TREATING SEPSIS

Step E: Empiric Therapy: Activated Protein C

• Activated protein C modulates both inflammation and coagulation in severe sepsis, and reduces mortality

Activated protein C (drotrecogin alfa) is an endogenous protein that promotes fibrinolysis and inhibits thrombosis and inflammation. It is an important modulator of the coagulation and inflammation associated with severe sepsis Activated protein C is converted from its inactive precursor, protein C, by thrombin coupled to thrombomodulin.  The conversion of protein C to activated protein C may be impaired during sepsis as a result of the down-regulation of thrombomodulin by inflammatory cytokines. Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death. This led to interest in therapeutic administration of activated protein C (and similar agents) in early sepsis.

A large randomized controlled trial has confirmed the efficacy of Activated Protein C (drotrecogin alfa). In patients with severe sepsis, an intravenous infusion of drotrecogin alfa activated at a dose of 24 µg per kilogram per hour for 96 hours is associated with a significant reduction in mortality (1). The use of this drug is indicated if the patient has a systemic inflammatory response, at least one organ dysfunction and known or suspected infection.

When using an infusion of activated protein C, it is important to monitor for signs of bleeding, an important side effect of therapy with this compound. The value of this agent in patients with multi-organ failure, or outside the first 24 hours of injury, is unknown.

References

(1)   Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344(10):699-709.

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