Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest

描述(由申请者提供)：项目摘要：儿童心脏骤停(CA)是一个重大的公共卫生问题，与仅13%的存活率有关。约50%的幸存者患有神经性残疾，这对家庭生活和资源产生了巨大的影响。我的研究记录专注于脑损伤的机制和在发育中的大脑中实验性CA的治疗，这为我将这项工作转移到儿科ICU做好了准备。我有出色的导师，在这项工作的其他关键领域与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，以及忙碌的儿科ICU临床实践招募患者。我的短期研究目标是比较24小时亚低温(32-34℃)和72小时亚低温(32-34℃)对CA患儿的神经保护作用。目前还没有针对儿童CA的神经保护性治疗，其病因主要是窒息。在成人室颤诱发的CA(12-24小时)和新生儿窒息(72小时)中使用不同持续时间的轻度羟色胺的随机对照试验显著改善了神经学结果，而不增加不良事件。然而，目前还没有关于羟色胺在尖锐湿疣儿童中使用的前瞻性数据。我们的经验表明，儿童CA后24小时以上有大量继发性神经元死亡(反映在神经元死亡生物标记物神经元特异烯醇化酶[NSE]的血清峰值水平)。因此，将持续时间从24小时延长到72小时可能会进一步减轻继发性神经元死亡。血清生物标记物如NSE和脑磁共振波谱(MRS)是用于评估大脑对CA和治疗(如HT)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小时接受轻度高温治疗，以检验这样一种假设，即72小时的轻度高温治疗将优于24小时，脑损伤的生化证据的减少证明了这一点。根据血清NSE和脑MRS中N-乙酰天冬氨酸、乳酸和钠浓度的生化测量，旨在找到显示神经保护证据的最佳HT持续时间。此外，还将比较两组不良事件的发生频率。这项建议的长期目标是作为优化临床试验的科学基础，旨在改善CA幸存者的神经学结果和生活质量。相关性：儿童心脏骤停的存活率只有13%，而且一半的幸存者有神经功能障碍。目前还没有治疗方法来改善心脏骤停儿童的存活率和神经功能。心脏骤停对家庭的影响是巨大的，对家庭生活和经济的影响是巨大的，因为照顾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.