Neurological and cognitive effects of hyperoxia after cardiac arrest

描述（由申请人提供）：在美国，心脏骤停是死亡和残疾的主要原因。即使复苏实现了自主循环恢复（ROSC），>50%的患者遭受致命或致残性脑损伤。最近的数据表明，ROSC后暴露于高氧（即由于吸入氧[FiO 2]分数过高而导致的超正常动脉氧分压）可能加速氧化应激，加重脑中的再灌注损伤，并导致不良结局。长时间的高氧暴露在复苏后护理中极为常见;然而，没有临床研究测试复苏后快速降低FiO 2是否会降低氧化应激并改善结局。我们的假设是，ROSC后FiO 2快速下降可降低氧化应激，并与神经、神经心理和功能结局改善相关。为了检验这一假设，我们将使用一个经验丰富的六中心急诊科（艾德）为基础的研究联盟（急诊医学休克研究网络）追求以下特定目标。我们的第一个目的是测试ROSC后快速FiO 2下降的方案是否降低复苏后护理期间的体内氧化应激。我们将进行一项多中心前瞻性方案实施前后研究，在266例院外室颤心脏骤停复苏的成人艾德患者中测试ROSC后快速降低FiO 2方案的效果。目前，所有研究中心都采用统一的复苏后护理方法，包括治疗性低温。在“治疗前”阶段，患者将接受标准治疗。在“治疗后”阶段，患者将接受标准治疗，并通过实施临床方案在ROSC后快速降低FiO 2。我们将比较最敏感和特异性的体内氧化应激生物标志物-血浆和尿液中的异前列腺素和异呋喃通过质谱测量-在前24小时之间的组。我们的第二个目的是测试快速FiO 2降阶梯方案是否与减少神经功能障碍相关。我们将在出院时确定改良兰金量表（mRS）（一种经过充分验证的神经功能障碍量表，范围从0=无残疾/无症状到6=死亡），并比较两组之间具有良好神经功能结局（定义为mRS <3）的患者比例。我们的第三个目的是测试快速FiO 2降阶梯方案是否与改善的神经心理和功能结局相关。我们将使用经过验证的工具在五个认知领域（记忆，执行功能，词汇语义，视觉感知，精神）和重返工作岗位的能力中比较幸存者在90天时的神经心理和功能结果。意义：该项目将产生关于心脏骤停后护理基本要素的新的、至关重要的知识。研究新的方法来改善这种毁灭性疾病的结果是一个关键和紧迫的优先事项。考虑到心脏骤停给美国人带来的死亡和残疾的严重程度，即使是适度的改善也会带来重大的公共卫生效益。

DESCRIPTION (provided by applicant): Sudden cardiac arrest is a leading cause of death and disability in the U.S. Even if resuscitation achieves return of spontaneous circulation (ROSC), >50% of patients suffer fatal or crippling brain injury. Recent data suggest that exposure to hyperoxia (i.e. supranormal arterial oxygen partial pressure due to an excessively high fraction of inspired oxygen [FiO2]) after ROSC may accelerate oxidative stress, worsen reperfusion injury in the brain, and contribute to poor outcome. Prolonged hyperoxia exposure is extremely common in post- resuscitation care; however, no clinical study has tested if rapidly reducing FiO2 after resuscitation reduces oxidative stress and improves outcomes. Our hypothesis is that rapid FiO2 de-escalation after ROSC reduces oxidative stress and is associated with improved neurological, neuropsychological, and functional outcomes. To test this hypothesis, we will pursue the following Specific Aims using an experienced six center Emergency Department (ED)-based research consortium (Emergency Medicine Shock Research Network). Our first aim is to test if a protocol for rapid FiO2 de-escalation after ROSC lowers in vivo oxidative stress during post- resuscitation care. We will conduct a multicenter prospective before-and-after protocol implementation study testing the effects of a protocol for rapid FiO2 de-escalation after ROSC among 266 adult ED patients resuscitated from out-of-hospital ventricular fibrillation cardiac arrest. All sites currently employ uniform methods of pos-resuscitation care including therapeutic hypothermia. In the "before" phase, patients will receive standard care. In the "after" phase, patients will receive standard care plus rapid FiO2 de-escalation after ROSC via implementation of a clinical protocol. We will compare the most sensitive and specific in vivo biomarkers of oxidative stress - plasma and urine isoprostanes and isofurans measured by mass spectroscopy - over the first 24 hours between groups. Our second aim is to test if the rapid FiO2 de- escalation protocol is associated with reduced neurological disability. We will determine the Modified Rankin Scale (mRS) (a well-validated scale of neurological disability ranging from 0=no disability/asymptomatic to 6=death) at hospital discharge, and compare the proportion of patients with good neurological outcome (defined as a mRS <3) between groups. Our third aim is to test if the rapid FiO2 de-escalation protocol is associated with improved neuropsychological and functional outcomes. We will compare neuropsychological and functional outcomes between groups among survivors at 90 days using validated instruments across five cognitive domains (memory, executive function, lexical-semantic, visuoperceptual, psychomotor) and ability to return to work. Significance: This project will generate new, critically important knowledge about a fundamental element of post-cardiac arrest care. Research on new methods to improve outcomes from this devastating condition is a crucial and urgent priority. Given the magnitude of death and disability that cardiac arrest imparts upon Americans, even modest improvements would provide a major public health benefit.