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 幸存者的不良后果很普遍，几乎都是脑损伤的次要后果。我们的 长期研究计划研究CA引起的全球脑缺血的影响。在第一项研究中 在这一阶段，我们开发并广泛验证了CA后脑损伤的测量方法。在第二阶段，我们 开始展示治疗严重神经缺陷的解决方案。虽然高质量的 心肺复苏术(CPR)已被证明可以改善全身血流灌注，这是特异的和经过验证的 与CA术后脑灌注和血压管理相关的指南是不存在的(1-3)。我们的钥匙 为这一提议奠定基础的假设是，大脑功能和神经结果是相互依赖的 关于脑血管自动调节(CVAR)的状态。CVAR维持动态平衡的脑血流 (CBF)在平均动脉压(MAP)范围内，在极端压力下保护大脑免受损伤 和流动。全脑缺氧缺血性损伤后，CVAR常受损或缺失。有必要发展 直接测量CVaR，并进行严格验证。我们的中心假设是个性化地图，CBF 在CVAR监测的指导下进行低温治疗将最大限度地减少脑损伤并改善 神经学结果。我们有5个目标。目标1：我们将开发一种微型多对比显微镜来 在CA术后恢复期内持续询问CVAR和COX。我们获得了脑电测量结果， 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 生物标记物，客观地校准我们的CVAR(和COX)测量与神经学结果。目标2，我们将 应用新型MRI评价CVAR功能障碍与CA术后全脑损伤的关系 基于血液动力学、氧合和代谢的生物标志物。因此，我们的目标1和2将使我们能够 将CVAR描述为实时治疗指南以及结果的预测者。对于AIMS 3、4和 5、我们将应用治疗手法来恢复和优化以技术衡量的CVaR 在目标1和目标2中开发。目标3：我们将重点关注心肺复苏后的地图管理和滴定地图，以实现最佳 CVaR联合肾上腺素和硝酸甘油输注分别提高和降低MAP改善 神经学结果。目的：研究低功率治疗性超声对脑血流量的增强作用。 目的：我们将重点研究CA术后的靶向温度管理疗法(TTM)，并研究 正规化CVaR斜率/位移的滴定温度。总而言之，我们的提案开发了新技术和 治疗以解决心肺复苏后CVAR管理中的关键知识差距。我们希望我们的根本 这项工作可能会转化为CA管理的修改临床实践，在这种实践中，除了拯救 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.