Cerebral Oxygeneration During Cardiopulmonary Bypass

心肺绕道期间的脑氧生成

• 批准号: 6751600
• 负责人: RICHARD A JONAS
• 金额: $ 33.3万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751600
• 关键词: body temperature; brain circulation; cerebral ischemia /hypoxia; enzyme activity; heart /lung bypass; immature animal; immunocytochemistry; infrared spectrometry; intravital microscopy; method development; microcirculation; neurotoxicology; nitric oxide synthase; oxygen transport; oxyhemoglobin; respiratory oxygenation; swine; tissue /cell culture; vascular endothelium; western blottings

DESCRIPTION (Provided by Applicant): Brain damage including focal and global cerebral injury as well as suboptimal cognitive developmental outcome continue to be important problems after pediatric heart surgery. Previous work in this area has focused on deep hypothermic circulatory arrest (DHCA) which is now used infrequently. As an alternative to DHCA reduced flow hypothermic cardiopulmonary bypass (CPB) is employed. However in the absence of a validated method for real time monitoring of brain oxygenation there are no guidelines for minimal safe flow and pressure under specific CPB conditions of pH, hematocrit and temperature. The proposed study will employ the new techniques of near infrared spectroscopy (NIRS) and intravital microscopy (IVM) to defme a minimal safe flow rate for specific perfusion conditions. The study will be conducted using a juvenile piglet model exposed to various degrees of flow reduction with survival for 4 days postoperatively. Survival allows assessment of functional evidence of brain injury through behavioral assessment by a blinded veterinarian observer as well as meaningful histology determined by a blinded neuropathologist. These functional and structural endpoints will be correlated with indices of brain oxygenation measured by NIRS (Tissue Oxygenation Index (TOl), Oxyhemoglobin nadir time (Hb02 nadir time)) as well as indices of microvascular perfusion measured by IVM (functional capillary density (FCD), NADH fluorescence). The second phase of the proposed study will test the hypothesis that critically reduced low flow perfusion causes hypoxic endothelial injury of cerebral blood vessels. This results in reduced constitutive endothelial nitric oxide synthase (eNOS) activity resulting in microvascular regional ischemia previously described as the "no reflow phenomenon." Acute studies will be undertaken in the piglet model using Western immunoblotting and immunocytochemistry as well as resistance vessel myography to measure eNOS activity. eNOS activity will be manipulated by substrate enhancement and inhibition. The role of inducible NOS (iNOS) in causing neurotoxicity in this setting will also be explored. The proposed study has the potential to reduce the risk of brain injury in children undergoing heart surgery by defining the margin of safety achieved with various perfusion conditions. By enhancing understanding of mechanisms of cardiopulmonary bypass-related brain injury it will facilitate development of novel pharmacologic methods to further reduce the risk of brain damage.

描述（由申请人提供）：脑损伤，包括局灶性和全局性 脑损伤以及次优的认知发育结果继续 是小儿心脏手术后的重要问题。以前的工作在此 该领域的重点是深低温循环停止（DHCA），现在 很少使用。作为DHCA的替代方案，减少流量，降低体温 采用心肺分流术（CPB）。然而，在缺乏有效的 脑氧合的真实的实时监测方法 对于在特定pH的CPB条件下的最小安全流量和压力， 血细胞比容和体温。 拟议的研究将采用近红外光谱新技术 （NIRS）和活体显微镜（IVM），以确定最低安全流速， 特定灌注条件。该研究将使用青少年 暴露于不同程度流量减少的仔猪模型，存活4 术后24天。生存率允许评估功能性证据， 通过盲态兽医观察员的行为评估进行脑损伤 以及由不知情的神经病理学家确定的有意义的组织学。这些 功能和结构终点将与脑指数相关 通过NIRS（组织氧合指数（TOI）、氧合血红蛋白（OHb））测量氧合 最低点时间（Hb02最低点时间））以及微血管灌注指数 通过IVM（功能毛细管密度（FCD），NADH荧光）测量。 拟议研究的第二阶段将检验以下假设： 低流量灌注减少导致脑血缺氧性内皮损伤 船舶.这会导致组成型内皮一氧化氮合酶减少 （eNOS）活性导致微血管局部缺血， 被描述为“无回流现象"。“急性研究将在 采用免疫印迹和免疫细胞化学方法， 阻力血管造影法测定eNOS活性。eNOS活动将是 通过底物增强和抑制来操纵。诱导型一氧化氮合酶的作用 在这种情况下，诱导型一氧化氮合酶（iNOS）引起神经毒性也将进行探讨。 这项拟议的研究有可能降低脑损伤的风险， 通过定义达到的安全范围， 不同的灌注条件。通过加强对 心肺转流相关的脑损伤，它将促进发展， 新的药理学方法，以进一步降低脑损伤的风险。