Another perspective on the significance of endotoxins and the inflammatory response:
Ann Intern Med 1994 May 1;120(9):771-83
Selected treatment strategies for septic shock based on proposed mechanisms of
pathogenesis.
Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL
Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892-0010.
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.
Publication Types:
Review
Review, academic
PMID: 8147551, UI: 94197369
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