Brain metabolism and neuroprotection in cardiopulmonary bypass

描述(申请人提供)：先天性心脏病(CHD)是最常见的重大出生缺陷，每1000名活产中就有8名受到影响(估计每年有30-40,000名儿童)。患有CHD的儿童经常需要手术干预。心脏手术不可或缺的支持技术包括体外循环(CPB)和深低温停循环(DHCA)。这些手术可能会对这些脆弱的儿科患者造成不利影响。早期热情的使用，特别是在新生儿中，已经被发现与其长期暴露相关的显著的神经系统疾病所影响。在婴儿期和婴儿期接受体外循环和深低温体外循环心脏手术的儿童在达到学龄前和学龄期后进行评估。这些儿童被发现有不同的神经障碍模式，特征是认知障碍、执行功能受损、表达能力和语言异常、视觉空间和视觉运动技能受损、注意力缺陷/多动障碍、运动延迟和学习障碍。这些障碍的神经病理学基础包括：(I)手术后脑室周围白质软化，出现在超过50%的手术后MRI扫描中；(Ii)手术后癫痫发作，出现在约11%；(Iii)中风，出现在约9%的手术后磁共振成像中。因此，寻找能够减少体外循环和深低温停循环的神经后遗症，保护大脑免受损伤的条件是极其重要的。在改善体外循环期间脑损伤的治疗和预防策略方面的进一步进展取决于对深低温停循环如何影响导致细胞死亡的关键细胞神经病理过程的进一步了解。本研究将继续研究DHSA依赖的神经元损伤的机制，并确定两种有希望的化合物GCSF和托吡酯对神经保护的效果，以及低温在体外循环后恢复过程中的效果。在这一系列实验中，我们将使用临床常用的深低温体外循环和体外循环策略来描述脑损伤模式，并通过单独或联合研究新出现的神经保护策略(低温32-34C)和临床适用的药物(GCSF、托吡酯)来扩展神经保护的潜力。我们将发现神经保护性暴露的时间、强度和持续时间如何影响脆弱的新生儿脑损伤以及细胞损伤和死亡过程的激活。这些发现将有助于确定深低温停循环、体外循环和再灌注可能导致的缺氧缺血性脑损伤的特定机制的贡献，以及评估临床适用的神经保护策略，这些策略有可能显著改善婴儿和儿童的神经预后。公共卫生相关性：心脏手术后存活的新生儿面临各种神经缺陷，包括全球认知功能障碍、视觉空间障碍、精细和粗大运动控制受损、执行/规划功能受损和注意力缺陷多动障碍。这项研究将通过手术确定脑损伤的机制，并严格评估亚低温以及两种有前景的保护剂，粒细胞集落刺激因子(GCSF)和托吡酯单独和联合使用在保护大脑免受手术损伤方面的有效性。

DESCRIPTION (provided by applicant): Congenital heart disease (CHD), the most common significant birth defect, affects 8 per 1000 live births (estimated 30-40,000 children each year). Children with CHD often require surgical interventions. Support techniques integral to cardiac surgery include cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). These procedures may result in detrimental effects in these vulnerable pediatric patients. The early, enthusiastic use of DHCA, particularly in neonates, has been tempered by the finding of significant neurological morbidity associated with its prolonged exposure. Children who had undergone heart surgery with CPB and DHCA as neonates and infants were evaluated after they reached preschool and school age. These children were found to have distinctive patterns of neurological disturbance characterized by cognitive impairment, impaired executive function, expressive speech and language abnormalities, impaired visual-spatial and visual-motor skills, attention deficit/hyperactivity disorder, motor delays, and learning disabilities The neuropathological basis for these disturbances include (i) post-operative periventricular leukomalacia, seen in over 50% of post- operative MRI scans; (ii) post-operative seizures which arise in about 11%; and (iii) stroke, demonstrated in about 9% of post-operative MRIs. It is therefore extremely important to find the conditions which will decrease the neurologic sequelae of CPB and DHCA and protect the brain from injury. Further progress in the improvement of therapeutic and preventive strategies with respect to cerebral injury during cardiac bypass depends on increased understanding of how DHCA affects the critical cellular neuropathologic processes that lead to cell death. This research will continue to study the mechanisms responsible for DHCA-dependent neuronal injury and determine the efficacy of neuroprotection by two promising compounds, GCSF and topiramate, and of hypothermia during post-bypass recovery. In this series of experiments, we will characterize the brain injury patterns with commonly used clinical DHCA and CPB strategies, and extend the potential for neuroprotection by studying emerging neuroprotective stategies (hypothermia 32-34C) and clinically applicable agents (GCSF, topiramate), alone or in combination. We will discover how the timing, intensity, and duration of neuroprotective exposure affects vulnerable neonatal brain injury and the activation of cell injury and death processes. These findings will help define the contributions of selected mechanisms by which hypoxic- ischemic brain injury induced by DHCA, CPB and reperfusion is likely to occur, as well as evaluate clinically applicable neuroprotective strategies that have the potential to significantly improve neurologic outcomes for infants and children. PUBLIC HEALTH RELEVANCE: Newborns who survive heart surgery face a variety of neurological deficits, including global cognitive dysfunction, visual-spatial disorders, impaired fine and gross motor control, impaired executive/planning function and attention deficit hyperactivity disorder. This research will determine the mechanisms brain injury by the surgical procedures, and critically evaluate mild hypothermia as well as two promising protective agents, Granulocyte Colony-Stimulating Factor (GCSF) and Topiramate both alone and together, for their efficacy in protecting the brain from injury resulting from the surgery.