Charles Natanson, MD; William D. Hoffman, MD; Anthony F. Suffredini, MD; Peter Q. Eichacker, MD; Robert L. Danner, MD
To review selected new therapies for septic shock designed to inhibit bacterial toxins or endogenous mediators of inflammation.
Scientific journals, scientific meeting proceedings, and Food and Drug Administration advisory committee proceedings.
Preclinical and clinical data from trials using core-directed antiendotoxin antibodies and anticytokine therapies for sepsis and studies in animal models of sepsis from our laboratory.
Ten clinical trials using core-directed antiendotoxin antibodies produced inconsistent results and did not conclusively establish the safety or benefit of this approach. Both anti-interleukin-1 and anti-tumor necrosis factor (TNF) therapies have been beneficial in some animal models of sepsis but did not clearly improve survival in initial human trials, and one anti-TNF therapy actually produced harm. Neutrophils, another target for therapeutic intervention, protect the host from infection but may also contribute to the development of tissue injury during sepsis. In a canine model of septic shock, granulocyte colony-stimulating factor increased the number of circulating neutrophils and improved survival, but an anti-integrin (CD11/18) antibody that inhibits neutrophil function worsened outcome. Nitric oxide, a vasodilator produced by the host, causes hypotension during septic shock but may also protect the endothelium and maintain organ blood flow. In dogs challenged with endotoxin, the inhibition of nitric oxide production decreased cardiac index and did not improve survival.
No new therapy for sepsis has shown clinical efficacy. Perhaps more accurate clinical and laboratory predictors are needed to identify patients who may benefit from a given treatment strategy. On the other hand, the therapeutic premises may be flawed. Targeting a single microbial toxin such as endotoxin may not represent a viable strategy for treating a complex inflammatory response to diverse gram-negative bacteria. Similarly, the strategy of inhibiting the host inflammatory response may not be beneficial because immune cells and cytokines play both pathogenic and protective roles. Finally, our scientific knowledge of the complex timing of mediator release and balance during sepsis may be insufficient to develop successful therapeutic interventions for this syndrome.
Solid black arrows follow the pathogenesis of septic shock beginning with a nidus of infection and ending in shock and multiple organ failure. Open arrows indicate treatment stategies.
HA-1A (10 mg/kg) significantly decreased survival. In this model, a control human IgM (10 mg/kg) had no harmful effects compared with human serum albumin (HSA).
Reproduced from R. Fernandez-Botran and the American Physiological Society and modified with permission.
Nitric oxide synthase converts L-arginine and O to L-citrulline and nitric oxide . Nitric oxide activates soluble guanylate cyclase, inducing smooth-muscle relaxation. Adapted from Cobb, Cunnion, and Danner with permission.
The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.
Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL. Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis. Ann Intern Med. 1994;120:771-783. doi: 10.7326/0003-4819-120-9-199405010-00009
Download citation file:
Published: Ann Intern Med. 1994;120(9):771-783.
Copyright © 2017 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Conditions of Use
This PDF is available to Subscribers Only