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1 May 1994 | Volume 120 Issue 9 | Pages 771-783
Purpose: To review selected new therapies for septic shock designed to inhibit bacterial toxins or endogenous mediators of inflammation.
Data Sources: Scientific journals, scientific meeting proceedings, and Food and Drug Administration advisory committee proceedings.
Study Selection and Extraction: 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.
Results of Data Synthesis: 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.
Conclusions: 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.
Author and Article Information
An updated edited summary of a Clinical Staff Conference held on 28 April 1993 at the National Institutes of Health Clinical Center, Bethesda, Maryland.
NIH CONFERENCE
Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis
Authors who wish to cite a section of the conference and specifically indicate its author can use this example for the form of reference:
Hoffman WD. Anti-endotoxin therapies in septic shock, pp. 772-5. In: Natanson C, moderator. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med. 1994; 120:771-83.
Requests for Reprints: Charles Natanson, MD, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Building 10, Room 7D43, Bethesda, MD 20892-0010.
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