Developing and characterizing a translational neonatal rat cardiac arrest and cardiopulmonary resuscitation model

项目摘要 心脏骤停是发病率和死亡率的主要潜在原因，也是儿科心脏骤停的危险因素 包括年幼（<1岁）、男性、需要外科手术或通气和心脏缺陷。 复苏的改善增加了复苏后的生存结局， 缺乏改善长期神经学结果。心脏骤停引起的全身缺血 全身性缺氧/缺氧、高碳酸血症和酸中毒，导致脑和其他器官系统损伤。的 全脑缺血（GCI）后的神经系统后遗症包括脑损伤、癫痫发作和长期 运动认知和情绪异常围产期新生儿的低温治疗 缺氧缺血性事件和小于6小时的年龄仍然是唯一的干预措施，以改善结果，但 对于年龄较大的新生儿和长期神经损伤的应用有限，即使在接受 日该提案的目标是通过开发一种治疗新生儿全脑缺血的药物， 更接近临床情况的动物模型。重要的是，新生儿CA/CPR模型将更多地 概括了在严重灌注不足或心脏骤停期间发生的全身性血流减少。 因此，我们可以检查脑后部区域对缺血性损伤和器官-脑的反应， 这是以前不可能在长期等效啮齿动物的相互作用。在目标1中，我们将优化我们的心脏 停搏持续时间，以产生类似于新生儿GCI中发现的病理生理学，并将表征大脑 损伤组织学和磁共振成像。在目标2中，我们将描述行为缺陷， 新生儿GCI。通过完成这些目标，我们将提供一个新的工具来研究新生儿全脑缺血 这将为未来的机制研究和合作奠定基础。

Project Summary Cardiac arrest is a major underlying cause of morbidity and mortality and risk factors for pediatric cardiac arrest include early age (<1 year), male sex, requirement for surgical intervention or ventilation and cardiac defects. Improvements in resuscitation have increased survival outcomes after resuscitation however therapies to improve long-term neurological outcomes are lacking. Global ischemia resulting from cardiac arrest causes systemic anoxia/hypoxia, hypercapnia and acidosis, causing injury to the brain and other organ systems. The neurological sequelae following global cerebral ischemia (GCI) include cerebral lesions, seizures and long-term motor, cognitive and emotional abnormalities. Therapeutic hypothermia for neonates suffering a perinatal hypoxic-ischemic event and are less than 6 hours old remains the only intervention to improve outcomes but has limited application for older neonates and long-term neurological impairments remain even in those receiving TH. The goal of this proposal is to advance therapies for neonatal global cerebral ischemia by developing an animal model that more closely resembles the clinical scenario. Importantly, a neonatal CA/CPR model will more recapitulate the systemic reduction in blood flow that occurs during severe hypoperfusion or cardiac arrest. Therefore, we can examine the response of posterior brain regions to ischemic injury and organ-brain interactions that was not previously possible in term-equivalent rodents. In aim 1, we will optimize our cardiac arrest duration to generate pathophysiology that resembles that found in neonatal GCI and will characterize brain injury with histology and magnetic resonance imagine. In aim 2, we will characterize the behavioral deficits that result from neonatal GCI. By completing these aims we will provide a new tool to study neonatal global ischemia that will serve as a foundation for future mechanistic studies and collaborations.