Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest

描述（由申请人提供）：项目总结：儿童心脏骤停（CA）是一个重要的公共卫生问题，与生存率仅为13%相关。大约50%的幸存者患有神经残疾，这对家庭生活和资源产生了巨大的影响。我的研究记录主要集中在脑损伤的机制和发育中大脑的实验性CA治疗，这使我准备将这项工作转化为儿科ICU。我有杰出的导师，与其他关键领域的专家研究人员建立了关系，并拥有一流的研究环境，包括萨法尔复苏研究中心，磁共振研究中心和忙碌临床儿科ICU实践，用于患者招募。我的短期研究目标是比较24小时与72小时的轻度低温（HT）（32-34 9 C）作为CA儿童神经保护策略的疗效。儿童CA的病因主要是窒息，目前尚无神经保护性治疗。在成人室颤诱导的CA（12-24 h）和新生儿窒息（72 h）中使用不同持续时间的轻度HT的随机对照试验显著改善了神经系统结局，而没有增加不良事件。然而，没有关于在CA儿童中使用HT的前瞻性数据。我们的经验显示，儿童CA后超过24小时，大量继发性神经元死亡（如神经元死亡生物标志物神经元特异性烯醇化酶[NSE]的血清峰值水平所反映的）。因此，将HT的持续时间从24 h延长至72 h可进一步减轻继发性神经元死亡。血清生物标志物如NSE和脑磁共振波谱（MRS）是用于评估大脑对CA和HT等治疗的生化反应的微创方法。我建议前瞻性地将40名CA儿童随机分为24小时或72小时轻度HT治疗组，以检验这一假设，即轻度HT治疗72小时上级24小时，这一假设可以通过减少脑损伤的生化证据来证明。具体的目标是找到HT的最佳持续时间，显示神经保护的证据，如使用血清NSE和N-乙酰天冬氨酸，乳酸和钠的脑MRS浓度进行生物化学测量。此外，还将比较两组之间不良事件的发生频率。这项提案的长期目标是作为优化临床试验的科学基础，旨在改善CA幸存儿童的神经学结局和生活质量。相关性：儿童心脏骤停的存活率仅为13%，一半的幸存者患有神经功能障碍。目前还没有治疗方法可以改善心脏骤停儿童的生存率和神经功能。心脏骤停对家庭的影响在家庭生活和经济方面都很大，因为照顾一个心脏骤停幸存下来的孩子一生可能需要100万美元。

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.