Neuroprotection After Cardiac Arrest

描述（由申请人提供）：在使用高氧和正氧通气的动物心脏骤停（CA）和复苏后，致命前神经化学改变与神经预后和神经病理学的比较强烈地暗示了线粒体蛋白的早期氧化修饰和相关的代谢功能障碍在延迟性神经细胞死亡和永久性脑损伤的病因学中。为了加快改善人类CA后神经系统预后的进展，我们建议改变标准复苏方案，显着降低激发02 （Fi02）的浓度，使其达到足以为大脑和其他组织充氧的水平，但最大限度地减少氧化应激、细胞死亡和神经系统损伤。我们的具体目标是验证一个假设，即在基于血氧计的血红蛋白02饱和度（SpO2）测量的指导下，通过维持正常的缺血后PaO2，可以将CA和复苏后的神经元细胞死亡和短期和长期神经功能损伤降至最低，这在该领域是实用的。目的1。比较犬心脏骤停和复苏后的神经系统结果：*高氧复苏- 100% FiO2 1小时，然后调整FiO2以维持正常的PaO2 *常氧复苏- 21% FiO2 1小时，然后调整FiO2以维持正常的PaO2 *基于氧饱和度的复苏-调整FiO2以维持SpO2在94%至96% *目标2。利用犬模型和三种复苏方案建立复苏FiO2与神经元细胞死亡之间的关系。目标3。将短期犬CA模型的结果扩展为一种短暂性全脑缺血模型，并对成熟和老年大鼠进行长期结果测量。我们将在临床非常相关的犬心脏骤停模型中使用不同的方案来比较神经系统结果和神经元细胞死亡。此外，利用一过性全脑缺血大鼠模型来测量长期结果，并在代表典型CA患者年龄组的老年动物上测试不同的方案。在这个项目的前两到三年内，我们的结果可以用于设计临床试验，以改善心脏骤停和复苏后的神经系统预后。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，拟议的转化研究项目的潜在影响非常显著。

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.