Neuroprotection After Cardiac Arrest

描述（由申请人提供）：在使用高氧和常氧通气的动物中，致死前神经化学改变与心脏骤停（CA）和复苏后神经学结局和神经病理学的比较强烈暗示了线粒体蛋白的早期氧化修饰和相关代谢功能障碍在迟发性神经细胞死亡和永久性脑损伤的病因学中的作用。为了加快改善人类CA后的神经学结果的进展，我们提出了标准复苏方案的改变，其将吸入的O2（FiO 2）的浓度显著降低至足以使脑和其他组织充氧但使氧化应激、细胞死亡和神经损伤最小化的水平。我们的具体目标是测试这样的假设：根据基于血氧测定的血红蛋白O2饱和度（SpO 2）测量结果的指导，通过维持正常的缺血后PaO 2，可以最大限度地减少CA和复苏后的神经元细胞死亡以及短期和长期神经功能损伤。适用于该领域。目标1。比较犬心脏骤停和复苏后的神经功能结局：* 高氧复苏- 100% FiO 2持续1小时，然后调整FiO 2以维持正常PaO 2 * 常氧复苏- 21% FiO 2持续1小时，然后调整FiO 2以维持正常PaO 2 * 基于血氧测定的复苏-调整FiO 2以维持SpO 2在94%至96% * 目标2。使用犬模型和三种复苏方案建立复苏FiO 2和神经元细胞死亡之间的关系。目标3。使用短暂性全脑缺血模型扩展短期犬CA模型获得的结果，并对成熟和老年大鼠进行长期结局测量。我们将在临床上非常相关的犬心脏骤停模型中使用不同的方案比较神经学结果和神经元细胞死亡。此外，短暂性全脑缺血的大鼠模型用于测量长期结果，并在代表典型CA患者年龄组的老年动物上测试不同方案。在该项目的前两三年内，我们的结果可用于设计临床试验，以改善心脏骤停和复苏后的神经结局。仅在美国，每年就有超过250，000名心脏骤停患者复苏，其中一半以上患有神经系统疾病和死亡率，拟议的转化研究项目的潜在影响非常重要。

DESCRIPTION (provided by applicant):Comparisons of pre-lethal neurochemical alterations to neurologic outcome and neuropathology following cardiac arrest (CA) and resuscitation in animals using hyperoxic and normoxic ventilation strongly implicate early, oxidative modification to mitochrondial proteins and associated metabolic dysfunction in the etiology of delayed neural cell death and permanent brain injury. To expedite progress in improving neurologic outcome following human CA, we propose a change in standard resuscitative protocols that dramatically lowers the concentration of inspired 02 (Fi02) to a level that sufficiently oxygenates the brain and other tissues but that minimizes oxidative stress, cell death, and neurologic impairment. Our specific aims test the hypothesis that neuronal cell death and both short- and long-term neurologic impairment following CA and resuscitation are minimized by maintaining normal post-ischemic PaO2, as guided by oximetry-based measurements of hemoglobin 02 saturation (SpO2) that are practical for use in the field. Aim 1. Compare neurologic outcome following canine cardiac arrest and resuscitation using:* Hyperoxic Resuscitation - 100% FiO2 for 1 hr then adjust FiO2 to maintain normal PaO2 * Normoxic Resuscitation - 21% FiO2 for 1 hr then adjust FiO2 to maintain normal PaO2 * Oximetry-Based Resuscitation - Adjust FiO2 to maintain SpO2 at 94% to 96% *Aim 2. Establish relationships between resuscitative FiO2 and neuronal cell death using the canine model and three resuscitation protocols. Aim 3. Extend the results obtained with the short-term canine CA model using a transient global cerebral ischemia model with long-term outcome measures performed on mature and aged rats. We will compare both neurologic outcome and neuronal cell death using different protocols in a clinically very relevant canine model of cardiac arrest. In addition, a rat model of transient global cerebral ischemia is utilized to measure long-term outcome and to test different protocols on aged animals, representing the typical CA patient age-group. Within the first two - three years of this project, our results could be used to design clinical trials to improve neurologic outcome following cardiac arrest and resuscitation. With over 250,000 cardiac arrest victims resuscitated each year in the U.S. alone, and over half of these suffering from neurological morbidity and mortality, the potential impact of the proposed translational research project is highly significant.