Real-time Monitoring of cerebral tissue oxygen in ischemic stroke

缺血性脑卒中脑组织血氧实时监测

• 批准号: 8638097
• 负责人: NADEEM KHAN
• 金额: $ 20.25万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638097
• 关键词: Address; Alteplase; Anesthesia procedures; Animal Model; Blood flow; Brain; Brain region; Cause of Death; Cerebral hemisphere; Cerebrovascular Circulation; Cerebrum; Clinic; Clinical; Clinical Trials; Coagulation Process; Contralateral; Data; Development; Diffusion; Electron Spin Resonance Spectroscopy; Goals; Hour; Human; Infarction; Injury; Intervention; Ischemia; Ischemic Stroke; Isoflurane; Location; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modeling; Monitor; Nervous System Physiology; Noise; Obstruction; Oryctolagus cuniculus; Outcome; Oxygen; Oxygen saturation measurement; Partial Pressure; Patients; Perfusion; Plasminogen Activator; Positioning Attribute; Pre-Clinical Model; Research; Resources; Rodent; Signal Transduction; Site; Stroke; Techniques; Technology; Testing; Time; Tissues; Translating; Translations; United States; Water; Weight; base; clinically relevant; design; disability; effective therapy; improved; in vivo; insight; method development; nonhuman primate; novel; pre-clinical; prevent; public health relevance; research study; therapy development; thrombolysis; tool

Abstract A rapid decline in the cerebral blood flow leads to regions with very low levels of oxygen, which is a major cause of tissue damage in ischemic stroke. Several strategies have been developed to rescue ischemic tissue using animal models, especially rodents, but they failed in the clinical trials. In order to rationally develop effective therapies, it is crucial to understand the effect of ischemic stroke on cerebral tissue oxygen (pO2, partial pressure of oxygen) in the ischemic as well as contralateral regions of a clinically pertinent model of stroke. However, there are no suitable techniques for repeated measurement of cerebral pO2 and this has severely limited the understanding and development of effective therapies to improve the outcome of ischemic stroke. Our goal is to develop in vivo Electron Paramagnetic Resonance (EPR) oximetry with a novel class of implantable resonators for real-time monitoring of cerebral pO2 during ischemic stroke induced by embolic clot in rabbits. The rabbit embolic clot model has shown promising translational potential with the development of plasminogen activator for thrombolysis during ischemic stroke in humans. We hypothesize that the changes in cerebral pO2 during ischemic stroke can be used as a marker to predict outcome, testing the validity of the method by correlating with outcome when blood flow is restored by recombinant tissue plasminogen activator (rtPA). We will test the hypothesis by using the proposed implantable resonator-based EPR oximetry. We will first establish the implantable resonator technology for pO2 measurement in the ischemic and contralateral regions of the rabbit brain by EPR oximetry. Ischemic stroke will be induced by embolic clot for 3 hour and 6 hour, followed by treatment with rtPA to investigate the temporal changes in cerebral pO2. The position of the implantable resonator in the cerebral subcortex, perfusion, apparent diffusion coefficient of water (ADC) and infarct volume will be assessed non-invasively by MRI. The extent of decrease in cerebral pO2 during ischemia and re-oxygenation after rtPA treatment and its effect on the infarct volume will be determined to test the hypothesis. Additionally, we will study the effect of changes in the blood flow on cerebral pO2 and ADC in stroke. The data from these studies will facilitate the potential translation of the approaches developed in rabbit embolic clot model to treat patient's using MRI to guide the treatment. The research team, Drs. Khan and Hou (in vivo EPR oximetry and stroke), and Dr. Gimi (MRI) along with the consultants Drs. Swartz and Kuppusamy (pioneers of EPR technique), Dr. Gui (biostatistician) and Dr. Culp (stroke research) have the expertise and resources necessary to carry out the study. If successful, this project will establish the validity of using in vivo EPR oximetry to assess the dynamics of cerebral pO2 in a clinically relevant model of ischemic stroke, a unique capability not available at present.

抽象的 脑血流的迅速下降导致氧气水平非常低的区域，这是一个主要的区域 缺血性中风的组织损伤原因。已经制定了几种策略来营救缺血性 使用动物模型，尤其是啮齿动物的组织，但在临床试验中失败了。为了合理 发展有效的疗法，了解缺血性卒中对脑组织的影响至关重要 缺血性和对侧区域的氧气（PO2，氧气的氧） 相关的中风模型。但是，没有合适的技术来重复测量大脑 PO2严重限制了对有效疗法的理解和发展，以改善 缺血性中风的结果。 我们的目标是用新颖的类别开发体内电子顺磁共振（EPR）血氧蛋白 栓塞引起的缺血性中风期间对脑PO2进行实时监测的植入谐振器 兔子中的凝块。兔栓塞凝块模型已显示出有希望的翻译电位 在人类缺血性卒中期间的纤溶酶原激活剂的开发。我们假设 缺血性中风期间脑PO2的变化可以用作预测结果的标志物， 通过重组恢复血流时与结果相关，测试该方法的有效性 组织纤溶酶原激活剂（RTPA）。我们将使用建议的植入剂来检验假设 基于谐振器的EPR血氧仪。 我们将首先建立可植入的谐振器技术，用于缺血性的PO2测量 EPR血氧仪的对侧区域。缺血性中风将被栓塞凝块诱导 3小时6小时，然后对RTPA进行治疗，以研究脑PO2的时间变化。这 可植入谐振器在脑子皮层，灌注，明显扩散系数中的位置 水（ADC）和梗塞量将通过MRI无创评估。大脑减少的程度 RTPA治疗后缺血期间的PO2和对梗塞体积的影响将是 确定检验假设。此外，我们将研究血流变化的影响 中风的大脑PO2和ADC。这些研究的数据将有助于促进 在兔栓塞凝块模型中开发的方法使用MRI来治疗患者来指导治疗。 研究团队，博士。可汗和侯（体内EPR血氧仪和中风）以及Gimi（MRI）以及 顾问博士。 Swartz和Kuppusamy（EPR技术的先驱），Gui博士（生物统计学家）和 Culp博士（中风研究）具有进行研究所需的专业知识和资源。如果成功， 该项目将确定使用体内EPR血氧仪来评估脑PO2动力学的有效性 临床相关的缺血性中风模型，目前尚不可用。