Neurological and cognitive effects of hyperoxia after cardiac arrest

描述（由申请人提供）：心脏骤停是美国死亡和残疾的主要原因，即使复苏实现了自发循环恢复（ROSC），仍有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（即由于吸入氧分数过高[FiO2]而导致动脉氧分压异常）可能加速氧化应激，加重脑再灌注损伤，并导致预后不良。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FiO2是否能降低氧化应激并改善预后。我们的假设是，ROSC后FiO2的快速降低可减少氧化应激，并与神经、神经心理和功能结果的改善有关。为了验证这一假设，我们将使用一个经验丰富的六个中心急诊科（ED）为基础的研究联盟（急诊医学休克研究网络）来追求以下具体目标。我们的第一个目的是测试在ROSC后快速降低FiO2浓度的方案是否可以在复苏后护理期间降低体内氧化应激。我们将在266例院外心室颤动心脏骤停复苏的成人ED患者中进行一项多中心前瞻性方案实施前后对比研究，以测试ROSC后快速FiO2降级方案的效果。所有站点目前采用统一的复苏后护理方法，包括治疗性低温。在“术前”阶段，患者将接受标准治疗。在“术后”阶段，患者将接受标准护理，并通过实施临床方案在ROSC后快速降低FiO2水平。我们将比较各组前24小时内氧化应激最敏感和特异性的体内生物标志物——血浆和尿液异前列腺素和质谱测量的异呋喃。我们的第二个目的是测试快速二氧化碳浓度降低方案是否与减少神经功能障碍有关。我们将在出院时确定改良兰金量表（mRS）（一种经过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），并比较两组间神经功能预后良好（mRS <3）的患者比例。我们的第三个目标是测试快速FiO2降级方案是否与改善的神经心理和功能结果相关。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、精神运动）和重返工作岗位的能力，比较90天后幸存者组间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。研究新方法以改善这种毁灭性疾病的后果是一个至关重要和紧迫的优先事项。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给公众健康带来重大好处。

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.