 |
|
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
Alan M. Fein, MD;
Gordon R. Bernard, MD;
Gerard J. Criner, MD;
Eugene C. Fletcher, MD;
James T. Good, Jr, MD;
William A. Knaus, MD;
Howard Levy, MD;
George M. Matuschak, MD;
Harvey M. Shanies, PhD, MD;
Robert W. Taylor, Jr, MD;
Timothy C. Rodell, MD
JAMA. 1997;277(6):482-487.
Abstract
| |
Objective.
—To test the effect of a novel bradykinin antagonist, deltibant (CP-0127), on survival, organ dysfunction, and other outcomes in patients with the systemic inflammatory response syndrome (SIRS) and presumed sepsis.
Design.
—Multicenter, randomized, placebo-controlled, double-blind, parallel, dose-ranging trial. Follow-up for 28 days or until death.
Setting.
—A total of 47 US referral hospitals.
Patients.
—A total of 504 patients with SIRS and documented evidence of infection plus either hypotension or dysfunction of 2 organ systems.
Interventions.
—Three-day continuous intravenous infusion of either placebo or 1 of 3 doses (0.3,1.0, or 3.0 µg.kg-1.man-1) of deltibant. Concurrent therapy at the discretion of the treating physician.
Main Outcome Measure.
—Risk-adjusted, 28-day, log-normal intent-to-treat survival analysis. Risk adjustment was performed using a study-specific risk model derived from the APACHE III database.
Results.
—Deltibant had no significant effect on risk-adjusted 28-day survival. In a posthoc analysis, risk-adjusted 7-day survival showed a nonsignificant trend toward improvement (P=.09). The 28-day risk-adjusted survival in the prospectively defined subset of patients with gram-negative infections showed a statistically significant improvement (P=.005).
Conclusions.
—Deltibant may have some effect on survival in patients with SIRS and gram-negative sepsis; however, additional studies would be required to prove this.
Author Affiliations
for the CP-0127 SIRS and Sepsis Study Group
From the Winthrop-University Hospital, Mineola, NY (Dr Fein); Vanderbilt University, Nashville, Tenn (Dr Bernard); Temple University Hospital, Philadelphia, Pa (Dr Criner); Houston Veterans Affairs Medical Center, Houston, Tex (Dr Fletcher); University of Louisville Hospital and the Louisville Veterans Affairs Medical Center, Louisville, Ky (Dr Fletcher); Porter and Swedish Hospitals, Denver, Colo (Dr Good); George Washington University, Washington, DC (Dr Knaus); University of New Mexico, Albuquerque (Dr Levy); Saint Louis University Medical Center, St Louis, Mo (Dr Matuschak); Elmhurst Hospital Center, Elmhurst, NY (Dr Shanies); St John's Mercy Medical Center, St Louis, Mo; (Dr Taylor); and Cortech, Inc, Denver, Colo (Dr Rodell).
Footnotes
A complete list of the members of the CP-0127 SIRS and Sepsis Study Group appears at the end of this article.
Dr Rodell was an employee of and continues to be a shareholder in and consultant to Cortech, Inc, Denver, Colo, the inventor and owner of deltibant. Dr Knaus is a director and shareholder in APACHE Medical Systems, Washington, DC, which had a contract from Cortech, Inc, for risk model development and analysis of trial data. Dr Bernard has received compensation for consulting services from Cortech, Inc.
Reprints: Alan M. Fein, MD, Winthrop-University Hospital, 222 Station Plaza N, Mineola, NY 11501.
Concepts in Emergency and Critical Care section editor:Roger C. Bone, MD, Consulting Editor, JAMA.
Advisory Panel: Bart Chernow, MD, Baltimore, Md; David Dantzker, MD, New Hyde Park, NY; Jerrold Leiken, MD, Chicago, III; Joseph E. Parrillo, MD, Chicago, III; William J. Sibbald, MD, London, Ontario; and Jean-Louis Vincent, MD, PhD, Brussels, Belgium.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Statins and Sepsis: Good Bullet, Disappearing Target
Woerndle and Maxwell
JAOA: Journal of the American Osteopathic Association 2008;108:486-490.
ABSTRACT
| FULL TEXT
Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions
Mosnier et al.
J. Biol. Chem. 2007;282:33022-33033.
ABSTRACT
| FULL TEXT
Understanding the Inflammatory Cytokine Response in Pneumonia and Sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study
Kellum et al.
Arch Intern Med 2007;167:1655-1663.
ABSTRACT
| FULL TEXT
Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension
Cayla et al.
FASEB J. 2007;21:1689-1698.
ABSTRACT
| FULL TEXT
Management of Sepsis
Russell
NEJM 2006;355:1699-1713.
FULL TEXT
Kinin receptor expression during Staphylococcus aureus infection
Bengtson et al.
Blood 2006;108:2055-2063.
ABSTRACT
| FULL TEXT
Use of drotrecogin alfa (activated) for severe sepsis in New Jersey acute care hospitals.
Dombrovskiy et al.
Am J Health Syst Pharm 2006;63:1151-1156.
ABSTRACT
| FULL TEXT
Infection-Induced Kinin B1 Receptors in Human Pulmonary Fibroblasts: Role of Intact Pathogens and p38 Mitogen-Activated Protein Kinase-Dependent Signaling
Phagoo et al.
J. Pharmacol. Exp. Ther. 2005;313:1231-1238.
ABSTRACT
| FULL TEXT
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences
Leeb-Lundberg et al.
Pharmacol. Rev. 2005;57:27-77.
ABSTRACT
| FULL TEXT
The Significance of Vasoactive Intestinal Peptide in Immunomodulation
Delgado et al.
Pharmacol. Rev. 2004;56:249-290.
ABSTRACT
| FULL TEXT
A new method for removing endotoxin from plasma using hemocompatible affinity chromatography technology, applicable for extracorporeal treatment of septic patients
Amoureux et al.
Innate Immunity 2004;10:85-95.
ABSTRACT
Highly Purified Vitamin B2 Presents a Promising Therapeutic Strategy for Sepsis and Septic Shock
Toyosawa et al.
Infect. Immun. 2004;72:1820-1823.
ABSTRACT
| FULL TEXT
Review: The plasma kallikrein/kinin and renin angiotensin systems in blood pressure regulation in sepsis
Shariat-Madar and Schmaier
Innate Immunity 2004;10:3-13.
ABSTRACT
Does the Kinin System Mediate in Cardiovascular Abnormalities? An Overview
Sharma
J Clin Pharmacol 2003;43:1187-1195.
ABSTRACT
| FULL TEXT
The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome
Aird
Blood 2003;101:3765-3777.
ABSTRACT
| FULL TEXT
The Problems and Challenges of Immunotherapy in Sepsis
Nasraway
Chest 2003;123
:451S-459S.
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
Activation of the kallikrein-kinin system by cardiopulmonary bypass in humans
Campbell et al.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001;281:R1059-R1070.
ABSTRACT
| FULL TEXT
Clinically-oriented therapies in sepsis: a review
Dubois and Vincent
Innate Immunity 2000;6:463-469.
ABSTRACT
Kinin B1 receptors and the cardiovascular system: regulation of expression and function
McLean et al.
Cardiovasc Res 2000;48:194-210.
ABSTRACT
| FULL TEXT
Treating Patients with Severe Sepsis
Wheeler and Bernard
NEJM 1999;340:207-214.
FULL TEXT
The B1 Receptors for Kinins
Marceau et al.
Pharmacol. Rev. 1998;50:357-386.
ABSTRACT
| FULL TEXT
Novel Insights Into the Pathogenesis and Therapy of Circulatory Shock
Steingrub
SEMIN CARDIOTHORAC VASC ANESTH 1998;2:31-45.
ABSTRACT
|
