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）：急性脑卒中护理正在从治疗虚无主义向在梗死发生前迅速逆转缺血的实践发展。这项关于在六家合作医院开展急性中风转化研究的专业项目的提案，将通过其三个综合研究项目，以及通过其对一个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，推进中风护理。项目1：脑梗死部分与向大脑输送氧气受损有关。我们已经发现，动物中风模型的常压高氧延迟永久性脑损伤。初步研究表明，用常压高氧治疗急性脑卒中患者是有希望的。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治疗方法单独使用或与溶栓治疗联合使用的安全性。在一项II期随机、双盲试验中，我们将测试常压高氧治疗改善神经功能缺陷和降低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治疗方法的兴趣相联系，在这里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。Partners的SPOTRIAS团队成员研究了动物基质金属蛋白酶（MMPs）的激活和急性中风患者的血清氧化应激标志物。在此，我们建议在动物脑卒中模型中进行血清和脑标志物的研究，以补充急性脑卒中患者的MMP和氧化血清标志物的研究，因为它们与预后、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。项目第三。卒中研究人员已经开发出急性卒中患者的缺血性改变成像方法。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，以划定哪些组织可以再灌注，哪些不能再灌注。这项技术将被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功能，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中检验新疗法挽救脑组织能力的有用工具。这些项目中的每一个都有重叠的调查线以及执行的共同程序。项目1和项目2是真正的转化，因为动物研究计划加强临床项目。我们相信，通过合作伙伴网络，将我们强大的中风实验室科学与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，有效地为社区实践带来新的治疗方法。