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Published ahead of print on July 19, 2002, doi:10.1164/rccm.200204-302OC

Am. J. Respir. Crit. Care Med., Volume 166, Number 9, November 2002, 1197-1205

A more recent version of this article appeared on November 1, 2002
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Submitted on April 11, 2002
Accepted on July 16, 2002

Risk and the Efficacy of Antiinflammatory Agents in Sepsis: Retrospective and Confirmatory Studies

Peter Q Eichacker1*, Chantal Parent1, Andre Kalil2, Claire Esposito3, Xizhong Cui1, Steven M Banks1, Eric P Gerstenberger1, Yvonne Fitz1, Robert L Danner1, and Charles Natanson1

1 Clinical Center/Critical Care Medicine Department, National Institutes of Health, Bethesda, MD, USA, 2 Eli Lilly and Company, Indianapolis, IN, USA, 3 Department of Anesthesiology, Cornell University, New York, NY, USA

* To whom correspondence should be addressed. E-mail: peichacker{at}nih.gov.

We investigated if a relationship between risk of death and treatment effect could explain the disparate results between the preclinical and clinical sepsis trials of anti-inflammatory agents over the last decade. A metaregression analysis of cited preclinical studies showed that the treatment effects of these agents were highly dependent on risk of death (p=0.0001) and that animals were studied at significantly higher control mortality rates than humans [median (25th-75th quartile) 88% (79-96%) vs. 39% (32-42%)] (p=0.0001). An analysis of the clinical trials showed that antiinflammatory agents were also significantly more efficacious in septic patients with higher risk of death (p=0.002) and were harmful in those with low risk. To test this relationship prospectively, we studied antiinflammatory agents in models employing differing doses of bacterial challenge to produce the full range of risk of death. We found the efficacy of these agents, although very beneficial at high control mortality rates, was much reduced (p=0.0001) and similar to those in human trials at moderate control mortality rates (i.e., 30 to 40%). The efficacy of antiinflammatory agents during sepsis is dependent on risk of death, an observation that explains the apparent contradiction between preclinical and clinical trial results. Accounting for this relationship may be necessary for the safe and effective development of antiinflammatory therapies for sepsis.




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