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Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial
Simon Nadel1, Brahm Goldstein2, Mark D Williams3
1St Mary's Hospital and Imperial College, London, UK.
Insights
Drotrecogin alfa (activated) did not show efficacy in treating severe sepsis in children. While overall safety was acceptable, increased CNS bleeding occurred in infants, necessitating further research in pediatric critical care.
Area of Science:
- Pediatric Critical Care Medicine
- Sepsis Pathophysiology
- Pharmacological Interventions
Background:
- Drotrecogin alfa (activated) (DrotAA) is an established treatment for severe sepsis in adults.
- Previous studies suggest similar pharmacokinetics and pharmacodynamics of DrotAA in children and adults.
- The RESOLVE trial was initiated to evaluate DrotAA in pediatric severe sepsis patients.
Purpose of the Study:
- To investigate the efficacy and safety of Drotrecogin alfa (activated) in children with severe sepsis.
- To assess the primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score.
- To evaluate secondary endpoints including 28-day mortality, major amputations, and safety.
Main Methods:
- A randomized, placebo-controlled trial involving 477 children (38 weeks' corrected gestational age to 17 years) with sepsis-induced cardiovascular and respiratory failure.
- Patients received either placebo or DrotAA (24 microg/kg/h) for 96 hours.
- Intention-to-treat analysis was performed using a novel primary endpoint: CTCOFR score.
Main Results:
- No significant difference was observed between DrotAA and placebo groups in CTCOFR score (p=0.72) or 28-day mortality (17.2% vs 17.5%, p=0.93).
- Overall serious bleeding events were similar (6.7% vs 6.8%, p=0.97), but CNS bleeding was numerically higher in the DrotAA group (4.6% vs 2.1%, p=0.13), particularly in infants under 60 days.
- No significant correlation was found between CTCOFR score and mortality.
Conclusions:
- Drotrecogin alfa (activated) demonstrated no efficacy in improving outcomes for children with severe sepsis.
- The overall safety profile was acceptable, with similar serious bleeding rates, except for a concerning trend of increased CNS bleeding in neonates and young infants.
- The study provided valuable insights into childhood severe sepsis and identified critical areas for future research in pediatric critical care.
Background:
Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children.
Methods:
Children aged between 38 weeks' corrected gestational age and 17 years with sepsis-induced cardiovascular and respiratory failure were randomly assigned to receive placebo or DrotAA (24 microg/kg/h) for 96 h. We used a prospectively defined, novel primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score. Secondary endpoints were 28-day mortality, major amputations, and safety. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov, number NCT00049764.
Findings:
477 patients were enrolled; 237 received placebo, and 240 DrotAA. Our results showed no significant difference between groups in CTCOFR score (p=0.72) or in 28-day mortality (placebo 17.5%; DrotAA, 17.2%; p=0.93). Although there was no difference in overall serious bleeding events during the 28-day study period (placebo 6.8%; DrotAA 6.7%; p=0.97), there were numerically more instances of CNS bleeding in the DrotAA group (11 [4.6%], vs 5 [2.1%] in placebo, p=0.13), particularly in children younger than 60 days. For CTCOFR score days 1-14, correlation coefficient was -0.016 (95% CI -0.106 to 0.74); relative risk for 28-day mortality was 1.06 (95% CI 0.66 to 1.46) for DrotAA compared with placebo.
Interpretation:
Although we did not record any efficacy of DrotAA in children with severe sepsis, serious bleeding events were similar between groups and the overall safety profile acceptable, except in children younger than 60 days. However, we gained important insights into clinical and laboratory characteristics of childhood severe sepsis, and have identified issues that need to be addressed in future trials in critically ill children.
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