Normobaric Hyperoxia in Acute Ischemic Stroke

广泛的可用性，低成本，以及多种生化，分子和血液动力学效应， 高氧使其理想地适合作为神经保护策略。在动物研究中，以及最近的一项人体试验中， 在一项研究中，我们已经证明，在呼吸高流量氧气（常压高氧治疗或NBO）期间， 脑缺血赋予有效的神经保护作用。NBO的好处似乎是短暂的，类似于 在之前的高压氧研究中观察到。然而，如果NBO治疗的组织是 再灌注。我们相信，今天，随着新疗法如tPA的再灌注率提高， MRI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的短暂组织挽救作用是否可以转换（通过诱导或 自发再灌注）转化为持续获益。通过防止早期缺血性细胞死亡，NBO可能是一种治疗方法。 延长IV组织纤溶酶原激活剂（tPA）治疗的狭窄时间窗的可行策略。 在这项建议中，我们的目标是扩大我们的初步工作，在双盲研究招募150急性（<12 小时）缺血性中风患者超过5年。患者将接受NBO或室内空气治疗8小时， 进行系列临床检查和弥散灌注MRI（DWI/PWI）。NBO的安全性和有效性将 在NIH卒中量表评分变化的“意向治疗”统计分析中确定， 在治疗后。将评估NBO与再灌注的潜在协同益处。我们还将 比较MRI缺血性病变生长和出血率，并进行新的基于体素的分析， DWI和PWI参数。在第1年，我们将排除tPA治疗的患者，并研究NBO的安全性 与tPA在栓塞（基于血栓）啮齿动物中风模型中的作用。如果这种组合在啮齿动物中是安全的， 第1年的人体数据未引起安全性问题，我们将扩展到包括tPA治疗的患者。最后我们 将在啮齿动物中风模型中进行病理和体内MRI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在缺血性脑损伤中的作用。 个脑袋呼吸高流量氧气可能被证明是一种简单，实用，便携，并具有潜在的成本效益 单独或通过延长IV tPA的时间窗来改善卒中结局的治疗。

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.