Optimizing therapeutic hypothermia after cardiac arrest

描述（由申请人提供）：每年大约有15万美国人因院外心脏骤停而接受治疗，但只有不到5%的人存活下来并获得良好的神经系统预后。诱导低温是临床证明的唯一一种能提高心脏骤停复苏患者存活率和改善神经系统预后的治疗方法。虽然最佳温度范围（32至34℃）已经确定，但我们在最佳发病时间、持续时间和复温率方面的基础知识存在重大差距，这使得临床医生猜测如何最好地应用这种临床有效的干预措施。然而，临床试验中的综合优化受到可行性、时间和成本的严重限制。为了解决这些问题，我们建议使用大鼠心脏骤停模型来系统评估治疗性低温应用中的两个关键变量：最佳起始时间和最佳治疗持续时间。我们假设，心脏骤停后的治疗性低温在心脏骤停后1至8小时内开始治疗是一样有效的，2)维持至少48小时最有效。我们提出的特异性目标将使用3 × 3因子研究设计来检验这些假设，该研究将比较在心脏骤停复苏后1、4或8小时开始的治疗性低温（33.0 +/-1.0℃），维持24、48或72小时，并以每小时0.25℃的固定速率重新加热。这项研究设计将使我们能够确定治疗性低温的最佳起始时间和持续时间，以及这两个参数之间潜在的相互作用。主要转归参数包括生存和Morris水迷宫行为功能，次要转归参数为神经功能良好的生存。我们的结构替代结果将是基于总脑容量的形态计量量化的总脑萎缩。一部分大鼠将进行连续血液采样，用于未来的生物标志物分析。这项研究将首次系统地优化心脏骤停复苏患者的唯一经证实的治疗方法。研究结果将为设计可行、重点突出和明确的临床试验提供急需的基础知识。此外，这种转化范例将可用于有效地评估和优化可能与治疗性低温相比较或联合使用的治疗方法。

DESCRIPTION (provided by applicant): Approximately 150,000 Americans are treated for out-of-hospital cardiac arrest every year, but less than 5% survive with good neurological outcome. Induced hypothermia is the only therapy clinically proven to increase survival and improve neurological outcome of patients resuscitated from cardiac arrest. Although the optimal temperature range (32 to 34 ¿C) is well established, critical gaps in our fundamental knowledge regarding the optimal time of onset, duration, and rate of rewarming have left clinicians guessing how to best apply this clinically effective intervention. Unfortunately, comprehensive optimization in clinical trials is profoundly limited by feasibility, time, and cost. To address these issues, we propose using a rat model of cardiac arrest to systematically evaluate two critical variables in the application of therapeutic hypothermia: optimal time of onset, and optimal duration of therapy. We hypothesize that therapeutic hypothermia after cardiac arrest is 1) equally effective when initiated between 1 and 8 hours after cardiac arrest, and 2) most effective when maintained for at least 48 hours. Our proposed Specific Aim will test these hypotheses using a 3 x 3 factorial study design that will compare therapeutic hypothermia (33.0 +/-1.0 ¿C) initiated 1, 4, or 8 hours after resuscitation from cardiac arrest, maintained for 24, 48 or 72 hours, and rewarmed at a fixed rate of 0.25 ¿C per hour. This study design will allow us to identify the optimal onset and duration of therapeutic hypothermia as well as potential interactions between the two parameters. Primary outcome parameters will include survival and Morris water maze behavioral function, and secondary outcome will be survival with good neurological function. Our structural surrogate outcome will be total brain atrophy based on morphometric quantification of total brain volume. A subset of rats will be instrumented for serial blood sampling to be used for future biomarker analysis. This study will, for the first time, systematically optimize the only proven therapy for patients resuscitated from cardiac arrest. The results will provide the fundamental knowledge that is urgently needed to design feasible, focused, and definitive clinical trials. In addition, this translational paradigm will be available to efficiently evaluate and optimize therapies that might be compared to or used in combination with therapeutic hypothermia.