Specialized Program of Translational Research in Acute Stroke at the Partners Hea

合作伙伴医院急性中风转化研究专门项目

• 批准号: 7551928
• 负责人: Michael Lev
• 金额: $ 27.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7551928
• 关键词: Academic Medical Centers; Acute; Air; Alteplase; Animal Model; Animals; Antioxidants; Atmospheric Pressure; Birth; Blood Volume; Blood flow; Brain; Brain Infarction; Brain Injuries; Brain hemorrhage; Breathing; Caring; Cell Death; Clinical; Clinical Trials; Coagulation Process; Community Hospitals; Community Practice; Controlled Clinical Trials; Data; Development; Doctor of Medicine; Double-Blind Method; Enrollment; Foundations; Future; Growth; Hemorrhage; Hospitals; Hour; Human; Hyperbaric Oxygen; Hyperoxia; Image; Infarction; Intention; Ischemia; Ischemic Stroke; Laboratories; Lesion; Link; Matrix Metalloproteinases; Medical; Methods; Modeling; Neurologic Deficit; Outcome; Oxidative Stress; Oxygen; Oxygen Therapy Care; Patients; Perfusion; Phase; Physiological reperfusion; Placebo Control; Procedures; Process; Public Health; Randomized; Rate; Reperfusion Therapy; Research Personnel; Research Project Grants; Rodent; Role; Safety; Scanning; Science; Score; Serum Markers; Stroke; Study of serum; System; Techniques; Technology; Testing; Therapeutic; Thrombolytic Therapy; Time; Tissues; Translational Research; Work; X-Ray Computed Tomography; acute stroke; base; brain tissue; cost; experience; human data; improved; interest; member; neuroprotection; novel; prevent; programs; tool

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）：急性卒中护理正在从治疗虚无主义向梗死发生前快速逆转缺血的实践发展。在六家合作医院开展急性卒中转化研究专业项目的提案将通过其三个综合研究项目以及对大型医疗系统的影响来推进卒中护理，该系统拥有两个学术医疗中心，四家社区医院和每年1500名卒中患者。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，常压高氧在动物中风模型延迟永久性脑损伤。在常压高氧治疗急性中风患者的初步研究似乎是有希望的。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时的安全性。在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：与我们对氧气作为治疗方法的兴趣有关，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中基质金属蛋白酶（MMPs）的激活以及急性中风患者中氧化应激的血清标志物。在这里，我们建议在动物中风模型中的血清和脑标志物的研究，以补充MMP和氧化血清标志物在急性中风患者的研究，因为它们涉及到的结果，氧暴露和再灌注。本研究将为急性脑卒中抗氧化治疗的发展奠定基础。项目三.中风研究人员已经开发出对急性中风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，以建立阈值的血流和血容量的划定组织，这是挽救与再灌注，这是不。将测试该技术有助于预测临床和组织结局的能力。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的技术将指导急性卒中患者的临床决策，并成为大型临床试验中检查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相互重叠的调查范围以及共同的执行程序。项目1和2是真正的翻译，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化研究中心，有效地为社区实践带来新的治疗方法。 项目1：缺血性卒中中的常压高氧 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（常压氧气治疗，NBO）可能是维持缺血性脑组织（“争取时间”）直到自发或治疗性再灌注发生的简单策略，从而改善卒中结局。通过预防早期缺血性细胞死亡，NBO可能是一种有用的连续治疗，延长了IV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飞行员人类中风研究提供了令人信服的证据，早期NBO赋予强大的神经保护作用。虽然这种益处似乎是短暂的，类似于在先前的高压氧研究中观察到的，但如果NBO治疗的缺血组织后来再灌注，则确实会产生持续的益处。在这项提案（Spotrias项目1）中，我们的目标是扩展我们在一项为期5年的双盲、随机、安慰剂对照临床试验中的初步工作，该试验招募了240名急性（< 9小时）缺血性卒中患者。患者将接受NBO或Room Air治疗8小时，并接受系列临床评估和CT扫描。NBO的治疗潜力将在治疗期间NIHSS评分变化的“意向治疗”统计分析中进行评估。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。其他次要分析将包括治疗后临床功能评分、脑出血率和CT扫描病灶体积增长的评估。在第1年，我们将排除tPA治疗的患者，并在栓塞（基于血栓）啮齿动物卒中模型中研究NBO与tPA联合治疗的安全性和实用性。如果联合治疗在啮齿类动物中安全，并且如果第1年的人体数据没有引起安全性问题，我们将在NBO的临床试验中纳入tPA治疗的患者。通过这些研究，我们希望收集初步的数据，并获得试点经验，为未来的多中心试验的NBO启动EMS在现场。从公共卫生的角度来看，这些研究具有重要意义，因为它们将评估呼吸高流量氧气（一种潜在的简单、实用、广泛使用、便携且具有成本效益的治疗方法）是否可以独立或通过延长IV tPA的时间窗来改善卒中结局。