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  • Read Letter to the Editor on the CHEST website: AC Kalil, S Puumala, J Stoner. Unresolved questions with the use of linezolid versus vancomycin for nosocomial pneumonias. Chest. 2004;125(6):2370-1

     


    AC Kalil, S Coyle, J Um, S LaRosa, MA Turlo, D Nelson, D Sundin, J Brandt, S Calvano, S Lowry. The effects of Dotrecogin alfa (activated) in Human Endotoxemia. Shock 2004;21(3):222-9.

    Abstract

    In a phase III clinical trial, drotrecogin alfa (activated) was shown to improve survival and promote faster improvement of cardiovascular and respiratory dysfunction in patients with severe sepsis. To further examine mechanisms involved in the action of this drug, a healthy human endotoxin model was used. Healthy volunteers (eight per group) received drotrecogin alfa (activated) or placebo intravenously for 8 h in a randomized, double-blind, controlled manner. After 2 h of study drug infusion, endotoxin (2 ng/kg) was infused and measurement of physiologic responses and biomarkers continued for 24 h. Consistent with results from severe sepsis clinical trials, drotrecogin alfa (activated) improved mean arterial pressure during the period of infusion after endotoxin exposure. In contrast to severe sepsis clinical trials using drotrecogin alfa (activated) but similar to another human endotoxin study, no significant antithrombotic, profibrinolytic, or anti-inflammatory effects were observed. These results suggest a novel role for drotrecogin alfa (activated) in the human endotoxin model.


    Peter Q. Eichacker, Chantal Parent, Andre Kalil, Claire Esposito, Xizhong Cui, Steven Banks, Eric P. Gerstenberger, Robert L. Danner, Charles Natanson. Odds of dying and the efficacy of antiinflamatory agents in sepsis: an allometric model for testing new therapies in lethal diseases. Am J Respir Crit Care Med. 2002;166(9):1197-205.

    Abstract

    We investigated whether a relationship between risk of deathand treatment effect could explain the disparate results betweenthe preclinical and clinical sepsis trials of antiinflammatoryagents over the last decade. A metaregression analysis of citedpreclinical studies showed that the treatment effects of theseagents were highly dependent on risk of death (p = 0.0001) andthat animals were studied at significantly higher control mortalityrates than humans (median [25th-75th quartile], 88% [79-96%]versus 39% [32-42%], p = 0.0001). An analysis of the clinicaltrials showed that antiinflammatory agents were also significantlymore efficacious in septic patients with higher risk of death(p = 0.002) and were harmful in those with low risk. To testthis relationship prospectively, we studied antiinflammatoryagents in models employing differing doses of bacterial challengeto produce the full range of risk of death. We found that theefficacy of these agents, although very beneficial at high controlmortality rates, was much reduced (p = 0.0001) and similar tothose in human trials at moderate control mortality rates (i.e.,30 to 40%). The efficacy of antiinflammatory agents during sepsisis dependent on the risk of death, an observation that explainsthe apparent contradiction between preclinical and clinicaltrial results. Accounting for this relationship may be necessaryfor the safe and effective development of antiinflammatory therapiesfor sepsis.