Drotrecogin Alfa: Unproven Efficacy in Children with Severe Sepsis

Drotrecogin alfa (Xigris) is a recombinant human-activated protein C approved in more than 50 countries for the treatment of severe sepsis in adults but not children. Despite modern supportive care and antibiotics, severe sepsis remains the second-leading cause of mortality worldwide in children aged 1 to 14 years.

In the manufacturer-sponsored, international RESOLVE trial, researchers prospectively randomized 477 children aged 38 weeks to 17 years with sepsis-induced cardiovascular and respiratory failure to receive an intravenous infusion of either drotrecogin alfa or saline placebo for 96 hours. Children at high risk for intracranial bleeding, end-stage liver or renal disease, or death from underlying conditions were excluded. An initial fluid bolus of at least 40 mL/kg within 2 hours was required for study entry, but the type of fluid and all other care were at the discretion of the treating physician.

The primary endpoint was a reduction in the Composite Time to Complete Organ Failure Resolution score of three organ systems: cardiovascular, respiratory, and renal. Resolution was defined as discontinuation of vasopressors, mechanical ventilation, or dialysis.

Even after adjusting for differences in baseline characteristics between the drotrecogin alfa and placebo groups, no significant differences in the primary endpoint were detected. There also were no differences in 14-day, 28-day, or inhospital mortality; serious adverse events, such as bleeding; or rates of amputation, hearing loss, and skin grafts in patient with meningitis.