Neurometabolic Outcomes of Different Cardiopulmonary Bypass Strategies

不同心肺绕道策略的神经代谢结果

• 批准号: 10580676
• 负责人: FRANK HANLEY
• 金额: $ 73.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580676
• 关键词: Affect; Anatomy; Animals; Benchmarking; Birth; Blood; Blood specimen; Brain; Brain Injuries; Brain imaging; Bypass; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cerebral cortex; Cerebrum; Clinical; Comparative Study; Data; Diffusion Magnetic Resonance Imaging; Energy Metabolism; Exposure to; Glucose; Heart Abnormalities; Histologic; Ischemia; Kidney; Learning; Length; Life; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Memory; Metabolic; Metabolic Marker; Metabolic stress; Methodology; Modeling; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurodevelopmental Impairment; Operative Surgical Procedures; Outcome; Patients; Perfusion; Phase; Procedures; Protons; Pump; Recovery; Risk; Safety; Temperature; Time; Tissue Harvesting; Tissues; United States; brain metabolism; cell injury; clinical practice; cognitive development; cognitive testing; congenital heart disorder; design; high risk; insight; natural hypothermia; neonate; porcine model; preclinical study; predictive marker; preservation; prevent; success; time use

Project Description Patients with congenital cardiac diseases undergoing surgery requiring cardiopulmonary bypass (CPB) are at risk for impaired neurodevelopmental progression due to time-related ischemia and exposure to toxic levels of brain metabolites. Two competing CPB methodologies are currently practiced for certain commonly occurring cardiac defects: 1) Deep Hypothermic Circulatory Arrest (DHCA), in which the pump is turned off to provide a bloodless surgical field at the expense of no cerebral perfusion, and 2) Antegrade Cerebral Perfusion (ACP), whereby selective perfusion of the brain is maintained throughout surgery. Importantly, DHCA in cardiac surgery is strongly associated with long-term neurocognitive deficits in a manner proportional to length of the circulatory arrest time. The alternative use of ACP for CPB, designed as a strategy to protect the cerebral cortex, has become a common approach, though the value of ACP over DHCA remains hotly debated, with well-designed and objective comparative studies lacking. Here we propose preclinical studies of a piglet model using MRI and dynamic proton magnetic resonance spectroscopy (MRS) which measures metabolite activity in real time, to quantify alterations in the brain’s metabolic state continuously over time during all phases of these CPB strategies. Preliminary data reveal that DHCA causes marked alterations in brain energy metabolism, (e.g., a > 10-fold buildup in brain lactate and a reduction in glucose), while no such derangement is seen with ACP. Importantly, post- surgery quantitative spatial learning assessments will be used to identify metabolic markers most strongly associated with poor clinical outcomes. Success of this project will demonstrate for the first time the advantages of ACP over DHCA in preventing brain cellular injury-inducing metabolite derangements that may hinder normal cognitive development. The real time continuous measurements used in this study will also provide insights into underlying causes of the correlation between DHCA duration and neurological injury. Data from these studies are expected to establish a benchmark for safety when DHCA or ACP is required in the clinical setting. We anticipate that the results of this objective study in the piglet will be directly and rapidly translatable to clinical practice. The Specific Aims are: 1) Using a CPB piglet model we will image the brain metabolic state continuously in real time using MRS. The CPB model will utilize the two commonly used forms of CPB, DHCA and ACP. Both DHCA and ACP will be performed under varying conditions of temperature, flow and time, to determine the most effective methodology to preserve a healthy brain metabolic state., and 2) To evaluate neurocognitive outcomes and correlate with observed alterations in brain metabolism.

项目描述 患有先天性心脏病并接受体外循环（CPB）手术的患者 由于时间相关的缺血和接触有毒物质，存在神经发育进展受损的风险 脑代谢物水平。目前在某些方面实践了两种相互竞争的 CPB 方法 常见的心脏缺陷： 1) 深低温循环骤停 (DHCA)，其中泵处于停止状态 关闭以提供无血手术野，但以无脑灌注为代价，以及 2) 顺行 脑灌注（ACP），在整个手术过程中保持大脑的选择性灌注。 重要的是，心脏手术中的 DHCA 与患者的长期神经认知缺陷密切相关。 方式与停循环时间的长度成正比。 ACP 用于 CPB 的替代用途，设计 作为一种保护大脑皮层的策略，已成为一种常见的方法，尽管 ACP 的价值 关于 DHCA 的争论仍然很激烈，缺乏精心设计和客观的比较研究。 在这里，我们建议使用 MRI 和动态质子磁力对仔猪模型进行临床前研究 共振光谱 (MRS) 实时测量代谢物活性，以量化代谢物的变化 在这些 CPB 策略的所有阶段中，大脑的代谢状态随着时间的推移不断变化。初步的 数据显示，DHCA 会导致大脑能量代谢发生显着改变（例如，能量代谢增加 > 10 倍） 脑乳酸和葡萄糖减少），而 ACP 则没有观察到这种紊乱。重要的是，后 手术定量空间学习评估将用于最有力地识别代谢标记物 与不良的临床结果相关。该项目的成功将首次证明 ACP 相对于 DHCA 在预防脑细胞损伤引起的代谢紊乱方面的优势 可能会阻碍正常的认知发展。本研究中使用的实时连续测量将 还深入了解 DHCA 持续时间与神经系统疾病之间相关性的根本原因 受伤。当 DHCA 或 ACP 被使用时，这些研究的数据预计将建立安全基准。 临床环境中需要。我们预计这项针对仔猪的客观研究的结果将是 可直接、快速地转化为临床实践。具体目标是： 1) 使用 CPB 仔猪模型 我们将使用 MRS 对大脑代谢状态进行连续实时成像。 CPB 模型将 利用 CPB 的两种常用形式：DHCA 和 ACP。 DHCA 和 ACP 都将 在不同的温度、流量和时间条件下进行，以确定最有效的 保持健康的大脑代谢状态的方法。2) 评估神经认知 结果并与观察到的大脑代谢变化相关。