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Optimizing therapeutic hypothermia after cardiac arrest

优化心脏骤停后的低温治疗

基本信息

批准号：
7391275
负责人：
ROBERT W. NEUMAR
金额：
$ 17.23万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-05-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：每年约有15万美国人在院外接受心脏骤停治疗，但只有不到5%的人存活下来，神经功能恢复良好。诱导低温是临床上证明的唯一治疗方法，可以提高心脏骤停复苏患者的生存率并改善神经功能结局。虽然最佳温度范围（32至34 ℃）已经确立，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。不幸的是，临床试验中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，我们建议使用大鼠模型的心脏骤停系统地评估两个关键变量的应用治疗性低温：最佳的发病时间，和最佳的治疗持续时间。我们假设，心脏骤停后的治疗性低温1）在心脏骤停后1至8小时之间开始时同样有效，2）维持至少48小时时最有效。我们提出的具体目标将使用3 × 3析因研究设计来测试这些假设，该设计将比较心脏骤停复苏后1、4或8小时开始的治疗性低温（33.0 +/-1.0 <$C），维持24、48或72小时，并以每小时0.25 <$C的固定速率复温。这项研究设计将使我们能够确定治疗性低温的最佳开始和持续时间以及两个参数之间的潜在相互作用。主要结局参数包括生存率和Morris水迷宫行为功能，次要结局为神经功能良好的生存率。我们的结构替代结果将是基于总脑体积的形态定量的总脑萎缩。将对一部分大鼠进行连续采血，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患者复苏的唯一有效疗法。这些结果将为设计可行的、有针对性的和确定的临床试验提供迫切需要的基础知识。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结合使用的疗法。