Consequences of Cardiac Arrest: Brain Injury

心脏骤停（CA）具有毁灭性的后果，即使成功复苏，存活率也很低 并且幸存者中的不利结果是普遍的，这几乎一致地继发于脑损伤。我们 一项长期研究计划研究了CA引起的全脑缺血的影响。在第一项研究中， 阶段，我们开发并广泛验证了CA后脑损伤的措施。在第二阶段，我们 开始展示主要神经功能缺损的治疗方案。虽然高质量的 心肺复苏术（CPR）已被证明可以改善全身灌注，特异性和有效性 与CA后脑灌注和血压管理相关的指南不存在（1-3）。我们的关键 为这一提议奠定基础的一个假设是，脑功能和神经学结果是依赖的 脑血管自动调节（CVAR）状态。CVAR维持脑血流量的稳态 (CBF)在平均动脉压（MAP）范围内，并在极端压力下保护大脑免受损伤 和流动。在全脑缺氧缺血损伤后，CVAR常常受损或缺失。需要开发 直接测量CVAR并严格验证。我们的中心假设是个体化MAP、CBF CVAR监测指导下的低温管理将最大限度地减少脑损伤， 神经学结果我们有五个目标。目标1：我们将研制一种微型多对比度显微镜， 在CA后恢复期内持续询问CVAR和考克斯。我们进行了脑电图测量， 急性和晚期神经病理学研究，早期和长期行为分析以及基于血液的血管 生物标志物来客观地校准我们的CVAR（和考克斯）指标与神经系统结局。目标2，我们将 通过新型MRI评估，确定CVAR功能障碍与CA后全脑损伤之间的关系 基于血流动力学、氧合和代谢生物标志物。因此，我们的目标1和2将使我们能够 将CVAR表征为真实的时间治疗指南以及结果的指示器。对于目标3、4和 5，我们将应用治疗策略来恢复和优化CVAR， 在目标1和2中制定。目标3：我们将专注于CPR后MAP管理，并滴定MAP， CVAR联合肾上腺素和硝酸甘油输注分别升高和降低MAP以改善 神经学结果。目的4：研究低功率治疗性超声对脑血流的影响。 目的5：我们将重点关注CA后靶向温度管理治疗（TTM），并研究 标准化CVAR斜率/偏移时的滴定温度。总之，我们的提案开发了新技术， 治疗，以解决CPR后CVAR管理中的关键知识缺口。我们希望我们的基本 这项工作将有可能转化为CA管理的修改后的临床实践，其中，除了挽救 心脏功能，通过基于CVAR的神经功能管理使大脑成为焦点。

Cardiac arrest (CA) has devastating consequences, even with successful resuscitation survival rates are low and unfavorable outcomes in survivors are rampant which are almost uniformly secondary to brain injury. Our long-term research program studies the effects of global brain ischemia resulting from CA. In the first research phase, we developed and extensively validated measures of brain injury after CA. In the second phase, we embarked on demonstrating therapeutic solutions for major neurologic deficit. While high quality of cardiopulmonary resuscitation (CPR) has been shown to improve systemic perfusion, specific and validated guidelines related to post-CA brain perfusion and blood pressure management are non-existent (1-3). Our key hypothesis, laying the foundation for this proposal, is that brain function and neurologic outcome are dependent on the state of cerebrovascular autoregulation (CVAR). CVAR maintains a homeostatic cerebral blood flow (CBF) within a mean arterial pressure (MAP) range and protects the brain from injury during extremes of pressure and flow. After global hypoxic ischemic injury, CVAR is often impaired or absent. There is a need to develop direct measures of CVAR and validate it rigorously. Our central hypothesis is that individualizing MAP, CBF and hypothermia management as guided by CVAR monitoring will minimize brain injury and improve neurologic outcome. We have 5 aims. Aim 1: we will develop a miniature multicontrast microscope to continuously interrogate CVAR and COx throughout the post-CA recovery period. We acquired EEG measures, acute and late neuropathologic studies, early and long-term behavioral analyses as well as blood-based vascular biomarkers to objectively calibrate our CVAR (and COx) measures with neurologic outcomes. Aim 2, we will determine the relationship between CVAR dysfunction and post-CA whole brain injury as assessed by novel MRI based hemodynamic, oxygenation and metabolic biomarkers. Therefore, our aims 1 and 2 will enable us to characterize CVAR as a real time therapeutic guide as well as a prognosticator of outcome. For aims 3, 4 and 5, we will apply therapeutic maneuvers to restore and optimize CVAR as measured by the technologies developed in aims 1 and 2. Aim 3: we will focus on post-CPR MAP management and titrate MAP for optimal CVAR with epinephrine and nitroglycerine infusion to increase and decrease MAP respectively to improve neurologic outcomes. Aim 4: we study the effect CBF augmentation using low power therapeutic ultrasound. Aim5: We will focus on post-CA targeted temperature management therapy (TTM) and study the effects of titrating temperature on normalizing CVAR slope/shift. In summary, our proposal develops new technologies and therapies to address a critical knowledge gap in post-CPR CVAR management. We hope that our fundamental work will potentially translate into modified clinical practices for CA management in which, beyond rescuing the heart function, makes the brain the focus through CVAR based management of neurological function.