Normobaric Hyperoxia in Acute Ischemic Stroke

广泛的可获得性、低成本以及多种生化、分子和血液动力学效应 高氧血症使其成为一种理想的神经保护策略。在动物研究中，在最近的一项人类试验中 研究，我们已经记录了呼吸高流量氧气(常压高氧疗法或NBO)在 脑缺血提供了强有力的神经保护。NBO的好处似乎是暂时的，类似于 在先前的高压氧研究中观察到。然而，如果NBO处理的组织是 再灌流。我们认为，如今，随着tPA等新疗法的再灌注率提高，以及 磁共振成像的进展，允许连续评估组织缺血-再灌注，存在一个令人兴奋的 有机会评估NBO的瞬时组织挽救效应是否可以转化(通过诱导或 自发再灌流)转化为持续受益。通过防止早期缺血细胞死亡，NBO可能是一种 延长静脉注射组织型纤溶酶原激活剂(TPA)治疗时间窗的可行策略。 在这项提案中，我们的目标是扩展我们在一项双盲研究中的初步工作，该研究招募了150名急性(&lt；12 小时)5年以上的缺血性中风患者。患者将接受NBO或房间空气，为期8小时，并将 行系列临床检查和磁共振弥散成像(DWI/PWI)。NBO Will的安全性和有效性 在对美国国立卫生研究院卒中量表评分变化的统计分析中确定治疗意向 在治疗之后。将评估NBO与再灌注的潜在协同效益。我们还将 比较MRI缺血病变生长和出血率，并执行新的基于体素的分析 DWI和PWI参数。在第一年，我们将排除接受tPA治疗的患者，并调查NBO的安全性 在栓塞性(基于血栓的)啮齿动物中风模型中使用tPA。如果这种组合对啮齿动物来说是安全的，并且如果 第一年的人类数据不会引起安全问题，我们将扩大到包括接受tPA治疗的患者。最后，我们 将在啮齿动物中风模型上进行病理和体内核磁共振研究，以调查NBO是否可以 延长tPA时间窗，观察NBO对脑血流动力学的影响。 这些研究意义重大，因为它们将全面测试氧气在脑缺血中的作用。 大脑。呼吸高流量氧气可能被证明是一种简单、实用、便携和潜在的成本效益 独立或通过延长静脉注射tPA的时间窗来改善卒中结果的治疗。

The wide availability, low cost, and multiple biochemical, molecular and hemodynamic effects of hyperoxia make it ideally suited as a neuroprotective strategy. In animal studies, and in a recent pilot human study, we have documented that breathing high-flow oxygen (normobaric hyperoxia therapy or NBO) during brain ischemia confers potent neuroprotection. The benefit of NBO appears to be transient, similar to that observed in prior hyperbaric oxygen studies. However, sustained benefit does occur if NBO-treated tissue is reperfused. We believe that today, with enhanced reperfusion rates from newer therapies such as tPA, and advances in MRI that allow serial assessment of tissue ischemia-reperfusion, there exists an exciting opportunity to assess whether NBO's transient tissue-salvaging effects can be converted (via induced or spontaneous reperfusion) into sustained benefit. By preventing early ischemic cell death, NBO may be a feasible strategy to extend the narrow time window for IV tissue plasminogen activator (tPA) therapy. In this proposal we aim to extend our preliminary work in a double-blind study enrolling 150 acute (<12 hours) ischemic stroke patients over 5 years. Patients will receive NBO or Room Air for 8 hours and will undergo serial clinical examinations and diffusion-perfusion MRI (DWI/PWI). Safety and efficacy of NBO will be determined in an 'intention to treat' statistical analysis of change in NIH stroke scale scores during and after therapy. The potential synergistic benefit of NBO with reperfusion will be assessed. We will also compare MRI ischemic lesion growth and hemorrhage rates, and perform novel voxel-based analyses of DWI and PWI parameters. In year 1 we will exclude tPA-treated patients and investigate the safety of NBO with tPA in an embolic (clot-based) rodent stroke model. If the combination appears safe in rodents, and if the year 1 human data raises no safety concerns, we will expand to include tPA-treated patients. Finally, we will conduct pathological and in-vivo MRI studies in rodent stroke models to investigate whether NBO can extend the tPA time window, and to investigate NBO's effects on cerebral hemodynamics. These studies are significant because they will comprehensively test the effects of oxygen in the ischemic brain. Breathing high-flow oxygen may prove to be a simple, practical, portable, and potentially cost-effective therapy that improves stroke outcomes, either independently or by extending the time window for IV tPA.