Specialized Program of Translational Research In Acute Stroke at the Partners

合作伙伴急性中风转化研究专门项目

• 批准号: 7138842
• 负责人: Karen L Furie
• 金额: $ 168.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7138842
• 关键词: brain; clinical research; oxygen; stroke; tissues

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.

描述（由申请人提供）：急性中风护理正在从治疗虚无主义发展到在梗塞发生之前快速逆转缺血的实践。这项在六家合作医院开展急性中风转化研究专门计划的提案将通过其三个综合研究项目及其对拥有两个学术医疗中心、四家社区​​医院和 1500 所医院的大型医疗系统的影响来促进中风护理。每年都有中风患者。项目 1：脑梗塞部分与大脑供氧受损有关。我们发现，动物中风模型中的常压高氧可以延缓永久性脑损伤。对接受常压高氧治疗的急性中风患者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给药或与溶栓疗法联合使用时的安全性。在一项 II 期随机双盲试验中，我们将测试常压高氧改善神经功能缺损和减少患者缺血性损伤程度的能力。项目二：与我们对氧气作为一种疗法的兴趣相关，我们建议还研究氧化过程在组织破坏和继发性出血中的作用。 Partners 的 SPOTRIAS 团队成员研究了动物基质金属蛋白酶 (MMP) 的激活以及急性中风患者氧化应激的血清标志物。在这里，我们建议对动物中风模型中的血清和脑标记物进行研究，以补充急性中风患者中的 MMP 和氧化血清标记物的研究，因为它们与结果、氧暴露和再灌注有关。这项工作将为急性脑卒中抗氧化治疗的发展奠定基础。项目三。合作伙伴中风研究人员开发了对急性中风患者缺血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量和血容量的阈值，以区分可通过再灌注挽救的组织和不可挽救的组织。该技术将测试其预测临床和组织结果的能力。我们假设，通过预测组织命运作为治疗的函数，这种广泛使用的基于 CT 的技术将指导急性中风患者的临床决策，并成为大型临床试验的有用工具，检查新疗法挽救脑组织的能力。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 是真正的转化性项目，因为计划通过动物研究来加强临床计划。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，将诞生一个强大的转化研究中心，有效地将新的治疗方法引入社区实践。 项目 1：缺血性中风的常压高氧症 PI：Aneesh B. Singhal，医学博士 - P.I. 描述（由申请人提供）：在正常大气压下呼吸高流量氧气（常压氧疗，NBO）可能是维持缺血脑组织（“争取时间”）直到发生自发或治疗性再灌注的简单策略，从而改善中风结果。通过预防早期缺血性细胞死亡，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。我们最近的啮齿动物和人类中风试验研究提供了令人信服的证据，证明早期 NBO 具有有效的神经保护作用。虽然这种益处似乎是短暂的，与之前高压氧研究中观察到的情况类似，但如果 NBO 治疗的缺血组织随后再灌注，确实会产生持续的益处。在这项提案（Spotrias 项目 1）中，我们的目标是在一项双盲、随机、安慰剂对照临床试验中扩展我们的初步工作，该试验招募了 240 名急性（< 9 小时）缺血性中风患者，为期 5 年。患者将接受 8 小时的 NBO 或 Room Air 治疗，并接受一系列临床评估和 CT 扫描。 NBO 的治疗潜力将通过治疗期间 NIHSS 评分变化的“治疗意向”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。其他二次分析将包括评估治疗后临床功能评分、脑出血率和 CT 扫描上的病灶体积增长。在第一年，我们将排除接受 tPA 治疗的患者，并研究 NBO 与 tPA 联合治疗在栓塞（基于凝块的）啮齿动物中风模型中的安全性和实用性。如果联合疗法对啮齿动物来说是安全的，并且如果第一年的人体数据没有引起安全性问题，我们将把接受 tPA 治疗的患者纳入 NBO 的临床试验。我们希望通过这些研究收集初步数据，为未来EMS在现场启动的NBO多中心试验积累试点经验。从公共卫生的角度来看，这些研究意义重大，因为它们将评估呼吸高流量氧气（一种可能简单、实用、广泛使用、便携式且具有成本效益的治疗方法）是否可以独立或通过延长时间窗来改善中风结果用于静脉注射 tPA。