Brain Monitoring and Therapeutic Hypothermia after Cardiac Arrest

描述(由申请人提供)： 美国每年发生40多万例心脏性猝死。在心脏骤停(CA)的幸存者中，脑损伤是功能恢复的最大障碍。诱导低温是目前唯一能同时改善CA幸存者的生存和神经预后的治疗形式。然而，几十年来，低温治疗一直盲目地朝着更快的冷却方向发展，而没有客观的指标来衡量大脑对温度的反应。到目前为止，还没有一种监测方法来指导低温治疗并提高其疗效。这种疗法更有益的结果的一个主要障碍是低温的最佳水平和持续时间尚不清楚。低温保护作用的详细机制也在很大程度上还不清楚。目的1：我们的第一个目标是开发和评估新的、无创的、定量的脑电(QEEG)标记物，以评估CA术后的功能结果。我们检验了这样的假设：a)基于我们的新的基于熵的算法的qEEG分析将捕捉到CA前基线的电生理恢复，以及b)子带中的顺序恢复将具有高度区分的熵水平，并且相应地对损伤后恢复的不同阶段和治疗低温的影响显示出更高的敏感性。目的2：我们将使用qEEG标记来获得大脑对a)深度(温度水平)和b)低温持续时间的反应的反馈。我们将验证QEEG电生理监测将作为大脑恢复的生物标志物的假设，从而为低温治疗提供客观指导。目的3：通过小动物正电子发射断层扫描(PET)和电生理恢复(EEG)，客观分析低温对CA术后葡萄糖利用时空模式的影响。我们验证了这样的假设，即低温会增加葡萄糖的再利用，改变皮质下和皮质脑区的空间格局，从而有助于相应的脑电变化，信号恢复，更早地恢复正常化，以改善CA术后的功能结果。该项目的意义有三个方面：1)开发和系统评估CA后脑损伤的简单和客观的qEEG监测工具；2)动态低温滴定改善功能和电生理结果的预期益处；3)预期发现治疗低温背后的保护机制以及随后的葡萄糖利用和皮质电生理功能。本项目的创新之处在于：1)全面、新颖的量化算法对CA后觉醒进行系统的监测和预测；2)首次通过脑温度反应的qEEG标记物指导低温治疗；3)CA后独特的双重监测方法(PET和EEG)，以揭示低温的保护机制。使用葡萄糖代谢和电生理恢复(EEG)模式来评估改善的方法对于了解其机制和开发合理的低温治疗方法具有非常重要的意义。我们的实验模型和建议的技术方法很容易用于临床翻译：例如，qEEG标记物可以很容易地合并到临床床边监护仪中。就像无处不在的体外除颤器给心脏保护带来了革命性的变化一样，我们希望我们的新型低温监测和滴定将进入临床实践。

DESCRIPTION (provided by applicant): More than 400,000 sudden cardiac deaths occur in the USA annually. Among survivors of cardiac arrest (CA), brain injury is the biggest impediment to functional recovery. Induced hypothermia is currently the only form of therapy that improves both survival and neurological outcome for CA survivors. However, for decades, hypothermia delivery has been blindly directed toward faster cooling, and without objective indicators of the brain's response to temperature. So far, there is no monitoring methodology to guide hypothermia therapy and to improve its efficiency. A major hindrance for more beneficial results of this therapy is that optimal level and duration of hypothermia is unknown. The detail mechanisms underlying the protective effect of hypothermia are also largely unknown. Aim 1: Our first goal is to develop and evaluate novel, non-invasive, quantitative EEG (qEEG) marker of functional outcome after CA. We test the hypotheses that a) qEEG analysis, based on our novel entropy based algorithms, will capture electrophysiological recovery to pre-CA baseline, and b) sequential recovery in subbands will have highly differentiated entropy level, and correspondingly show greater sensitivity to different phases of recovery after injury and effects of therapeutic hypothermia. Aim 2: We will use the qEEG marker to obtain feedback on brain's response to the a) depth (temperature level) and b) duration of hypothermia delivery. We will test the hypothesis that electrophysiological monitoring by qEEG will serve as a biomarker of the brain's recovery and, thus, will provide objective guidance for hypothermia delivery. Aim 3: Our last broad goal is to provide an objective analysis of hypothermia's effect on spatio-temporal pattern of glucose utilization (via small animal positron emission tomography (PET) imaging and electrophysiological recovery (EEG)) after CA. We test the hypotheses that hypothermia will increase the glucose re-utilization and change the spatial pattern in subcortical and cortical brain regions, which contribute to corresponding EEG changes signaling recovery with an earlier return of normalization, to improve the functional outcome after CA. The significance of this project is three fold: 1) development and systematic evaluation of simple and objective qEEG monitoring tools of brain injury after CA, 2) the expected benefits of improved functional and electrophysiological outcomes with dynamic hypothermia titration, and 3) expected discovery of the protective mechanism behind therapeutic hypothermia and consequent glucose utilization and cortical electrophysiological function. The innovation in this project lies in 1) comprehensive and novel quantitative algorithm to systemically monitor and predict arousal after CA, 2) for the first time, guiding hypothermia delivery by the qEEG markers of brain's response to temperature, and 3) unique dual monitoring approach (PET and EEG) after CA to uncover hypothermia's protective mechanism. The approach to assess the improvement using glucose metabolic and electrophysiological recovery (EEG) patterns will be highly important to understand the mechanisms and develop a rational approach to hypothermia treatment. Our experimental model and the proposed technical approaches readily lend themselves to clinical translation: for example qEEG markers could easily be incorporated in a clinical bedside monitor. Like ubiquitous external defibrillator revolutionized heart protection, our novel monitoring and titration of hypothermia we hope will enter clinical practice.