Collaborative Pediatric Critical Care Research Network

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Project Summary In 2005, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Collaborative Pediatric Critical Care Research Network (CPCCRN) to support multi-institutional randomized controlled trials (RCTs) and observational studies in critically ill children. This PL1 proposal from the University of Utah is submitted on behalf of a newly configured CPCCRN network increased to 12 Clinical Sites and 12 ancillary sites with > 61,000 annual ICU admissions. The expanded network has geographic, racial/ethnic and socioeconomic diversity, and will be a platform to develop additional investigators, especially young clinician scientists. The network will conduct a highly innovative large-scale multi-center study of personalized, targeted immune modulation in children with sepsis-induced multiple organ dysfunction syndrome (MODS). The study includes two concurrent, immunophenotype-driven placebo controlled RCTs that will address the central hypoth- esis that individualized, pathophysiology-specific immunomodulation will improve outcomes from sepsis-induced MODS in children. This study builds on R01-funded CPCCRN studies that have demonstrated the existence of specific immune phenotypes among children with sepsis-induced MODS (R01GM108618 PI: Carcillo) and suc- cessful reversal of immunosuppression by administration of the immunostimulant granulocyte macrophage-colony stimulating factor (GM-CSF) (R01GM094203 PI: Hall). It also complements the ongoing NICHD R01-funded study investigating the risk factors for immunoparalysis in pediatric MODS (R01HD095976 MPI: Hall, Zuppa). This application has three specific aims: (1) Implement the CPCCRN organization; (2) Mount a comprehen- sive strategy for development of young clinician scientists and submission of rigorous proposals to fund additional research in critical care; (3) Conduct the Personalized Immunomodulation in Sepsis-induced MODS study. The first trial focuses on the use of the drug GM-CSF for the reversal of immunoparalysis. The second trial uses adaptive randomization and focuses on the drugs anakinra and tocilizumab for the targeted treatment of hyper- inflammation. The primary outcome of both trials will be duration and severity of organ dysfunction using the cumulative PELOD-2 score, and secondary outcomes will assess health related quality of life and family function- ing at 3 and 12 months. The Personalized Immunomodulation in Sepsis-Induced MODS study represents a paradigm shift in the man- agement of pediatric sepsis, finally moving beyond simple supportive care. We are uniquely positioned to suc- cessfully execute this approach to personalized, real-time, pathophysiology-directed sepsis treatment, leveraging the strengths of a diverse and highly accomplished group of investigators to deliver high-impact science to the benefit of our patients and our field.