Optimizing therapeutic hypothermia after cardiac arrest

描述(由申请人提供)：每年约有15万美国人因院外心脏骤停而接受治疗，但只有不到5%的人存活并获得良好的神经预后。诱导低温是唯一一种临床证明可以提高心脏骤停复苏患者存活率和改善神经预后的治疗方法。尽管最佳温度范围(32℃至34℃)已经确定，但我们关于最佳发病时间、持续时间和复温速度的基础知识的关键差距让临床医生猜测如何最好地应用这种临床有效的干预措施。不幸的是，临床试验的全面优化受到可行性、时间和成本的严重限制。为了解决这些问题，我们建议使用心脏骤停的大鼠模型来系统地评估治疗性低温应用中的两个关键变量：最佳起效时间和最佳治疗时间。我们假设，心脏骤停后的治疗降温1)在心脏骤停后1至8小时内开始降温同样有效，2)维持至少48小时最有效。我们提出的具体目标将使用3x3析因研究设计来检验这些假设，该设计将比较从心脏骤停复苏后1、4或8小时开始的治疗性低温(33.0+/-1.0℃)、维持24、48或72小时以及以每小时0.25℃的固定速率复温。这项研究设计将使我们能够确定治疗低温的最佳开始和持续时间，以及这两个参数之间的潜在相互作用。主要结果参数将包括存活和Morris水迷宫行为功能，次要结果将是存活并具有良好的神经功能。我们的结构性替代结果将是基于对总脑体积的形态计量量化的全脑萎缩。将对一部分大鼠进行连续血液采样，以用于未来的生物标记物分析。这项研究将首次系统地优化唯一被证明适用于心脏骤停患者复苏的治疗方法。这些结果将提供设计可行的、有重点的和决定性的临床试验迫切需要的基本知识。此外，这一转换范式将可用于有效地评估和优化可能与治疗性低温治疗相比较或结合使用的治疗方法。

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.