Recombinant human activated protein C for the treatment of severe sepsis: is there a role in pediatrics?

Sepsis with organ failure (severe sepsis) remains an important cause of morbidity and mortality among children. The clinical pathophysiology of severe sepsis reflects a coordinated activation of the innate immune response, including elaboration of proinflammatory cytokines and the induction of the extrinsic pathway of coagulation (sepsis-induced coagulopathy). These proinflammatory and procoagulant pathways are linked, and are similarly coregulated by a number of proteins and factors, including protein C. However, at least 80% of children and adults with severe sepsis develop acquired deficiency of protein C because of factor consumption. This deficiency is associated with poor outcomes, including multiple organ failure and mortality. Recently, recombinant activated protein C was shown to reduce the mortality of adults with severe sepsis, and is now approved for such use in the United States and Europe. The rationale for pediatric applications of protein C and ongoing clinical trials in children are reviewed.