Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest

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DESCRIPTION (provided by applicant): PROJECT SUMMARY: Cardiac arrest (CA) in children is a significant public health problem that is associated with a survival rate of only 13%. About 50% of survivors sustain neurological disability, which produces an enormous impact on family life and resources. My research track record has focused on mechanisms of brain injury and therapies in experimental CA in the developing brain, which has prepared me to translate this work to the pediatric ICU. I have outstanding mentors, have developed relationships with expert researchers in other key area for this work, and have a superb research environment including the Safar Center for Resuscitation Research, the Magnetic Resonance Research Center, and a busy clinical pediatric ICU practice for patient recruitment. My short term research goal is to compare the efficacy of 24 h versus 72 h of mild hypothermia (HT) (32-34 9C) in children with CA as a neuroprotective strategy. There isnot neuroprotective therapy for CA in children, where the etiology is primarily asphyxia. Randomized controlled trials using mild HT with varying durations in adult ventricular fibrillation-induced CA (12-24 h) and neonatal asphyxia (72 h) significantly improved neurological outcome without increasing adverse events. However, there are no prospective data on the use of HT in children with CA. Our experience shows substantial secondary neuronal death beyond 24 h after CA in children (as reflected by peak serum levels of the neuronal death biomarker neuron specific enolase [NSE]). Thus, prolonging the duration of HT from 24 h to 72 h may further attenuate secondary neuronal death. Serum biomarkers such as NSEand brain magnetic resonance spectroscopy (MRS) are minimally invasive methods used to evaluate the brain's biochemical response to CA and therapies such as HT. I propose to prospectively randomize 40 children with CA to either 24 h or 72 h of mild HT to test the hypothesis that treatment with mild HT for 72 h will be superior to 24 h as evidenced by the reduction of biochemical evidence of brain injury. Specific aims are designed to find the best duration of HT that shows evidence of neurological protection, as measured biochemically using serum NSE and brain MRS concentrations of N-acetyl aspartate, lactate and sodium. In addition, the frequency of adverse events will be compared between the two groups. The long- term aim of this proposal is to serve as the scientific foundation for optimized clinical trials designed to improve neurological outcome and quality of life in children who survive CA. RELEVANCE: Cardiac arrest in children has a survival rate of only 13%, and half of the survivors have neurological disability. There are currently no therapies to improve survival and neurological function in children with cardiac arrest. The impact of cardiac arrest for families is significant in terms of effects on family life and financially, since care for a child surviving cardiac arrest can amount to one million dollars over a lifetime.