The efficacy of rhAPC has been tested in a large multicenter study, the results of which have been widely debated. This compound was initially designed to compensate for a deficit in the natural anticoagulant protein C during sepsis, and thus it limited organ failures and improved the survival of septic shock patients [96] . Since then a number of studies have demonstrated that it has additional beneficial effects on complex interactions with inflammation, innate immunity, and apoptosis [97, 98] . rhAPC also protected animals and healthy volunteers from hypotension after lipopolysaccharide challenge. A similar finding was also reported in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, with more rapid improvement in hypotension and vasopressor withdrawal [99] . These clinical effects could be related to endocrine modulation (adrenomedullin was implicated in this regard) and vasoactive capacity. Mechanisms, efficacy, and safety of rhAPC are discussed in other reviews included in this supplement.