. Schromm AB, Brandenburg K, Loppnow H, et al. The charge of endotoxin molecules influences their conformation and IL-6-inducing capacity. J Immunol 1998;161:5464-5471.
7. Schromm AB, Brandenburg K, Loppnow H, et al. Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion. Eur J Biochem 2000;267:2008-2013.
8. Cohen J, Lynn WA. Microbiological considerations in sepsis. Sepsis 1998;2:101-106.
9. Kobayashi T, Tani T, Yokota T. Plasma levels of peptidoglycan detected with silkworm larvae plasma in septic patients (abstract 556). Shock 1997;7:139.
10. Heumann D, Barras C, Severin A, et al. Gram-positive cell walls stimulate synthesis of tumor necrosis factor alpha and interleukin-6 by human monocytes. Infect Immun 1994;62: 2715-2721.
11. Timmerman CP, Mattsson E, Martinez-Martinez L, et al. Induction of release of tumor necrosis factor from human monocytes by staphylococci and staphylococcal peptidoglycans. Infect Immun 1993;61:4167-4172.
12. Mattsson E, Verhage L, Rollof J, et al. Peptidoglycan and teichoic acid from Staphylococcus epidermidis stimulate human monocytes to release tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6. FEMS Immunol Med Microbiol 1993;7:281-287.
13. Lichtman SN, Bachmann S, Munoz SR, et al. Bacterial cell wall polymers (peptidoglycan-polysaccharide) cause reactivation of arthritis. Infect Immun 1993;61:4645-4653.
14. De Kimpe SJ, Kengatharan M, Thiemermann C, Vane JR. The cell wall components peptidoglycan and lipoteichoic acid from Staphylococcus aureus act in synergy to cause shock and multiple organ failure. Proc Natl Acad Sci USA 1995;92:10359-10363.
15. Majcherczyk PA, Langen H, Heumann D, et al. Digestion of Streptococcus pneumoniae cell walls with its major peptidoglycan hydrolase releases branched stem peptides carrying proin-flammatory activity. J Biol Chem 1999;274: 12537-12543.
16. Lavoie PM, Thibodeau J, Erard F, Sekaly RP. Understanding the mechanism of action of bacterial superantigens from a decade of research. Immunol Rev 1999;168:257-269.
17. de Azavedo JC, Foster TJ, Hartigan PJ, et al. Expression of the cloned toxic shock syndrome toxin 1 gene (tst) in vivo with a rabbit uterine model. Infect Immun 1985;50:304-309.
18. Sloane R, de Azavedo JC, Arbuthnott JP, et al. A toxic shock syndrome toxin mutant of Staphylococcus aureus isolated by allelic replacement lacks virulence in a rabbit uterine model. FEMS Microbiol Lett 1991;62:239-244.
19. Mascini EM, Jansze M, Schellekens JF, et al. Invasive group A streptococcal disease in the Netherlands: evidence for a protective role of anti-exotoxin A antibodies. J Infect Dis 2000; 181:631-638.
20. Sriskandan S, Moyes D, Cohen J. Detection of circulating bacterial superantigen and lymphotoxin-alpha in patients with streptococcal toxicshock syndrome. Lancet 1996;348:1315-1316.
21. Hurley JC. Concordance of endotoxemia with gram-negative bacteremia in patients with gram-negative sepsis: a meta-analysis. J Clin Microbiol 1994;32:2120-2127.
22. Stone RL, Schlievert PM. Evidence for the involvement of endotoxin in toxic shock syndrome. J Infect Dis 1987;155:682-689.
23. Le Roy D, Di Padova F, Tees R, et al. Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP) protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP or the presentation of LPS/LBP complexes to CD14. J Immunol 1999;162:7454-7460.
24. Wurfel MM, Wright SD. Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins. Prog Clin Biol Res 1995;392: 287-295.
25. Frey EA, Miller DS, Jahr TG, et al. Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med 1992;176: 1665-1671.
26. Wright SD, Ramos RA, Tobias PS, et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990;249:1431-1433.
27. Ingalls RR, Heine H, Lien E, et al. Lipopolysaccharide recognition, CD14, and lipopolysaccharide receptors. Infect Dis Clin North Am 1999;13:341-353, vii.
28. Hamann L, Schumann RR, Flad HD, et al. Binding of lipopolysaccharide (LPS) to CHO cells does not correlate with LPS-induccd NF-kappaB activation. Enr J Immunol 2000;30: 211-216.
29. Rock FL, Hardiman G, Timans JC, et al. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 1998;95:588-593.
30. Ulevitch RJ. Endotoxin opens the Tollgates to innate immunity. Nat Med 1999;5:144-145.
31. Modlin RL, Brightbill HD, Godowski PJ. The toll of innate immunity on microbial pathogens. N Engl J Med 1999;340:1834-1835.
32. Muzio M, Natoli G, Saccani S, et al. The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med 1998;187:2097-2101.
33. Kirschning CJ, Wesche H, Merrill Ayres T, Rothe M. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med 1998;188:2091-2097.
34. Yang RB, Mark MR, Gray A, et al. Tolllike receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 1998;395: 284-288.
35. Chow JC, Young DW, Golenbock DT, et al. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999;274:10689-10692.
36. Nomura F, Akashi S, Sakao Y, et al. Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression. J Immunol 2000;164:3476-3479.
37. Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749-3752.
38. Burns K, Martinon F, Esslinger C, et al. MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 1998;273: 12203-12209.
39. Kawai T, Adachi O, Ogawa T, et al. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999;11:115-122.
40. Shimazu R, Akashi S, Ogata H, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 1999;189:1777-1782.
41. Akashi S, Shimazu R, Ogata H, et al. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J Immunol 2000;164:3471-3475.
42. 41a Dziarski R, Wang Q, Miyake K, et al. MD-2 enables toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components. J Immunol 2001;166:1938-1944.
43. Schromm AB, Brandenburg K, Rietschel ET, et al. Lipopolysaccharide-binding protein mediates CD14-independent intercalation of lipopolysaccharide into phospholipid membranes. FEBS Letters 1996;399:267-271.
44. Detmers PA, Thieblemont N, Vasselon T, et al. Potential role of membrane internalization and vesicle fusion in adhesion of neutrophils in response to lipopolysaccharide and TNF. J Immunol 1996;157:5589-5596.
45. Joseph CK, Wright SD, Bornmann WG, et al. Bacterial lipopolysaccharide has structural similarity to ceramide and stimulates ceramide-activated protein kinase in myeloid cells. J Biol Chem 1994;269:17606-17610.
46. Knapp KM, English BK. Ceramide-mediated stimulation of inducible nitric oxide syntnase (iNOS) and tumor necrosis factor (TNF) accumulation in murine macrophages requires tyrosine kinase activity. J Leukoc Biol 2000;67: 735-741.
47. Lentschat A, El-Samalouti VT, Schletter J, et al. The internalization time course of a given lipopolysaccharide chemotype does not correspond to its activation kinetics in monocytes. Infect Immun 1999;67:2515-2521.
48. Wright SD, Jong MT. Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide. J Exp Med 1986;164:1876-1888.
49. Ingalls RR, Arnaout MA, Golenbock DT. Outside-in signaling by lipopolysaccharide through a tailless integrin. J Immunol 1997;159: 433-438.
50. Ingalls RR, Monks BG, Savedra R Jr, et al. CD11/CD18 and CD14 share a common lipid A signaling pathway. J Immunol 1998;161: 54B-5420.
51. 49a Perera PY, Mayadas TN, Takeuehi O, et al. CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol 2001;166:574-581.
52. Elshourbagy NA, Li X, Terrett J, et al. Molecular characterization of a human scavenger receptor, human MARCO. Eur J Biochem 2000;267:919-926.
53. Haworth R, Platt N, Keshav S, et al. The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock. J Exp Med 1997;186:1431-1439.
54. Weidemann B, Schletter J, Dziarski R, et al. Specific binding of soluble peptidoglycan and muramyldipeptide to CD14 on human monocytes. Infect Immun 1997;65:858-864.
55. Gupta D, Kirkland TN, Viriyakosol S, Dziarski R. CD14 is a cell-activating receptor for bacterial peptidoglycan. J Biol Chem 1996; 271:23310-23316.
56. Cleveland MG, Gorham JD, Murphy TL, et al. Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway. Infect Immun 1996;64:1906-1912.
57. Thomas CA, Li Y, Kodama T, et al. Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis. J Exp Med 2000;191:147-156.
58. Yoshimura A, Lien E, Ingalls RR, et al. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J Immunol 1999;163:I-5.
59. Schwandner R, Dziarski R, Wesche H, et al. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 1999;274:17406-17409.
60. Takeuchi O, Hoshino K, Kawai T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999;11:443-451.
61. Haziot A, Hijiya N, Schultz K, et al. CD14 plays no major role in shock induced by Staphylococcus aureus but down-regulates TNF-alpha production. J Immunol 1999;162:4801-4805.
62. Sriskandan S, Cohen J. Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis. Infect Dis Clin N Am 1999;13: 397-412.
63. Faure E, Equils O, Sieling PA, et al. Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 2000;275:11058-11063.
64. Opal SM, Cohen J. Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med 1999; 27:1608-1616.
65. Bernhagen J, Calandra T, Mitchell RA, et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 1993;365: 756-759.
66. Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 1994; 179:1595-1902.
67. Calandra T, Spiegel LA, Metz CN, Bucala R. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc Natl Acad Sci USA 1998;95:11383-11388.
68. Bernhagen J, Mitchell RA, Calandra T, et al. Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry 1994;33:14144-14155.
69. Calandra T, Bernhagen J, Metz CN, et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995;377:68-71.
70. Bozza M, Satoskar AR, Lin G, et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 1999;189:341-346.
71. Calandra T, Echtenacher B, Roy DL, et al. . Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000;6:164-170.
72. Bustin M, Reeves R. High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol 1996;54:35-100.
73. Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999;285:248-251.
74. O'Sullivan MG, Chilton FH, Huggins EM Jr, McCall CE. Lipopolysaccharide priming of alveolar macrophages for enhanced synthesis of prostanoids involves induction of a novel prostaglandin H synthase. J Biol Chem 1992; 267:14547-14550.
75. 2 production in resting macrophages. Biochem Biophys Res Commun 1986;136:94-101.
76. Camussi G, Bussolino F, Salvidio G, Baglioni C. Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor. J Exp Med 1987;166:1390-1404.
77. Jones DA, Carlton DP, McIntyre TM, et al. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 1993;268:9049-9054.
78. Lefer AM. Significance of lipid mediators in shock states. Circulatory Shock 1989;27:3-12.
79. Conary JT, Parker RE, Christman BW, et al. Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene. J Clin Invest 1994;93:1834-1840.
80. Quinn JV, Slotman GJ. Platelet-activating factor and arachidonic acid metabolites mediate tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during bacteremic shock. Crit Care Med 1999;27:2485-2494.
81. van der Poll T, De Jonge E, Levi M, van Deventer SJ. Pathogenesis of DIC in sepsis. Sepsis 1999;3:103-110.
82. Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:27S-33S.
83. van Gorp EC, Suharti C, ten Cate H, et al. Review: infectious diseases and coagulation disorders. J Infect Dis 1999;180:176-186.
84. Boldt J, Papsdorf M, Rothe A, et al. Changes of the liemostatic network in critically ill patients - is there a difference between sepsis, trauma, and neurosurgery patients? Crit Care Med 2000;28:445-450.
85. Mavrommatis AC, Theodoridis T, Orfanidou A, et al. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 2000;28:451-457.
86. Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med 1974;140:797-811.
87. ten Cate H, Brandjes DP, Wolters HJ, van Deventer SJ. Disseminated intravascular coagulation: pathophysiology, diagnosis, and treatment. New Horizons 1993;1:312-323.
88. Citarella F, Misiti S, Felici A, et al. The 5′ sequence of human factor XII gene contains transcription regulatory elements typical of liver specific, estrogen-modulated genes. Biochimica Biophysica Acta 1993;1172:197-199.
89. Pixley RA, De La Cadena R, Page JD, et al. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest 1993; 91:61-68.
90. Erlich J, Feams C, Mathison J, et al. Lipopolysaccharide induction of tissue factor expression in rabbits. Infect Immun 1999;67: 2540-25-46.
91. Engelmann B, Zieseniss S, Brand K, et al. Tissue factor expression of human monocytes is suppressed by lysophosphatidylcholine. Arterioscler Throm Vasc Biol 1999;19:47-53.
92. Taylor FB Jr, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987;79:918-925.
93. Taylor F, Chang A, Ferrell G, et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood 1991;78:357-363.
94. Grey S, Hau H, Salem HH, Hancock WW. Selective effects of protein C on activation of human monocytes by lipopolysaccharide, interferon-gamma, or PMA: modulation of effects on CD11b and CD14 but not CD25 or CD54 induction. Transplant Proc 1993;25: 2913-2914.
95. Wilson RF, Mammen EF, Tyburski JG, et al. Antithrombin levels related to infections and outcome. J Trauma 1996;40:384-387.
96. Opal SM, Thijs LG. New potential therapeutic modalities: antithrombin III. Sepsis 1999; 3:153-160.
97. Lindahl AK, Jacobsen PB, Sandset PM, Abildgaard U. Tissue factor pathway inhibitor with high anticoagulant activity is increased in post-heparin plasma and in plasma from cancer patients. Blood Coagul Fibrinolysis 1991;2: 713-721.
98. Sevinsky JR, Rao LV, Ruf W. Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue factor-dependent coagulation pathway. J Cell Biol 1996;133:293-304.
99. Sandset PM, Warn-Cramer BJ, Maki SL, Rapaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. Blood 1991;78:1496-1502.
100. Creasey AA, Chang AC, Feigen L, et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993;91:2850-2856.
101. Lynn WA, Cohen J. Adjunctive therapy for septic shock: a review of experimental approaches. Clin Infect Dis 1995;20:143-158.
102. Vincent JL, Cohen J. Another antiendotoxin strategy to be added to the list. Crit Care Med 1997;25:1949-1950.
103. Appelmelk BJ, Cohen J. The protective role of antibodies to the lipopolysaccharide core region. In: Morrison DC, Ryan JL, eds. Bacterial endotoxic lipopolysaccharides, vol. II. New York: CRC Press, 1992:411-428.
104. Cross AS, Opal SM. Therapeutic intervention in sepsis with antibody to endotoxin: is there a future? J Endotoxin Res 1994;1:57-69.
105. Greisman SE, Johnston CA. Evidence against the hypothesis that antibodies to the inner core of lipopolysaccharides in antisera raised by immunization with enterobacterial deep-rough mutants confer broad spectrum protection during Gram-negative bacterial sepsis. J Endotoxin Res 1997;4:123-153.
106. Callay P, Heumann D, Le Roy D, et al. Lipopolysaccharide-binding protein as a major plasma protein responsible for endotoxemic shock. Proc Natl Acad Sci USA 1993;90:9935-9938.
107. Jack RS, Fan X, Bernheiden M, et al. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 1997;389:742-745.
108. Lamping N, Dettmer R, Schroder NW, et al. LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest 1998;101:2065-2071.
109. Leturcq DJ, Moriarty AM, Talbott G, et al. Antibodies against CD14 protect primates from endotoxin-induced shock. J Clin Invest 1996;98: 1533-1538.
110. Pugin J, Heumann ID, Tomasz A, et al. CD14 is a pattern recognition receptor. Immunity 1994;1:509-516.
111. Wurfel MM, Hailman E, Wright SD. Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein. J Exp Med 1995;181:1743-1754.
112. Yu B, Hailman E, Wright SD. Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. J Clin Invest 1997;99:315-324.
113. Netea MG, Demacker PN, Kullbcrg BJ, et al. Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections. J Clin Invest 1996;97:1366-1372.
114. Hubsch AP, Casas AT, Doran JE. Protective effects of reconstituted high-density lipoprotein in rabbit gram-negative bacteremia models. J Lab Clin Med 1995;126:548-558.
115. Parker TS, Levine DM, Chang JC, et al. Reconstituted high-density lipoprotein neutralizes gram-negative bacterial lipopolysaccharides in human whole blood. Infect Immun 1995;63: 253-258.
116. Pajkrt D, Doran JE, Koster F, et al. Anti-inflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J Exp Med 1996;184:1601-1608.
117. Demetriades D, Smith JS, Jacobson LE, et al. Bactericidal/permeability-increasing protein (rBPI21) in patients with hemorrhage due to trauma: results of a multicenter Phase II clinical trial. rBPI21 Acute Hemorrhagic Trauma Study Group. J Trauma 1999;46:667-676.
118. Giroir BP, Quint PA, Barton P, et al. Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis. Lancet 1997;350:1439-1443.
119. 21) as adjunctive treatment for children with severe meningococcal sepsis: a randomized trial. Lancet 2000;356:961-967.
120. Bucklin SE, Lake P, Logdberg L, Morrison DC. Therapeutic efficacy of a polymyxin B-dextran 70 conjugate in experimental model of endotoxemia. Antimicrob Agents Chemother 1995;39:1462-1466.
121. Camerota AJ, Logdberg L, Lake P, et al. Delayed therapy with a polymyxin B-dextran conjugate (PMX-622) improves survival in rabbits with Gram-negative peritonitis. J Endotoxin Res 1997;4:285-292.
122. Doig GS, Martin CM, Sibbald WJ. Polymyxin-dextran antiendotoxin pretreatment in an ovine model of norinotensive sepsis. Crit Care Med 1997;25:1956-1961.
123. Cohen J, Aslam M, Pusey CD, Ryan CJ. Protection from endotoxemia: a rat model of plasmapheresis and specific adsorption with polymyxin B. J Infect Dis 1987;155:690-695.
124. Aoki H, Kodama M, Tani T, Hanasawa K. Treatment of sepsis by extracorporeal elimination of endotoxin using polympin B-immobilized fiber. Am J Surg 1994;167:412-H7.
125. Imaizumi H, Voshida M, Satoh M, et al. Effects of endotoxin removal by direct hemoperfusion using polymyxin B-immobilized fibre (PMX-F) in patients with severe hyperdynamic septic shock treated with norepinephrine (abstract 198). Crit Care Med 1996;24.
126. Kodama M, Tani T, Hanasawa K, et al. Treatment of sepsis by plasma endotoxin removal: hemoperfusion using a polymyxin B immoblized column. J Endotoxin Res 1997;4: 293-300.
127. Nakamura T, Ebihara I, Shimada N, et al. Effects of hemoperfusion with polymyxin B-immobilized fibre on serum neopterin and soluble interleukin-2 receptor concentrations in patients with septic shock. J Infect 1998;37: 241-247.
128. Wang Y, Lin Y, Sarker KP, et al. Polymyxin B binds to anandamide and inhibits its cytotoxic effect. FEBS Lett 2000;470:151-15;.
129. Wyckoff TJO, Raetz CRH, Jackman JE. Antibacterial and antiinflammatory agents that target endotoxin. Trends Microbiol 1998;6:154-159.
130. Christ WJ, Asano O, Robidoux AL, et al. E5531, a pure endotoxin antagonist of high potency. Science 1995;268:SO-83.
131. Kengatharan KM, De Kimpe S, Robson C, et al. Mechanism of gram-positive shock: identification of peptidoglycan and lipoteichoic acid moieties essential in the induction of nitric oxide synthase, shock, and multiple organ failure. J Exp Med 1998;188:305-315.
132. Ulrich RG, Bavari S, Olson MA. Bacterial superantigens in human disease: structure, function and diversity. Trends Microbiol 1995;3: 463-468.
133. Bannan J, Visvanathan K, Zabriskie JB. Structure and function of streptococcal and staphylococcal superantigens in septic shock. Infect Dis Clin N Am 1999;13:387-396, ix.
134. Arad G, Levy R, Hillman D, Kaempfer R. Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation. Nat Med 2000;6:414-421.
135. 131a Visvanathan K, Charles A, Bannan J, et al. Inhibition of bacterial superantigens by peptides and antibodies. Infect Immun 2001;69:875-884.
136. Calandra T, Sehellekens JF, Verhoef J, Glauser MP. A comparative study of standard (IVIG) versus E. coli J5 hyperimmune intravenous gamma globulins (j5-IVIG) in the treatment of gram negative shock (abstract 128). 4th ICHS: Ronneby, 1986.
137. Just HM, Metzger M, Vogel W, Pelka RB. Effect of adjuvant immunoglobulin therapy on infections in patients in an surgical intensive care unit. Results of a randomized controlled study. Klin Wochenschr 1986;64:245-256.
138. Dominioni L, Dionigi R, Zanello M, et al. Effects of high-dose IgG on survival of surgical patients with sepsis scores of 20 or greater. Arch Surg 1991;126:236-240.
139. Schcdel I, Dreikhausen U, Nentwig B, et al. Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit Care Med 1991; 19:1104-1113.
140. Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection. The Intravenous Immunoglobulin Collaborative Study Group. N Engl J Med 1992;327:234-240.
141. Werdan K. Immunoglobulins in sepsis. Sepsis 2000;3:239-246.
142. Norrby-Teglund A, Kaul R, Low DE, et al. Evidence for the presence of streptococcal-superaǹtigen-neutralizing antibodies in normal polyspecific immunoglobulin G. Infect Immun 1996;64:5395-5398.
143. Kaul R, McGecr A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome - a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis 1999;28: 800-807.
144. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23:1430-1439.
145. Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038-1045.
146. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:64 5-650.
147. 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: 723-732.
148. 143a Annane D. Effects of the combination of hydrocortisone-fludro-cortisone on mortality in septic shock. Crit Care Med 2000;28(suppl):A46.
149. McGilvray ID, Rotstein OD. The role of coagulation in systemic inflammation: a review of experimental evidence. Sepsis 1999;1998:199-208.
150. Opal SM. New therapeutic modalities; antithrombin III. Sepsis 1999;3:153-160.
151. Creasey AA. New potential therapeutic modalities: tissue factor pathway inhibitor. Sepsis 2000;3:173-182..
152. Carr C, Bild GS, Chang AC, et al. Recombinant E. coli-derived tissue factor inhibitor reduces coagulopahtic and lethal effects in the baboon gram negative model of septic shock. Circulatory Shock 1995;44:126-137.
153. Esmon CT. New potential therapeutic modalities: aPC. Sepsis 1999;3:161-172.
154. 148a Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
155. van der Poll T, Lowry SF. Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense. Shock 1995;3:1-12.
156. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996;87:2095-2147.
157. 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. Phase III rhIL-Ira Sepsis Syndrome Study Group. JAMA 1994;271:1836-1843.
158. Opal SM, Fisher CJ Jr, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a Phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interlenkin-1 Receptor Antagonist Sepsis Investigator Croup. Crit Care Med 1997;25:1115-1124.
159. 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. TNF-alpha MAb Sepsis Study Croup. JAMA 1995;273:934-941.
160. Abraham E, Glauser MP, Butler T, 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.
161. Abraham E, Anzueto A, Gutierrez G, 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.
162. Fisher CJ Jr, Agosti JM, Opal SM, et al. 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.
163. 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 Croup. Crit Care Med 1996;24:1431-1440.
164. Grau GE, Maennel DN. TNF inhibition and sepsis-sounding a cautionary note. Nat Med 1997;3:1193-1195.
165. Reinhart K, Wiegand-Lohnert C, Grimminger F, 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.
166. Marchant A, Bruyns C, Vandenabeele P, et al. Interleukin-10 controls interferon-gamma and tumor necrosis factor production during experimental endotoxemia. Eur J Immunol 1994;24: 1167-1171.
167. 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;181:176-180.
168. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997;3: 678-681.
169. Cohen J. Adjunctive therapy in sepsis: a critical analysis of the clinical trial program. Brit Med Bull 1999;55:212-225.
170. Zeni F, Freeman B, Natanson C. Antiinflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25:1095-1100.
171. Fink MP. Therapeutic options directed against platelet activating factor, eicosanoids and bradykinin in sepsis. J Antimicrob Agent Chemother 1998;41(supPl A):81-94.
172. Cohen J, Guyatt G, Bernard GR, et al. New strategies for clinical trials in patients with sepsis and septic shock. Crit Care Med 2001 (in press).