Consequences of Cardiac Arrest: Brain Injury

描述（由申请人提供）：心脏骤停（CA）后的复苏有明显的昏迷或意识障碍风险，导致神经系统预后不良。迫切需要在复苏期间和之后监测脑功能，以优化干预和改善结果。我们研究了ca后脑损伤的电生理指标，包括定量脑电图（qEEG）和定量诱发电位（qEP），以及它们与预后和神经功能缺损的关系。此外，我们通过这些客观手段证明了治疗性低温的益处。我们发现了定量方法来追踪CA的神经损伤和复苏后相关的电节律模式，如爆发抑制，并利用这些新工具来证明在治疗性低温的帮助下电生理恢复和增强的神经预后。这种更新的中心假设是，皮层功能的恢复有皮层和皮层下的起源，昏迷和恢复的唤醒可以通过低温保护和皮层和皮层下结构的药物刺激来促进，并使用定量电生理标记来指导。具体目的是：1)发现与临床相关的、定量的皮层电生理指标。2)发现复苏后皮层-皮层下神经信号的变化及其耦合。3)通过恢复皮质电生理功能和皮质-皮质下网络连通性来评估治疗性低温的神经保护作用。4)通过输注Orexin-A并由此刺激皮层-皮层下网络连通性的药物干预促进昏迷唤醒。5)将本研究转化为客观反馈系统，优化Orexin-A输注滴定治疗性低温的神经保护和药理唤醒作用。CA每年导致数十万人死亡，即使对幸存者来说，结果仍然令人沮丧。我们多方面的方法将导致对觉醒的机制理解，监测皮层功能的手段，以及加速皮层功能恢复的治疗。从唤醒系统的皮层和皮层下成分的直接多单元记录开始，我们将提供唤醒和复苏后成功恢复的机制理解。此外，我们基于qEEG和qEP的监测方法将导致临床相关的、可翻译的干预监测，包括低温和药理学。因此，我们的研究将导致实时神经生理监测技术的全面发展，以优化治疗方案。经验证，所提出的定量的、神经电生理学指导的优化TH/Orexin-A给药应适用于监测患者和指导临床管理。

DESCRIPTION (provided by applicant): Resuscitation after cardiac arrest (CA) entails significant risk of coma or disorders of consciousness resulting in poor neurological outcome. There is an acute need to monitor the brain function during and after resuscitation to optimize intervention and improve outcome. Our previous studies developed electrophysiological markers of post-CA brain injury, including quantitative EEG (qEEG) and quantitative evoked potentials (qEP), and their relationship to outcome and neurological deficits. Further, we demonstrated benefits of therapeutic hypothermia using these objective means. We discovered quantitative methods to track neurological injury from CA and patterns of electrical rhythms associated following resuscitation, such as burst suppression, and utilized these novel tools to demonstrate electrophysiological recovery and enhanced neurological outcome assisted by therapeutic hypothermia. The central hypothesis for this renewal is that recovery of cortical function has both cortical and subcortical origins and arousal from coma and recovery can be facilitated through hypothermic protection and pharmacological stimulation of both cortical and subcortical structures, and guided using quantitative electrophysiological markers. The specific aims are: 1) To discover clinically relevant, quantitative cortical electrophysiological markers o arousal from coma. 2) To discover changes in cortical-subcortical neurological signals and their coupling after resuscitation. 3) To establish the neuroprotective effects of therapeutic hypothermia assessed through restoration of cortical electrophysiological function and cortical-subcortical network connectivity. 4) To promote arousal from coma through pharmacologic intervention by Orexin-A infusion and resulting stimulation of cortical-subcortical network connectivity. 5) To translate this research into an objective feedback system and optimization of delivery of titrated therapeutic hypothermia for neuroprotection and pharmacological arousal by Orexin-A infusion. CA results in hundreds of thousands of deaths each year and, even for survivors, the outcome remains dismal. Our multi-faceted approach will result in mechanistic understanding of arousal, means of monitoring cortical function, and treatments to accelerate recovery of cortical function. Starting with direct multi-unit recordings of cortical and subcorticl components of the arousal system, we will provide mechanistic understanding of arousal and successful restoration after resuscitation. Further, our qEEG and qEP based monitoring approaches will result in clinically relevant, translatable monitoring of interventions, both hypothermia and pharmacological. Our research will thus result in a comprehensive development of real-time neurophysiologic monitoring technology to optimize treatment options. Upon validation, the proposed quantitative, neuroelectrophysiology-guided optimization of TH/Orexin-A delivery should be applicable to monitoring patients and guiding clinical management.