Neurometabolic Outcomes of Different Cardiopulmonary Bypass Strategies

项目说明 需要体外循环(CPB)的先天性心脏病手术患者 因时间相关性缺血和暴露于有毒物质而面临神经发育进程受损的风险 脑部代谢物的水平。目前有两种相互竞争的CPB方法 常见的心脏缺陷：1)深低温停循环，其中泵是 关闭以提供无血手术场，代价是没有脑灌注，以及2)Antegrad 脑灌注(ACP)，在整个手术过程中保持对大脑的选择性灌流。 重要的是，心脏手术中的深低温停循环与长期的神经认知障碍密切相关。 方式与循环停止时间的长短成正比。为CPB替代使用ACP，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 关于深静脉血栓形成的争论仍然很激烈，缺乏精心设计和客观的比较研究。 在这里，我们提出了用核磁共振成像和动态质子磁学对仔猪模型进行临床前研究。 磁共振波谱(MRS)，实时测量代谢物活性，以量化 在这些体外循环策略的所有阶段，大脑的新陈代谢状态随着时间的推移而不断变化。初步 数据显示，深低温停循环会导致大脑能量代谢的显著变化(例如，脑部积聚了10倍 脑乳酸和葡萄糖的减少)，而ACP则没有这种紊乱。重要的是，后- 外科定量空间学习评估将被用来最强烈地识别代谢标记物 与不良的临床结果相关。这个项目的成功将第一次证明 ACP在预防脑细胞损伤所致代谢产物紊乱中的优势 可能会阻碍正常的认知发展。这项研究中使用的实时连续测量将 还提供了对深低温心脏骤停持续时间和神经学之间相关性的潜在原因的见解 受伤。这些研究的数据预计将建立一个安全基准，当DHCA或ACP 在临床环境中需要。我们预计在仔猪身上进行这项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连续实时成像大脑代谢状态。CPB模型将 使用两种常用的CPB形式：DHCA和ACP。DHCA和ACP都将是 在不同的温度、流量和时间条件下进行，以确定最有效的 保持健康大脑代谢状态的方法学，以及2)评估神经认知 结果与观察到的大脑新陈代谢的变化相关。

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.