Human models of endotoxemia and recombinant human activated protein C

To review human models of endotoxemia with an emphasis on the inflammatory and coagulopathic effects of lipopolysaccharide to describe the possible mechanisms of clinical benefit of recombinant human activated protein C (drotrecogin alfa [activated]) in severe sepsis.

A selected review of published literature in English on human endotoxemia models with special attention to studies using drotrecogin alfa (activated) in concert with endotoxemia.

After intravenous administration of purified lipopolysaccharide, subjects report constitutional influenza-like symptoms associated with an increase in temperature. Within 1 hr of lipopolysaccharide infusion, total leukocyte counts decline. Sustained leukocytosis, due to an increase in neutrophils counts, follows. An increase in markers of neutrophil activation (e.g., serum elastase) accompanies this leukocytosis. Production of tumor necrosis factor-alpha, interleukin-6, and interleukin-8 is also increased. In association with an inflammatory response, lipopolysaccharide administration also activates the coagulation system. Lipopolysaccharide infusion generates thrombin and initially activates fibrinolysis but subsequently generates inhibitors of the fibrinolytic system. Serum levels of endogenous inhibitors of coagulation (e.g., antithrombin, protein C, tissue factor pathway inhibitor) are not affected. Data are available for 40 subjects who have participated in placebo-controlled studies of drotrecogin alfa (activated) infusion before an intravenous dose of lipopolysaccharide. In these subjects, drotrecogin alfa (activated) has minimal effects on measured variables, including physiologic variables, markers of inflammation, and measures of sepsis-induced coagulopathy.

Human endotoxemia is, at best, an incomplete model of human sepsis. In two studies using recombinant human activated protein C in the setting of human endotoxemia, there were minimal effects on hemodynamics, inflammation, thrombin generation, fibrinolysis, and markers of cellular activation. Other putative mechanisms of recombinant human activated protein C, such as inhibition of apoptosis and leukocyte recruitment, remain to be studied.