Activated protein C in sepsis: a critical review

An impaired function of the protein C pathway plays a central role in the pathogenesis of sepsis. Administration of human recombinant activated protein C (Xigris) may restore the dysfunctional anticoagulant mechanism and may simultaneously modulate the pro-inflammatory response. Initial clinical studies with activated protein C in patients with sepsis showed a reduction of 28-day mortality. However, subsequent studies did cast some doubt on the efficacy and also the safety of this treatment.

A number of randomized controlled clinical studies confirm beneficial effects of activated protein C in patients with severe sepsis. Aggregate analyses, however, have cast some doubt on the usefulness of treatment with activated protein C. In some clinical situations, such as patients with a relatively low disease severity and pediatric patients, activated protein C was shown not to be effective. Activated protein C seems to increase the risk of (severe) bleeding, although the absolute risk is low in patients that were included in clinical trials.

Clinical studies support the use of activated protein C in patients with severe sepsis; however, in view of the substantial skepticism surrounding the efficacy and safety of this treatment, additional placebo-controlled data are required.