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September 25, 1991, Vol 266, No. 12 >
ARTICLE | September 25, 1991

A Critical Evaluation of New Agents for the Treatment of Sepsis FREE

Roger C. Bone, MD
[+] Author Affiliations

Reprint requests to Department of Internal Medicine, Section of Pulmonary Medicine, Rush-Presbyterian—St Luke's Medical Center, 1753 W Congress Pkwy, Chicago, L 60612 (Dr Bone).


JAMA. 1991;266(12):1686-1691. doi:10.1001/jama.1991.03470120088038
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Article
References

Objective.  —To evaluate new treatments directed against endotoxin, tumor necrosis factor α, and interleukin 1 for use in sepsis and related disorders (sepsis syndrome and septic shock).

Data Sources.  —Investigations of these treatments in animal models, healthy human volunteers, and patients with sepsis and related disorders.

Study Selection.  —Particular attention was paid to studies of patients with sepsis and related disorders, especially randomized, double-blind, controlled trials.

Data Extraction.  —Animal studies and investigations with human volunteers were judged by how closely the experimental model replicated the clinical disorder (sepsis). Patient trials were assessed by sample size and design. Results of all studies were used to evaluate the likelihood that a given treatment would reduce mortality.

Data Synthesis.  —Direct comparison of E5 and HA-1A antibody studies is difficult because of differences in their design, definitions of shock, and methods of subgroup analysis. However, both antibodies improve outcome in some subgroups: E5 benefits patients with gram-negative infection (bacteremic or focal) who do not have refractory shock, and HA-1A benefits those with gramnegative bacteremia (regardless of whether shock is present) but not those with focal gram-negative infection. Two agents that may be beneficial in gram-positive and gram-negative infection are monoclonal antibodies to tumor necrosis factor α and receptor antagonists to interleukin 1. Preliminary results with both are reviewed.

Conclusions.  —All three types of treatment may improve outcome in sepsis. The best results will probably be obtained with combination therapy that interrupts multiple points of the inflammatory cascade underlying sepsis.(JAMA. 1991;266:1686-1691)

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Bone RC.  Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions. Ann Intern Med . 1991;;114:332-333.
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Nawroth PP, Banks I, Handley D, et al.  Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med . 1986;;163:1363-1375.
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Petrak RA, Balk RA, Bone RC.  Prostaglandins, cyclo-oxygenase inhibitors, and thromboxane synthesis inhibitors in the pathogenesis of multiple organ failure. Crit Care Clin . 1989;;5:303-314.
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Sato N, Goto T, Haranaka K, et al.  Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Natl Cancer Inst . 1986;;76:1113-1121.
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Cotran RS, Pober JS.  Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol . 1990;;1:225-235.
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Nawroth PP, Stern DM.  Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med . 1986;;163:740-745.
34 +
Cunnion RE, Parrillo JE.  Myocardial dysfunction in sepsis: recent insights. Chest . 1989;;95:941-945.
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van der Poll T, Buller HR, ten Cate H, et al.  Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med . 1990;;322:1622-1627.
36 +
Waage A, Espevik T, Lamvik J.  Detection of tumour necrosis-like cytotoxicity in serum from patients with septicemia but not from untreated cancer patients. Scand J Immunol . 1986;;24:739-743.
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Waage A, Halstensen A, Espevik T.  Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet . 1987;;1:355-357.
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Girardin E, Grau GE, Dayer J-M, et al.  Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med . 1988;;319:397-400.
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Grau GE, Taylor TE, Molyneux ME, et al.  Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med . 1989;;320:1586-1591.
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de Groote MA, Martin MA, Densen P, et al.  Plasma tumor necrosis factor levels in patients with presumed sepsis. JAMA . 1989;;262:249-251.
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Waage A.  Production and clearance of tumor necrosis factor in rats exposed to endotoxin and dexamethasone. Clin Immunol Immunopathol . 1987;;45:348-355.
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Hesse DG, Tracey KJ, Fong Y, et al.  Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet . 1988;;166:147-153.
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Calandra T, Baumgartner J-D, Grau GE, et al.  Prognostic value of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferongamma in the serum of patients with septic shock. J Infect Dis . 1990;;161:982-987.
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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.
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Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Centers for Disease Control.  Increase in national hospital discharge survey rates for septicemia— United States, 1979-1987. MMWR . 1987;;39:31-34.
2 +
National Center for Health Statistics. Annual Summary of Births, Marriages, Divorces, and Deaths: United States, 1988 . Hyattsville, Md: US Dept of Health and Human Services; 1989;;37:7. Monthly Vital Statistics Report.
3 +
Centers for Disease Control.  Hospitalization for the leading causes of death among the elderly— United States, 1987. MMWR . 1987;;39:777-779.
4 +
Bone RC.  Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions. Ann Intern Med . 1991;;114:332-333.
5 +
Michalek SM, Moore RN, McGhee JR, et al.  The primary role of lymphoreticular cells in the mediation of host responses to bacterial endotoxin. J Infect Dis . 1980;;141:55-63.
6 +
Wolff SM.  Biological effects of bacterial endotoxin in man. J Infect Dis . 1973;;128( (suppl) ):S259-S264.
7 +
Johnston RB.  Monocytes and macrophages. N Engl J Med . 1988;;318:747-752.
8 +
Tracey KJ, Vlassara H, Cerami A.  Cachectin/ tumour necrosis factor. Lancet . 1989;;1:1122-1126.
9 +
Young LS.  Gram-negative sepsis.  In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Diseases . 3rd ed. New York, NY: Churchill Livingstone; 1990;:611-636.
10 +
Harris RL, Musher DM, Bloom K, et al.  Manifestations of sepsis. Arch Intern Med . 1987;;147:1895-1906.
11 +
Wichterman KA, Bauer AE, Chaudry IH.  Sepsis and septic shock: a review of laboratory models and a proposal. J Surg Res . 1980;;29:189-201.
12 +
Michie HR, Manoge KR, Spriggs DR, et al.  Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med . 1988;;318:1481-1486.
13 +
Suffredini AF, Fromm RE, Parker MM, et al.  The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med . 1989;;321:280-287.
14 +
Simpson SQ, Casey LC.  Role of tumor necrosis factor in sepsis and acute lung injury. Crit Care Clin . 1989;;5:27-47.
15 +
Ziegler EJ, McCutchan JA, Fierer J, et al.  Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med . 1982;;307:1225-1230.
16 +
Baumgartner J-D, Glauser MP, McCutchan JA, et al.  Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet . 1985;;2:59-63.
17 +
Calandra T, Glauser MP, Schellekens J, et al.  Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli: a prospective, double-blind randomized trial. J Infect Dis . 1988;;158:312-319.
18 +
Berger D. Anti-oxidant therapy with polyclonal and polyvalent immunoglobulins: in-vitro and in-vivo studies. In: Program and abstracts of the Second International Congress on the Immune Consequences of Trauma, Shock, and Sepsis: Mechanisms and Therapeutic Approaches; March 6-9, 1991; Munich, Germany. Abstract.
19 +
Fomsgaard A, Baek L, Fomsgaard JS, et al.  Preliminary study on treatment of septic shock patients with antilipopolysaccharide IgG from blood donors. Scand J Infect Dis . 1989;;21:697-708.
20 +
Greenman RL, Schein RMH, Martin MA, et al.  A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA . 1991;;266:1097-1102.
21 +
Ziegler EJ, Fisher CJ, Sprung CL, et al.  Treatment of gram-negative bacteremia and septic shock with a HA-1A human monoclonal antibody against endotoxin. N Engl J Med . 1991;;324:429-436.
22 +
Bone RC.  Monoclonal antibodies to endotoxin: new allies against sepsis. JAMA . 1991;;266:1125-1126.
23 +
Saravolatz L. Safety of pharmacokinetics of polyvalent P aeruginosa human monoclonal antibody (PsMab). In: Program and abstracts of the Second International Congress on the Immune Consequences of Trauma, Shock, and Sepsis: Mechanisms and Therapeutic Approaches; March 6-9, 1991; Munich, Germany. Abstract.
24 +
Dinarello CA, Cannon JG, Wolff SM.  New concepts on the pathogenesis of fever. Rev Infect Dis . 1988;;10:168-190.
25 +
Nawroth PP, Banks I, Handley D, et al.  Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med . 1986;;163:1363-1375.
26 +
Shalaby MR, Waage A, Aarden L, et al.  Endotoxin, tumor necrosis factor-alpha and interleukin 1 induce interleukin 6 production in vivo. Clin Immunol Immunopathol . 1989;;53:488-498.
27 +
Bonavida B, Paubert-Braquet M, Hosford D, et al.  The involvement of platelet-activating factor (PAF)-induced monocyte activation and tumor necrosis factor (TNF) production in shock. Prog Clin Biol Res . 1989;;308:485-489.
28 +
Petrak RA, Balk RA, Bone RC.  Prostaglandins, cyclo-oxygenase inhibitors, and thromboxane synthesis inhibitors in the pathogenesis of multiple organ failure. Crit Care Clin . 1989;;5:303-314.
29 +
Sato N, Goto T, Haranaka K, et al.  Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Natl Cancer Inst . 1986;;76:1113-1121.
30 +
Cotran RS, Pober JS.  Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol . 1990;;1:225-235.
31 +
Gamble JR, Harlan JM, Klebanoff SJ, et al.  Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A . 1985;;82:8667-8671.
32 +
Shalaby MR, Aggarwal BB, Rinderknect E, et al.  Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factor. J Immunol . 1985;;135:2069-2073.
33 +
Nawroth PP, Stern DM.  Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med . 1986;;163:740-745.
34 +
Cunnion RE, Parrillo JE.  Myocardial dysfunction in sepsis: recent insights. Chest . 1989;;95:941-945.
35 +
van der Poll T, Buller HR, ten Cate H, et al.  Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med . 1990;;322:1622-1627.
36 +
Waage A, Espevik T, Lamvik J.  Detection of tumour necrosis-like cytotoxicity in serum from patients with septicemia but not from untreated cancer patients. Scand J Immunol . 1986;;24:739-743.
37 +
Waage A, Halstensen A, Espevik T.  Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet . 1987;;1:355-357.
38 +
Girardin E, Grau GE, Dayer J-M, et al.  Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med . 1988;;319:397-400.
39 +
Grau GE, Taylor TE, Molyneux ME, et al.  Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med . 1989;;320:1586-1591.
40 +
de Groote MA, Martin MA, Densen P, et al.  Plasma tumor necrosis factor levels in patients with presumed sepsis. JAMA . 1989;;262:249-251.
41 +
Waage A.  Production and clearance of tumor necrosis factor in rats exposed to endotoxin and dexamethasone. Clin Immunol Immunopathol . 1987;;45:348-355.
42 +
Hesse DG, Tracey KJ, Fong Y, et al.  Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet . 1988;;166:147-153.
43 +
Calandra T, Baumgartner J-D, Grau GE, et al.  Prognostic value of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferongamma in the serum of patients with septic shock. J Infect Dis . 1990;;161:982-987.
44 +
Borm PJA, Palmen N, Engelen JJM, et al.  Spontaneous and stimulated release of tumor necrosis factor-alpha (TNF) from blood monocytes of miners with coal workers' pneumoconiosis. Am Rev Respir Dis . 1988;;138:1589-1594.
45 +
Stephens KE, Ishizaka A, Larrick JW, et al.  Tumor necrosis factor causes increased pulmonary permeability and edema: comparison to septic acute lung injury. Am Rev Respir Dis . 1988;;137:1364-1370.
46 +
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.
47 +
Tracey KJ, Fong Y, Hesse DG, et al.  Anticachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature . 1987;;330:662-664.
48 +
Opal SM, Cross AS, Kelly NM, et al.  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.
49 +
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.
50 +
Hinshaw LB, Tekamp-Olsen P, Chang AC, et al.  Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock . 1990;;30:279-292.
51 +
Bahrami S, Redl H, Schlag G, et al. Protective effects of monoclonal antibody (mAb) to tumor necrosis factor (TNF) in experimental endotoxic shock. In: Program and abstracts of the Second International Congress on the Immune Consequences of Trauma, Shock, and Sepsis: Mechanisms and Therapeutic Approaches; March 6-9,1991; Munich, Germany. Abstract.
52 +
Exley AR, Cohen J, Buurman W, et al.  Monoclonal antibody to TNF in severe septic shock. Lancet . 1990;;335:1275-1277.
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To understand the clinical management of acute heart failure syndromes.
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Compression-Only CPR: Pushing the Science Forward
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BMJ 2010;341:c5893-c1494.
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