Randomized clinical trial of sodium nitrite for out of hospital cardiac arrest

摘要 院外心脏骤停是一个常见的、令人衰弱的公共卫生问题。神经损伤是 这些患者的发病率和死亡率的主要原因是大多数复苏的受害者再也没有恢复 意识。尽管在复苏方面取得了进展，但超过70%的人在uchA后恢复了循环 出院前死亡。需要针对心脏和大脑保护的疗法来改善许多 复苏后阶段的生化/细胞变化，最终导致细胞死亡。这个 阴离子亚硝酸盐(NO2-)在低氧和低pH时转化为NO，不依赖于NOS的活性，使 NO2-一种理想的药物，可在缺血和再灌流早期增加NO的生物利用度 耗尽。亚硝酸盐在动物缺血期或再灌注期的治疗作用 心脏骤停的模型。在一项正在进行的亚硝酸钠(1-14 mg)静脉注射与 在从uchA复苏并送往医院的患者中，我们发现没有 亚硝酸盐对血流动力学的显著有害影响。我们认为，服用亚硝酸钠是 在这一人群中可行，并且与严重的不良事件无关。这些动物和人类的研究 展示了亚硝酸盐在复苏期间作为一种治疗方法的潜在前景，以减少神经损伤和 提高存活率。 这项研究的总体目标是确定服用亚硝酸钠是否安全和 院外心脏骤停持续复苏期间有效。我们建议分两个阶段 临床试验。第一阶段将是一项开放标签剂量发现试验，以确定亚硝酸钠的最佳剂量。 在复苏时给药，以在到达医院时达到10M的血浆水平。这个 第二阶段将是一项安慰剂对照的随机试验，研究亚硝酸钠的最佳单次给药剂量 在复苏期间，以确定安全性和有效性。在这两个阶段，所有患有uchA的患者(两者均为 西雅图的室颤(VF)和非室颤(Non-VF)，医护人员试图进行心脏复苏 已建立的静脉注射通道将符合条件。第二阶段试验的主要安全结果将是存活到 入院和次要疗效的结果将是存活到出院。

Abstract Out-of-hospital cardiac arrest (OHCA) is a common and debilitating public health problem. Neurologic injury is the major cause of morbidity and mortality in these patients with most resuscitated victims never regaining consciousness. Despite advances in resuscitation, over 70% of those who have circulation restored after OHCA die before hospital discharge. Therapies directed at heart and brain protection are needed to ameliorate many of the biochemical/cellular changes during the post resuscitation phase, which ultimately lead to cell death. The anion nitrite (NO2-) is converted to NO during hypoxia and during low pH, independent of NOS activity, making NO2- an ideal drug to increase NO bioavailability during ischemia and early in reperfusion when there is critical depletion. Therapeutic delivery of nitrite during ischemia or at time of reperfusion is cytoprotective in animal models of cardiac arrest. In an ongoing single-center pilot randomized trial of sodium nitrite (1-14 mg) IV vs. identically-appearing placebo in patients resuscitated from OHCA and transported to hospital, we found no significant deleterious effect of nitrite on hemodynamics. We believe that administration of sodium nitrite is feasible and not associated with serious adverse events in this population. These animal and human studies demonstrate the potential promise of nitrite as a therapy during resuscitation to reduce neurologic injury and improve survival. The overall goal of this study is to determine whether the administration of sodium nitrite is safe and efficacious during on going resuscitation for out-of-hospital cardiac arrest. We propose a two-stage clinical trial. The first phase will be an open-label dose finding trial to determine the optimal sodium nitrite dose to be administered at the time of resuscitation to achieve a plasma level of 10 M by hospital arrival. The second phase will be a placebo-control, randomized trial of the optimal single dose of sodium nitrite delivered during resuscitation to determine safety and efficacy. For both phases, all patients who have OHCA (both ventricular fibrillation (VF) and non-VF) in Seattle in which paramedics attempt cardiac resuscitation and have established IV access will be eligible. The primary safety outcome for the phase 2 trial will be survival to hospital admission and the secondary efficacy outcome will be survival to discharge.