Brain Monitoring and Therapeutic Hypothermia after Cardiac Arrest

描述（由申请人提供）： 美国每年发生超过40万例心脏猝死。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可以改善CA幸存者生存和神经系统结局的治疗形式。然而，几十年来，低温输送一直盲目地指向更快的冷却，并且没有大脑对温度反应的客观指标。到目前为止，还没有监测方法来指导低温治疗和提高其效率。这种疗法获得更有益结果的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很大程度上是未知的。目的1：我们的第一个目标是开发和评估新的，非侵入性的，定量脑电图（qEEG）标记CA后的功能结果。我们测试了以下假设：a）基于我们的基于熵的新算法的qEEG分析将捕获到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分化的熵水平，并且相应地显示出对损伤后恢复的不同阶段和治疗性低温的影响的更大的灵敏度。目的2：我们将使用qEEG标记来获得大脑对a）低温输送深度（温度水平）和B）持续时间的反应反馈。我们将测试的假设，即电生理监测qEEG将作为一个生物标志物的大脑的恢复，因此，将提供客观的指导低温交付。目标3：我们的最后一个广泛的目标是提供一个客观的分析低温对葡萄糖利用的时空模式（通过小动物正电子发射断层扫描（PET）成像和电生理恢复（EEG））CA后。我们测试的假设，低温将增加葡萄糖的再利用和改变的空间模式，在皮层下和皮层的大脑区域，这有助于相应的EEG变化信号恢复与早期恢复正常化，以改善CA后的功能结果。该项目的意义有三个方面：1）开发和系统评价CA后脑损伤的简单客观的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）预期发现治疗性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。该项目的创新之处在于：1）全面而新颖的定量算法，系统地监测和预测CA后的觉醒，2）首次通过大脑对温度反应的qEEG标记物指导低温输送，以及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理解机制和开发合理的低温治疗方法将非常重要。我们的实验模型和提出的技术方法很容易适用于临床翻译：例如，qEEG标记可以很容易地被纳入临床床边监护仪。就像无处不在的体外除颤器彻底改变了心脏保护一样，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.