Efficacy of Hypothermia in Pediatric TBI

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Treatment of traumatic brain injury (TBI) in the pediatric population has been totally dependent on adult paradigms, both experimentally and clinically with little attention paid to the potential unique responses of the developing brain after injury. There has been few experimental studies utilizing immature animals and even fewer clinical studies utilizing treatment interventions following pediatric TBI (e.g.) Hypothermia (HYPO). While there is over-whelming experimental evidence that HYPO is neuroprotective in a wide spectrum of different models of TBI, studies in children or utilizing immature models of TBI have been lacking. It is obvious that despite the evidence available in the adult, so little is known of the effect of HYPO following experimental and clinical pediatric TBI that it necessitates further study. Despite the recent disappointing results from the adult clinical trials using hypothermia, there was a suggestion of improved outcome in younger patients that may extend to the pediatric population. Efficacy from this study through cannot be translated to care of children since none of the patients in this trial were children and HYPO following pediatric TBI cannot be either prematurely discarded or utilized as a therapeutic intervention without further study. Based on the previous literature and our Preliminary Data, HYPO may be potentially more beneficial in children as compared to the adult. This initial data is compelling evidence for further study as to the potential children, there is currently no understanding of the potential age dependent impact nor limitations of HYPO treatment following pediatric TBI on subsequent neural development. Our Overall Hypothesis for this proposal is that while HYPO will be beneficial in the treatment of pediatric TBI, it will have an age related impact on development at different ages of injury and treatment.. This age at injury and treatment effect will in turn be governed by the sensitivity of the developing brain to neurotransmitter release and/or subsequent blockade. While HYPO following experimental and clinical pediatric TBI will positively impact on the attenuation of neurotransmitter release in all maturational ages, an age related effect, due to either inadequate blockade of excessive neurotransmitter release or the negative impact of neurotransmitter blockade on normal development, will be evidenced in post-injury markers of cell death, synaptic connectivity, and cognitive function. The Specific Aims will include defining the neurotransmitter release response following treatment with HYPO and the subsequent age related impact of injury and treatment of histologic damage, both early and delayed neuronal cell death, synaptogenesis, and functional outcome using different age at injury experimental models of TBI in the immature rat. Parallel clinical specific aims will define the effect of neurotransmitter release in response to treatment with HYPO and the age-related impact of HYPO on early and delayed cell death in children.