Critical Evaluation of the Design and Conduct of Previous Clinical Trials in Sepsis

Abstract

Sepsis is the clinical manifestation of the host-derived systemic inflammatory response resulting from invasive infection. Sepsis begins with a nidus of infection, frequently gram-negative or gram-positive organisms, which proliferate and either invade the bloodstream (bacteremia) or release various substances into the bloodstream. Microbial cellular components such as endotoxin, peptidoglycan, teichoic acid antigen, or various exotoxins released by microorganisms are thought to initiate the host systemic inflammatory response by stimulating monocytes or macrophages, endothelial cells or neutrophils to release the endogenous mediators of sepsis. The most important of these mediators are the proinflammatory cytokines, tumor necrosis factor-α (TNF), IL-1, and IL-8. These proinflammatory mediators in turn initiate a cascade of events resulting in the Systemic Inflammatory Response Syndrome (SIRS). Sepsis syndrome may be viewed as a dysregulation syndrome of these messenger molecules. Once initiated, this clinical syndrome can become self-perpetuating and independent of the original infection. A variety of approaches have been attempted to modulate this cascade of events.