Sepsis Trials What Have We Learned?

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Abstract
Sepsis is the dominant illness cared for in intensive care units. Historically, there have been two major concepts of sepsis pathophysiology. The first was the oxygen debt theory, suggesting that inadequate systemic oxygen delivery causes multisystem organ failure (MSOF) and death. Alternatively, the unregulated inflammation hypothesis postulates that MSOF is secondary to unchecked host inflammation. Randomized trials of augmenting oxygen delivery to supernormal levels, testing the first hypothesis, suggest this approach is without benefit. Testing the second hypothesis, mediator-specific, antinflammatory agents (e.g., antitumor necrosis factor [TNF] antibodies, soluble TNF receptors, and antagonists to interleukin-1 receptor), along with antibodies to endotoxin, and high-dose glucocorticosteroids have been used in human sepsis trials. Individual studies show no consistent evidence of improved survival, but pooled analysis of all studies reveals a small benefit of inhibiting circulating proinflammatory mediators, no effect of antiendotoxin antibodies, and a harmful effect of high-dose glucocorticoid use. Future studies using anti-inflammatory agents differently, or with newer agents, may yield novel therapies

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