Normobaric O2 in Ischemic Stroke

描述(由申请人提供)：急性中风护理正从治疗虚无主义演变为在梗死发生前迅速逆转缺血的做法。这项关于在六家合作医院设立急性中风转化性研究专门计划的提议，将通过其三个综合研究项目以及通过其对拥有两个学术医疗中心、四个社区医院和每年1500名中风患者的大型医疗系统的影响来推动中风治疗。项目1：脑梗塞在一定程度上与大脑氧气输送受损有关。我们发现，在动物中风模型中，常压高氧可延迟永久性脑损伤。在急性中风患者中使用常压高氧治疗的初步研究似乎很有希望。在这里，我们建议在动物模型和患者中进行协调研究，以测试这种广泛使用的疗法在单独使用或与溶栓治疗联合使用时的安全性。在第二阶段的随机双盲试验中，我们将测试常压高氧改善患者神经功能缺失和减少缺血损伤程度的能力。项目II：结合我们对氧气作为一种治疗的兴趣，我们建议也研究氧化过程在组织破坏和继发性出血中的作用。合作伙伴的SPOTRIAS团队成员研究了动物体内基质金属蛋白酶(MMPs)的激活情况，以及急性中风患者的血清氧化应激标志物。在这里，我们建议在动物卒中模型中进行血清和脑标志物的研究，以补充关于急性卒中患者的基质金属蛋白酶和氧化血清标志物的研究，因为它们与预后、氧气暴露和再灌注有关。本研究将为中风急性期抗氧化疗法的发展奠定基础。项目III：合作伙伴卒中研究人员开发了对急性卒中患者的缺血性变化进行成像的方法。在这里，我们建议使用CT灌注技术来建立血流和血容量的阈值，以区分哪些组织可以再灌注挽救，哪些组织不能再灌注。这项技术将被测试其对临床和组织结果的预测能力。我们假设，通过预测作为治疗功能的组织命运，这种广泛可用的基于CT的技术将指导急性中风患者的临床决策，并成为检验新疗法挽救脑组织能力的大型临床试验中的有用工具。这些项目中的每一个都有重叠的调查路线以及共同的执行程序。项目1和2是真正的翻译性的，因为动物研究计划加强临床计划。我们相信，将我们强大的中风实验室科学与整个合作伙伴网络中有效的临床中风核心相结合，将催生一个强大的转换研究中心，有效地为社区实践带来新的治疗方法。 项目1：缺血性卒中的常压高氧血症 派：Aneesh B.Singhal，M.D.-P.I. 描述(申请人提供)：在常压下呼吸高流量氧气(常压氧疗，NBO)可能是一种简单的策略，可以维持脑缺血组织(‘购买时间’)，直到发生自发或治疗性再灌注，从而改善中风预后。通过预防早期缺血细胞死亡，NBO可能是一种有用的辅助治疗，可以延长静脉注射组织纤溶酶原激活剂(TPA)治疗的狭窄(3小时)时间窗口。我们最近的啮齿动物和人类中风试点研究提供了令人信服的证据，表明早期NBO具有强大的神经保护作用。虽然这种益处似乎是暂时的，类似于之前的高压氧研究中观察到的那样，但如果NBO治疗的缺血组织稍后再灌流，确实会产生持久的益处。在这项提案(SPOTRIAS项目1)中，我们的目标是将我们的初步工作扩展到一项双盲、随机、安慰剂对照的临床试验中，纳入240名急性(9小时)缺血性中风患者，为期5年。患者将接受NBO或Room Air 8小时的治疗，并接受一系列临床评估和CT扫描。NBO的治疗潜力将通过对治疗过程中NIHSS评分变化的统计分析来评估。作为项目2(LEV)的一部分，将在接受基线和24小时CT灌注扫描以评估再灌注的患者中评估NBO与再灌注的潜在协同效益。其他二级分析将包括评估治疗后的临床功能评分、脑出血率和CT扫描上的病变体积增长。在第一年，我们将排除接受tPA治疗的患者，并调查NBO和tPA联合应用在栓塞性(基于血栓的)啮齿动物卒中模型中的安全性和有效性。如果联合治疗在啮齿动物中看起来是安全的，如果第一年的人类数据没有引起安全问题，我们将把接受tPA治疗的患者纳入NBO的临床试验。通过这些研究，我们希望为未来由EMS现场发起的NBO的多中心试验收集初步数据并获得试点经验。从公共卫生的角度来看，这些研究意义重大，因为它们将评估高流量吸氧疗法是否可以独立或通过延长静脉注射tPA的时间窗口来改善中风预后。

DESCRIPTION (provided by applicant): Acute stroke care is evolving from therapeutic nihilism towards the practice of rapidly reversing ischemia before infarction occurs. This proposal for a Specialized Program of Translational Research in Acute Stroke at the six Partners Hospitals will advance stroke care by its three integrated research projects, as well as through its impact on a large medical system with two academic medical centers, four community hospitals and 1500 stroke patients annually. Project 1: Brain infarction is related in part to impaired delivery of oxygen to the brain. We have discovered that normobaric hyperoxia in animal stroke models delays permanent brain injury. Preliminary studies in acute stroke patients treated with normobaric hyperoxia appear promising. Here we propose coordinated studies in both animal models and patients to test this widely accessible therapy for its safety when administered alone, or in combination with thrombolytic therapy. In a phase II randomized, double blind, trial we will test normobaric hyperoxia for its ability to improve neurologic deficits, and decrease the extent of ischemic damage in patients. Project II: Linked to our interest in oxygen as a therapy, here we propose to also investigate the role of oxidative processes in tissue destruction and secondary hemorrhage. Members of the SPOTRIAS team at Partners have investigated both the activation of matrix metalloproteinases (MMPs) in animals, and the serum markers of oxidative stress in acute stroke patients. Here we propose studies of serum and brain markers in the animal stroke models to compliment studies of MMP and oxidative serum markers in acute stroke patients as they relate to outcome, oxygen exposure, and reperfusion. This work will lay the foundation for the development of anti-oxidant therapy in acute stroke. Project III. Partners stroke researchers have developed methods of imaging ischemic changes in acute stroke patients. Here we propose to use CTperfusion technology to establish thresholds of blood flow and blood volume which delineate tissue which is salvageable with reperfusion from that which is not. The technique will be tested for its ability to contribute to prediction of clinical as well as tissue outcome. We hypothesize that by predicting tissue fate as a function of therapy, this widely accessible CT-based technique will direct clinical decisions in acute stroke patients and become a useful tool in large clinical trials examining novel therapies for their ability to salvage brain tissue. Each of these projects share overlapping lines of inquiry as well as common procedures for their execution. Projects 1 and 2 are truly translational in that animal studies are planned to enhance the clinical program. We believe that the integrating our strong stroke laboratory science with effective clinical stroke cores across the Partners network will give birth to a potent translational research center which efficiently brings new treatments to community practice. Project 1: Normobaric Hyperoxia in Ischemic Stroke PI: Aneesh B. Singhal, M.D. - P.I. DESCRIPTION (provided by applicant): Breathing high-flow oxygen at normal atmospheric pressure (Normobaric Oxygen Therapy, NBO) may be a simple strategy to sustain ischemic brain tissue ('buy time') until spontaneous or therapeutic reperfusion occurs, and thereby improve stroke outcome. By preventing early ischemic cell death, NBO may be a useful adjunctive therapy that extends the narrow (3-hour) time window for IV tissue plasminogen activator (tPA) therapy. Our recent rodent and pilot human stroke studies provide compelling evidence that early NBO confers potent neuroprotection. While the benefit appears to be transient, similar to that observed in prior hyperbaric oxygen studies, sustained benefit does occur if NBO-treated ischemic tissue is later reperfused. In this proposal (Spotrias Project 1), we aim to extend our preliminary work in a double blind, randomized, placebo-controlled clinical trial enrolling 240 acute (< 9 hours) ischemic stroke patients over 5 years. Patients will receive either NBO or Room Air for 8 hours and undergo serial clincial assessments and CT scans. NBO's therapeutic potential will be assessed in an "intention to treat" statistical analysis of change in NIHSS scores during therapy. The potential synergistic benefit of NBO with reperfusion will be assesed in patients who undergo a baseline and a 24-hour CT-perfusion scan to assess reperfusion, as part of Project 2 (Lev). Other secondary analyses will include an assessment of post-therapy clinical function scores, brain hemorrhage rates, and lesion volume growth on CT scans. In year 1 we will exclude tPA-treated patients and investigate the safety and utility of combined NBO with tPA in embolic (clot-based) rodent stroke models. If the combined therapy appears safe in rodents, and if the year 1 human data raises no safety concerns, we will include tPA-treated patients in the clinical trial of NBO. From these studies we hope to collect preliminary data and gain pilot experience for a future multi-center trial of NBO intiated by EMS at the scene. From a public health standpoint, these studies are significant because they will assess whether breathing high-flow oxygen, a potentially simple, practical, widely accessible, portable, and cost-effective therapy, can improve stroke outcomes either independently or by extending the time window for IV tPA.