 |
|
Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor  in Patients With Sepsis SyndromeA Randomized, Controlled, Double-blind, Multicenter Clinical Trial
Edward Abraham, MD;
Richard Wunderink, MD;
Henry Silverman, MD;
Trish M. Perl, MD, MSc;
Stanley Nasraway, MD;
Howard Levy, MD;
Roger Bone, MD;
Richard P. Wenzel, MD, MSc;
Robert Balk, MD;
Randy Allred, PhD;
James E. Pennington, MD;
Janice C. Wherry, MD, PhD;
TNF- MAb Sepsis Study Group;
Edward Abraham, MD;
Paul Bellamy, MD;
Henry Cryer, MD;
Ronald Busuttil, MD;
Drew Winston, MD;
Cindy Perry, RN;
Richard Wunderink, MD;
Kenneth V. Leeper, Jr, MD;
Carol Jones, RN, BSN;
Henry Silverman, MD;
Michael Martin, MD;
Pam Tuma, RN;
Ian Baird, MD;
Jane Brooks, RN;
Rebecca Baird, RN;
Richard P. Wenzel, MD, MSc;
Trish M. Perl, MD, MSc;
Sigfrido Rangel, MD, MSc;
Nancy Wagner, RN;
Michele Costigan, RN;
Guillermo Gutierrez, MD;
Phillip Johnson, MD;
Cinda Clark, RN;
Cindy Grover, RN;
Peter C. Gay, MD;
Jim Stekelberg, MD;
Phillip Van Steinburg, RN;
Stanley Nasraway, MD;
Jorge Ortiz, MD;
Pamel Sigel, RN;
Anne Murphy, RN;
William Lahey, RN;
Joseph Plouffe, MD;
Robert J. Fass, MD;
Jane Russell, RN;
Richard E. Crowell, MD;
Steven Q. Simpson, MD;
Mary Neidhart, RN;
Mark Dunn, MD;
Louis Saravolatz, MD;
Neena Griffin, RN;
Tobias C. Samo, MD;
Victor Feinstein, MD;
Kay Doyle, RN;
Collette Tuttle, RN;
Richard Brown, MD;
Jay Steingrub, MD;
Mary Jo Safford, RN;
Alfred Bacon III, MD;
William Holloway, MD;
Shirly Amato, RN;
Fay Schneider, RN;
Galen B. Toews, MD;
Robert Fekety, Jr, MD;
Julie Kugler, RN;
Janet Hampton, RN;
Faroque A. Kahn, MD;
Ashok Karnik, MD;
Michael Niederman, MD;
Burke Cunha, MD;
Nancy Clare, RN;
James Leatherman, MD;
Philip K. Peterson, MD;
Charlotte Doak, RN;
Laurie Zimmerman, RN;
Jonathan E. Gottlieb, MD;
Lisa Stokes, RN;
Curtis Sessler, MD;
Roger Bone, MD;
Robert Balk, MD;
Karen Deere, RN;
Debbie Gloskey, RN;
David Longworth, MD;
Jay Steingrub, MD;
Mary Jo Safford, RN;
Laura Liucchi, RN;
Charles Strange, MD;
Ruth Oser, RN, MS;
David Gilbert, MD;
James E. Leggett, MD;
Kay Waite, RN;
Nicolas V. Christou, MD;
Sheldon Magder, MD;
Micheline Bonneau, RN;
James S. Tan, MD;
Thomas File, MD;
Sara Jane Salstrom, MT;
Sydney Eaton, RN;
Gary Garber, MD;
Gynne Jones, MD;
Isabel Seguin, RN;
Anthony W. Chow, MD;
Martin Tweeddale, MD;
Linda Schwartz, RN;
George Pankey, MD;
Joan Vollenweider, RN;
Harold Neu;
Glenda Garvey, MD;
Patricia Dorney, RN;
Richard A. Jacobs, MD;
Michael Bernstein, MD;
Jackie Octavio, RN;
Brian Schillinger, RN;
Thomas Iberti, MD;
James Russell, MD;
John Sheagren, MD;
Donald Craven, MD;
Lona Poole, MD;
Warren Myers;
Maureen Ash, PhD;
Nancy Czarny;
George Arcieri, MD;
Gary Koch, PhD;
Johann Prove, PhD;
Daniel Remick, MD;
Michael Fournel
JAMA. 1995;273(12):934-941.
Abstract
| |
Objective.
—To evaluate the efficacy and safety of anti—tumor necrosis factor monoclonal antibody (TNF- MAb) in the treatment of patients with sepsis syndrome.
Design.
—Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.
Setting.
—A total of 31 hospitals in the United States and Canada.
Patients.
—There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug.
Intervention.
—Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF- MAb, 7.5 mg/kg of TNF- MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period.
Outcome Measure.
—Twenty-eight-day all-cause mortality.
Results.
—The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF- MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF- MAb. In septic patients with shock (n=478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF- MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF- MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P=.01; 7.5 mg/kg: 48.7% reduction vs placebo, P=.004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF- MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P=.20 for 7.5 mg/kg and P=.15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF- MAb were reported. Serum sickness—like reactions were seen in 2.5% of patients receiving TNF- MAb.
Conclusions.
—There was no decrease in mortality between placebo and TNF- MAb in all infused patients. In septic shock patients who received TNF- MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF- MAb, the difference in mortality among shock patients treated with placebo or TNF- MAb was not significant.
(JAMA. 1995;273:934-941)
Author Affiliations
| |
University of California at Los Angeles; University of Tennessee; University of Maryland; Riverside Methodist Hospital; University of Iowa; Hermann Hospital; Mayo Clinic; St Vincent Hospital; Ohio State University; University of New Mexico—Howard Levy, MD; Henry Ford Hospital; Methodist Hospital; Baystate Hospital; Medical Center of Delaware; University of Michigan; Nassau County Medical Center; Winthrop University Hospital; University of Minnesota; Jefferson Medical College; Medical College of Virginia; Lea Watson, RN; Rush-Presbyterian-St Luke's Hospital; Cleveland Clinic; Medical University of South Carolina; Providence Medical Center; Royal Victoria Hospital; Akron City Hospital; Ottawa General Hospital; Vancouver General Hospital; Ochsner Clinic; Columbia University; University of California at San Francisco; Scientific External Review Committee
From the Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver (Dr Abraham); Department of Medicine/Pulmonary Division, University of Tennessee, Memphis (Dr Wunderink); Division of Pulmonary and Critical Care Medicine, University of Maryland. Baltimore (Dr Silverman); Division of General Medicine/ Clinical Epidemiology and Health Services Research, University of Iowa College of Medicine, Iowa City (Drs Perl and Wenzel); Department of Anesthesiology, New England Medical Center, Boston, Mass (Dr Nasraway); Department of Medicine, University of New Mexico, Albuquerque (Dr Levy); Department of Medicine, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Drs Bone and Balk); and Clinical Research Department, Miles Inc, Berkeley, Calif (Drs Allred, Pennington, and Wherry). Dr Bone is now president of the Medical College of Ohio, Toledo.
Footnotes
Drs Allred, Pennington, and Wherry are employees of Miles Inc, Berkeley, Calif.
A complete list of participants in the TNF- MAb Study Group appears at the end of this article.
Presented in part at the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La, October 18, 1993, and at the American College of Chest Physicians Annual Scientific Assembly, Orlando, Fla, October 25, 1993.
Reprint requests to Division of Pulmonary Sciences and Critical Care Medicine, Box C272, University of Colorado Health Sciences Center, 4200 E Ninth Avenue, Denver, CO 80262 (Dr Abraham).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Immunomodulation in the critically ill
Webster and Galley
Br J Anaesth 2009;103:70-81.
ABSTRACT
| FULL TEXT
Infliximab and the TNF-{alpha} system
Ebert
Am. J. Physiol. Gastrointest. Liver Physiol. 2009;296:G612-G620.
ABSTRACT
| FULL TEXT
Essential Involvement of CX3CR1-Mediated Signals in the Bactericidal Host Defense during Septic Peritonitis
Ishida et al.
J. Immunol. 2008;181:4208-4218.
ABSTRACT
| FULL TEXT
Statins and Sepsis: Good Bullet, Disappearing Target
Woerndle and Maxwell
JAOA: Journal of the American Osteopathic Association 2008;108:486-490.
ABSTRACT
| FULL TEXT
miniTUBA: medical inference by network integration of temporal data using Bayesian analysis
Xiang et al.
Bioinformatics 2007;23:2423-2432.
ABSTRACT
| FULL TEXT
Pathophysiology of Sepsis
Remick
Am. J. Pathol. 2007;170:1435-1444.
ABSTRACT
| FULL TEXT
Cell Response to Surgery
Ni Choileain and Redmond
Arch Surg 2006;141:1132-1140.
ABSTRACT
| FULL TEXT
Management of Sepsis
Russell
NEJM 2006;355:1699-1713.
FULL TEXT
Obesity and Sepsis
Vachharajani and Vital
J Intensive Care Med 2006;21:287-295.
ABSTRACT
The cytokine activity of HMGB1
Yang et al.
J. Leukoc. Biol. 2005;78:1-8.
ABSTRACT
| FULL TEXT
Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-{kappa}B signal pathways
Ikezoe et al.
Molecular Cancer Therapeutics 2005;4:578-586.
ABSTRACT
| FULL TEXT
Inclusion Criteria for Clinical Trials in Sepsis: Did the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Definitions of Sepsis Have an Impact?
Trzeciak et al.
Chest 2005;127:242-245.
ABSTRACT
| FULL TEXT
CHRONIC ALCOHOLISM CAUSES DELETERIOUS CONDITIONING OF INNATE IMMUNITY
Frank et al.
Alcohol Alcohol 2004;39:386-392.
ABSTRACT
| FULL TEXT
Review: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed
Dinarello
Innate Immunity 2004;10:201-222.
ABSTRACT
The Significance of Vasoactive Intestinal Peptide in Immunomodulation
Delgado et al.
Pharmacol. Rev. 2004;56:249-290.
ABSTRACT
| FULL TEXT
Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-{alpha}, and FFAs to low-dose endotoxemia in humans
Krogh-Madsen et al.
Am. J. Physiol. Endocrinol. Metab. 2004;286:E766-E772.
ABSTRACT
| FULL TEXT
PC-SPES: A Potent Inhibitor of Nuclear Factor-{kappa}B Rescues Mice from Lipopolysaccharide-Induced Septic Shock
Ikezoe et al.
Mol. Pharmacol. 2003;64:1521-1529.
ABSTRACT
| FULL TEXT
Computational Design of Variant TNF Molecules: A Novel Methodology for Inhibition of Proinflammatory Cascades
Abraham
Sci Signal 2003;2003:pe51-pe51.
ABSTRACT
| FULL TEXT
The Problems and Challenges of Immunotherapy in Sepsis
Nasraway
Chest 2003;123
:451S-459S.
ABSTRACT
| FULL TEXT
A New Paradigm for the Treatment of Sepsis: Is It Time To Consider Combination Therapy?
Cross and Opal
ANN INTERN MED 2003;138:502-505.
ABSTRACT
| FULL TEXT
The Pathophysiology and Treatment of Sepsis
Hotchkiss and Karl
NEJM 2003;348:138-150.
FULL TEXT
Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice
Agelaki et al.
Infect. Immun. 2002;70:6068-6074.
ABSTRACT
| FULL TEXT
Template-Directed Dye-Terminator Incorporation with Fluorescence Polarization Detection for Analysis of Single Nucleotide Polymorphisms Implicated in Sepsis
Freeman et al.
J. Mol. Diagn. 2002;4:209-215.
ABSTRACT
| FULL TEXT
Risk and the Efficacy of Antiinflammatory Agents: Retrospective and Confirmatory Studies of Sepsis
Eichacker et al.
Am. J. Respir. Crit. Care Med. 2002;166:1197-1205.
ABSTRACT
| FULL TEXT
Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema
Matthay et al.
Physiol. Rev. 2002;82:569-600.
ABSTRACT
| FULL TEXT
Cardiac Inflammation and Innate Immunity in Septic Shock* : Is There a Role for Toll-Like Receptors?
Knuefermann et al.
Chest 2002;121:1329-1336.
ABSTRACT
| FULL TEXT
HMGB1 as a Late Mediator of Lethal Systemic Inflammation
WANG et al.
Am. J. Respir. Crit. Care Med. 2001;164:1768-1773.
FULL TEXT
Editorial I: Evidence based practice in intensive care--light on the horizon?
Webster
Br J Anaesth 2001;87:377-379.
FULL TEXT
A low level of TNF-{alpha} mediates hemorrhage-induced acute lung injury via p55 TNF receptor
Song et al.
Am. J. Physiol. Lung Cell. Mol. Physiol. 2001;281:L677-L684.
ABSTRACT
| FULL TEXT
Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-{alpha}
Ballard-Croft et al.
Am. J. Physiol. Heart Circ. Physiol. 2001;280:H1970-H1981.
ABSTRACT
| FULL TEXT
Clinically-oriented therapies in sepsis: a review
Dubois and Vincent
Innate Immunity 2000;6:463-469.
ABSTRACT
Chemokine C10 Promotes Disease Resolution and Survival in an Experimental Model of Bacterial Sepsis
Steinhauser et al.
Infect. Immun. 2000;68:6108-6114.
ABSTRACT
| FULL TEXT
Role of bacterial capsule in local and systemic inflammatory responses of mice during pulmonary infection with Klebsiella pneumoniae
YOSHIDA et al.
J Med Microbiol 2000;49:1003-1010.
ABSTRACT
| FULL TEXT
Passive Immunity in Prevention and Treatment of Infectious Diseases
Keller and Stiehm
Clin. Microbiol. Rev. 2000;13:602-614.
ABSTRACT
| FULL TEXT
Prolonged survival of mice with Pseudomonas aeruginosa-induced sepsis by rIL-12 modulation of IL-10 and interferon-{gamma}
YAMAGUCHI et al.
J Med Microbiol 2000;49:701-707.
ABSTRACT
| FULL TEXT
Group B Streptococcus Induces TNF-{alpha} Gene Expression and Activation of the Transcription Factors NF-{kappa}B and Activator Protein-1 in Human Cord Blood Monocytes
Vallejo et al.
J. Immunol. 2000;165:419-425.
ABSTRACT
| FULL TEXT
The Tyrosine Kinase Inhibitor Tyrphostin AG126 Reduces the Development of Acute and Chronic Inflammation
Cuzzocrea et al.
Am. J. Pathol. 2000;157:145-158.
ABSTRACT
| FULL TEXT
Impact of Immunomodulating Therapy on Morbidity in Patients with Severe Sepsis
PITTET et al.
Am. J. Respir. Crit. Care Med. 1999;160:852-857.
ABSTRACT
| FULL TEXT
Sepsis: Lessons Learned in the Last Century and Future Directions
Chaudry
Arch Surg 1999;134:922-929.
FULL TEXT
Association of TNF2, a TNF-{alpha} Promoter Polymorphism, With Septic Shock Susceptibility and Mortality: A Multicenter Study
Mira et al.
JAMA 1999;282:561-568.
ABSTRACT
| FULL TEXT
Immunomodulatory effects of glycine on LPS-treated monocytes: reduced TNF-{alpha} production and accelerated IL-10 expression
SPITTLER et al.
FASEB J. 1999;13:563-571.
ABSTRACT
| FULL TEXT
Immunological evaluation of cytokine and anticytokine immunotherapy in vivo: what have we learnt?
Jorgensen et al.
Ann Rheum Dis 1999;58:136-141.
FULL TEXT
Induction of Adrenomedullin mRNA and Protein by Lipopolysaccharide and Paclitaxel (Taxol) in Murine Macrophages
Zaks-Zilberman et al.
Infect. Immun. 1998;66:4669-4675.
ABSTRACT
| FULL TEXT
Hemolytically Active (Acylated) Alpha-Hemolysin Elicits Interleukin-1beta (IL-1beta ) but Augments the Lethality of Escherichia coli by an IL-1- and Tumor Necrosis Factor-Independent Mechanism
Gleason et al.
Infect. Immun. 1998;66:4215-4221.
ABSTRACT
| FULL TEXT
alpha -GlcNAc-1right-arrow2-alpha -Glc, the Salmonella Homologue of a Conserved Lipopolysaccharide Motif in the Enterobacteriaceae, Elicits Broadly Cross-Reactive Antibodies
Nnalue
Infect. Immun. 1998;66:4389-4396.
ABSTRACT
| FULL TEXT
Revisiting the Role of Tumor Necrosis Factor {alpha} and the Response to Surgical Injury and Inflammation
Ksontini et al.
Arch Surg 1998;133:558-567.
ABSTRACT
| FULL TEXT
Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon
Solorzano et al.
J. Appl. Physiol. 1998;84:1119-1130.
ABSTRACT
| FULL TEXT
The American-European Consensus Conference on ARDS, Part 2 . Ventilatory, Pharmacologic, Supportive Therapy, Study Design Strategies, and Issues Related to Recovery and Remodeling
ARTIGAS et al.
Am. J. Respir. Crit. Care Med. 1998;157:1332-1347.
ABSTRACT
| FULL TEXT
Novel Insights Into the Pathogenesis and Therapy of Circulatory Shock
Steingrub
SEMIN CARDIOTHORAC VASC ANESTH 1998;2:31-45.
ABSTRACT
Tumor necrosis factor in the heart
Meldrum
Am. J. Physiol. Regul. Integr. Comp. Physiol. 1998;274:R577-R595.
ABSTRACT
| FULL TEXT
Immunopharmacology: Immunomodulation and Immunotherapy
Ballow and Nelson
JAMA 1997;278:2008-2017.
ABSTRACT
Treatment of sepsis by plasma endotoxin removal: hemoperfusion using a polymyxin-B immobilized column
Kodama et al.
Innate Immunity 1997;4:293-300.
ABSTRACT
Soluble E-Selectin Levels in Sepsis and Critical Illness . Correlation with Infection and Hemodynamic Dysfunction
CUMMINGS et al.
Am. J. Respir. Crit. Care Med. 1997;156:431-437.
ABSTRACT
| FULL TEXT
Fundamental differences during Gram-positive versus Gram-negative sepsis become apparent during bacterial challenge of D-galactosamine-treated mice
Silverstein et al.
Innate Immunity 1997;4:173-181.
ABSTRACT
Protection against lethal polymicrobial sepsis by CNI-1493, an inhibitor of pro-inflammatory cytokine synthesis
Villa et al.
Innate Immunity 1997;4:197-204.
ABSTRACT
p55 Tumor Necrosis Factor Receptor Fusion Protein in the Treatment of Patients With Severe Sepsis and Septic Shock: A Randomized Controlled Multicenter Trial
Abraham et al.
JAMA 1997;277:1531-1538.
ABSTRACT
Inhaled Nitric Oxide Versus Conventional Therapy . Effect on Oxygenation in ARDS
MICHAEL et al.
Am. J. Respir. Crit. Care Med. 1997;157:1372-1380.
ABSTRACT
| FULL TEXT
Treatment of Septic Shock with the Tumor Necrosis Factor Receptor:Fc Fusion Protein
Fisher et al.
NEJM 1996;334:1697-1702.
ABSTRACT
| FULL TEXT
The Tumor Necrosis Factor Ligand and Receptor Families
Bazzoni and Beutler
NEJM 1996;334:1717-1725.
FULL TEXT
Critical Care Medicine
Hollenberg and Parrillo
JAMA 1996;275:1799-1800.
ABSTRACT
Lessons learned from clinical trials of sepsis
Opal
Innate Immunity 1995;2:221-226.
ABSTRACT
Can second-generation versions of existing therapeutics be successful in clinical trials of sepsis?
Fisher
Innate Immunity 1995;2:227-232.
ABSTRACT
ANOTHER DISAPPOINTING ANTI-SEPSIS TRIAL
JWatch General 1995;1995:3-3.
FULL TEXT
Apolipoprotein E Protects Against Bacterial Lipopolysaccharide-induced Lethality. A NEW THERAPEUTIC APPROACH TO TREAT GRAM-NEGATIVE SEPSIS
Van Oosten et al.
J. Biol. Chem. 2001;276:8820-8824.
ABSTRACT
| FULL TEXT
|
