Neuroprotection following cardiac arrest: A Randomized Control Trial of Magnesium

心脏骤停后的神经保护：镁的随机对照试验

• 批准号: 10742460
• 负责人: Sam Parnia
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742460
• 关键词: Adverse event; American Heart Association; Animals; Anoxia; Anoxic Encephalopathy; Apoptosis; Attenuated; Biological Assay; Biological Markers; Blood; Blood Pressure; Blood flow; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Caring; Cell Death; Cessation of life; Circulation; Collection; Critical Care; Data; Data Collection; Dedications; Eligibility Determination; Enzymes; Event; Goals; Grant; Heart Arrest; Hospitals; Hour; Human; Incidence; Inflammation; Inflammatory; Informed Consent; Infrastructure; Injury; Institutional Review Boards; International; Intervention; Ischemia; Link; MK801; Magnesium; Meta-Analysis; Methods; Mg supplementation; Minocycline; Mitochondria; Morbidity - disease rate; Multi-Institutional Clinical Trial; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nervous System Physiology; Neurological outcome; Neurological status; Neuroprotective Agents; Normal saline; Odds Ratio; Outcome; Oxidative Stress; Pathway interactions; Patients; Pilot Projects; Placebos; Process; Process Assessment; Process Measure; Randomized; Randomized, Controlled Trials; Reperfusion Injury; Reperfusion Therapy; Research; Research Design; Research Personnel; Resuscitation; Retrospective Studies; Sampling; Series; Serum; Serum Markers; Site; Standardization; Stroke; Survival Rate; Survivors; Temperature; Testing; Time; Traumatic Brain Injury; Ventilator; Work; design; excitotoxicity; feasibility testing; improved; mortality; neuroprotection; novel; oxidative damage; pharmacologic; pilot test; prevent; recruit; safety and feasibility; sample collection; secondary endpoint; severe injury; standard of care; survival outcome; timeline

Project Summary/Abstract Cardiac arrest has an estimated annual incidence of 250-350,000 out-of-hospital and 250-750,000 in-hospital events in the U.S., with survival rates as low as 5% and 20% respectively. These outcomes reflect a two-step injury process: a) ischemia during cessation of blood flow and b) secondary reperfusion and inflammatory injury following return of spontaneous circulation (ROSC). With only 3-7% of CA survivors recovering to their pre-CA neurological status, developing interventions to attenuate reperfusion injury are critical to improve patients’ survival and neurological outcomes. A series of animal and human studies have shown that the use of pharmacological interventions targeted against excitoxicity, oxidative injury and inflammatory pathways may reduce ischemia/reperfusion injury and improve post-CA survival and neurological outcomes. A small-scale randomized control trial (RCT) has provided preliminary evidence to support the hypothesis that magnesium (Mg) in the post-CA period as a neuroprotective agent may improve neurological outcomes among survivors. However, additional data is needed to support its use as standard of care in the post-CA period. We therefore propose to collect necessary and sufficient data to design a multisite RCT of Mg neuroprotection following CA. We hypothesize that administering Mg in the post-CA period is feasible and safe, and that it may attenuate excitotoxity, thereby ameliorating the downstream cascade of reperfusion injuries associated with morbidity and mortality. The current application proposes three aims: For Aim 1, a single site pilot RCT will assess the feasibility and safety of administrating Mg and collecting serum samples post-CA. The effects of Mg on serum markers of brain injury, inflammation, and oxidative stress, as well as, rates of ROSC, survival and independent neurological function will also be assessed. For Aim 2, researchers will establish single-IRB (S-IRB) approval for a multi-site pilot RCT of Mg post-CA using Exception From Informed Consent (EFIC). Eligible sites will then be invited to participate in a pilot study. For Aim 3, sites identified in Aim 2 will demonstrate capacity for recruitment and data collection by administering the Mg therapy in up to 4 and placebo in up to 4 post-CA patients. The data obtained through the execution of Aims 1-3 will be used to inform the design and implementation of a large-scale trial to assess the impact of Mg (with standard post-CA care) versus placebo (with standard post-CA care) on survival and independent neurological function after CA.

项目概要/摘要 据估计，每年院外心脏骤停发生率为 250-350,000 例，院内心脏骤停发生率为 250-750,000 例 在美国发生的事件，存活率分别低至 5% 和 20%。这些结果反映了两步走 损伤过程：a）血流停止期间的缺血和b）继发性再灌注和炎症损伤 自主循环恢复（ROSC）后。只有 3-7% 的 CA 幸存者恢复到 CA 前的状态 神经系统状态，制定减轻再灌注损伤的干预措施对于改善患者的 生存和神经系统结果。一系列动物和人类研究表明，使用 针对兴奋毒性、氧化损伤和炎症途径的药物干预可能 减少缺血/再灌注损伤并改善 CA 后生存和神经系统结果。一个小规模的 随机对照试验（RCT）提供了初步证据来支持镁的假设 (Mg) 在 CA 后时期作为神经保护剂可以改善幸存者的神经系统结果。 然而，需要更多数据来支持将其用作 CA 后时期的护理标准。我们因此 建议收集必要且充分的数据来设计 CA 后镁神经保护的多部位随机对照试验。 我们假设在CA后时期施用镁是可行且安全的，并且它可能会减弱 兴奋性毒性，从而改善与发病率相关的再灌注损伤的下游级联反应 死亡。当前的申请提出了三个目标： 对于目标 1，单站点试点 RCT 将评估可行性 CA 后施用镁和收集血清样本的安全性。镁对血清标志物的影响 脑损伤、炎症和氧化应激，以及 ROSC 率、存活率和独立神经功能 功能也将被评估。对于目标 2，研究人员将为多站点建立单一 IRB (S-IRB) 批准 使用知情同意例外 (EFIC) 对 CA 后 Mg 进行试点 RCT。符合条件的网站将被邀请 参加试点研究。对于目标 3，目标 2 中确定的地点将展示招募和数据能力 通过对最多 4 名 CA 后患者进行镁疗法和安慰剂进行收集。得到的数据 通过目标 1-3 的执行，将用于为大规模试验的设计和实施提供信息 评估镁（采用标准 CA 后护理）与安慰剂（采用标准 CA 后护理）对生存的影响 CA 后的独立神经功能。