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.

摘要 脑血流量的快速下降导致氧含量非常低的区域，这是一个主要的问题。 缺血性中风组织损伤的原因。已经开发了几种策略来挽救缺血性 组织使用动物模型，特别是啮齿动物，但他们在临床试验中失败了。为了合理 为了开发有效的治疗方法，了解缺血性卒中对脑组织的影响至关重要 氧（pO2，氧分压）在缺血以及对侧区域的临床 中风的相关模型。然而，没有合适的技术用于重复测量脑组织中的 这严重限制了对有效疗法的理解和开发，以改善 缺血性卒中的结局。 我们的目标是开发一种新的电子顺磁共振（EPR）血氧饱和度在体内 植入式共振器用于栓塞诱导的缺血性卒中期间脑pO2的实时监测 兔子的血凝块兔栓塞凝块模型已经显示出有希望的转化潜力， 开发纤溶酶原激活剂用于人类缺血性卒中的溶栓。我们假设 缺血性卒中时脑组织pO2的变化可作为预测预后的指标， 通过与当血液流动通过重组恢复时的结果相关联来测试该方法的有效性， 组织纤溶酶原激活物（rtPA）。我们将通过使用拟议的植入式 基于共振器的EPR血氧测定法。 我们将首先建立用于缺血性和缺血性脑组织中pO2测量的植入式谐振器技术， 通过EPR血氧测定法测定兔脑的对侧区域。栓塞凝块会诱发缺血性卒中， 3小时和6小时，随后用rtPA处理，以研究脑pO2的时间变化。的 植入式共振器在大脑皮层下的位置、灌注、 水（ADC）和梗塞体积将通过MRI非侵入性地评估。大脑皮层的减少程度 rtPA治疗后缺血和复氧期间的pO2及其对梗死体积的影响 决心检验这个假设。此外，我们还将研究血流变化对 脑卒中患者脑组织pO2和ADC值的变化。来自这些研究的数据将有助于潜在的翻译， 在兔栓塞凝块模型中开发的方法使用MRI指导治疗来治疗患者。 研究小组，Khan和Hou博士（体内EPR血氧测定和中风），Gimi博士（MRI）沿着， 顾问Swartz博士和Kuppusamy博士（EPR技术的先驱），Gui博士（生物统计学家）和 博士Culp（中风研究）拥有开展研究所需的专业知识和资源。如果成功， 本项目将建立使用体内EPR血氧测定法评估脑组织pO2动态的有效性， 缺血性中风的临床相关模型，目前尚不具备的独特能力。