Activated protein C in sepsis: a critical review

Purpose of 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. Recent findings 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. Summary 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.