ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis.

Objective. To gather additional 28-day all-cause mortality data and safety information for pediatric patients with severe sepsis who received drotrecogin alfa (activated) (DrotAA).Design and Setting. Single-arm, open-label, multicentered study conducted in 59 study sites in 15 countries.Patients: One-hundred eighty-eight children (term newborn to <18 yrs old) with severe sepsis were consecutively enrolled in the study.Intervention. Administration of DrotAA, 24 mu g/kg/hr for 96 hrs.Main Outcome Measures: Four-day and 28-day all-cause mortality, safety information, and protein C levels.Results: One-hundred eighty-seven patients completed the study. The 4-day mortality rate was 7.0%, and the 28-day mortality rate was 13.4%. At baseline, 57.6% of patients were severely deficient in protein C (a level <= 40% of normal). There was a statistically significant association between increased 28-day mortality and decreased end-of-infusion protein C levels (p <.001), greater number of baseline organ dysfunctions (P <.001), and greater baseline ventilator use (p =.03). Bleeding was the most significant complication observed. Serious bleeding events (including anemia without a bleeding source) were experienced by 27.7% of patients (n = 52). Six of the serious bleeding events (3.2%) were considered related to administration of DrotAA. During infusion, serious bleeding events with an identified source of bleeding were experienced by 5.9% of patients (n = 11). Central nervous system bleeding was experienced by 2.7% (n = 5). Two of the intracranial hemorrhages were fatal and occurred postinfusion.Conclusions. Without a placebo control, no efficacy conclusions are possible. Subgroups at higher risk of death were identified, and the change in protein C level from baseline was predictive of survival. The most significant complication observed was bleeding. Risk factors for serious bleeding appear to be multiple organ failure, thrombocytopenia, and coagulopathy.