Neurocognitive Outcomes and the Trajectory of Recovery One-year After Pediatric Sepsis - PROJECT SUMMARY Acute brain dysfunction (ABD) during sepsis occurs in 30% of children and is associated with a seven-fold increased risk of mortality. Survivors who experienced ABD during sepsis are more likely to have both functional morbidity and a reduction in health-related quality of life. However, there is a critical knowledge gap about the prevalence of new neurocognitive morbidities for sepsis survivors. With 100,000 children in the United States and 25 million children worldwide experiencing sepsis each year, new neurocognitive morbidities can have a lasting impact on their development. Our overarching goal is to identify the prevalence of new neurocognitive morbidities up to 12 months after hospital discharge and to determine if acute brain dysfunction during sepsis is a modifiable risk factor that can be targeted to improve these outcomes. This K23 proposal leverages the robust research infrastructure and resources at the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (UPENN). We propose a prospective longitudinal study of 180 school-aged sepsis survivors to evaluate the prevalence of new neurocognitive morbidity at 3 months after discharge, including the association of ABD during sepsis with new morbidity (Aim 1), the trajectory of neurocognitive recovery through 12 months for children with and without ABD during sepsis (Aim 2), and the association of high anticholinergic exposures during sepsis to ABD during sepsis (Aim 3). Neurocognitive status will be assessed at 1-, 3-, 6- and 12-months following discharge using two validated, caregiver-reported measures: PedsQL Cognitive Functioning Scale and the Behavior Rating Inventory of Executive Function. Additionally, in Aim 2, a subset of children will return for formal in-person, performance-based neuropsychological evaluation at 12 months to characterize neurocognitive function compared to age-matched normative data. In Aim 3, we will test the association between anticholinergic exposure with ABD during sepsis in the CHOP Sepsis Registry (6,500 patients) using a validated score to quantity the cumulative anticholinergic exposure. Many medications used to treat sepsis have unanticipated anticholinergic effects and high anticholinergic exposure has previously been associated with delirium (a form of ABD) and mortality in other pediatric critical illness. Identification of potential modifiable risk factors for ABD is imperative to target treatment strategies that can be implemented to improve outcomes. We have assembled a diverse, experienced, and multi-disciplinary mentorship and collaborative team that includes expertise in neurocritical care, long-term outcomes, neuropsychology, pediatric sepsis, and biostatistics. This team will guide the candidate through a rigorous training plan involving research conduct and career development training in neurocognitive domains and measurements, longitudinal study design with optimization of follow-up, and advanced biostatistical methods. Finally, the candidate will gain the necessary mentorship and training in clinical research and patient-centered outcomes to mature into an independent clinician-scientist studying neurocognitive outcomes secondary to ABD during sepsis.
