Brain metabolism and neuroprotection in cardiopulmonary bypass

体外循环中的脑代谢和神经保护

• 批准号: 8280214
• 负责人: Anna Pastuszko
• 金额: $ 45.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280214
• 关键词: Affect; Amyloid beta-Protein Precursor; Animals; Apoptotic; Attention deficit hyperactivity disorder; Brain; Brain Injuries; Brain region; Bypass; CREB1 gene; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Caspase; Cell Death; Cell Death Process; Cell Survival; Cerebrum; Child; Childhood; Clinical; Congenital Abnormality; Control Groups; Dopamine; Dose; Drug Kinetics; Experimental Designs; Face; Fresh Tissue; Glutamates; Goals; Granulocyte Colony-Stimulating Factor; Growth; Half-Life; Health; Heart Arrest; Hematoxylin and Eosin Staining Method; Hour; Hypoxia; Immunoassay; Impaired cognition; In Situ Nick-End Labeling; Infant; Injection of therapeutic agent; Injury; Ischemic-Hypoxic Encephalopathy; JAK2 gene; Janus kinase 2; Language; Lead; Learning Disabilities; Live Birth; MRI Scans; Measures; Mediating; Metabolic Pathway; Morbidity - disease rate; Motor; Motor Skills; Neonatal Brain Injury; Neurologic; Neurological outcome; Neuronal Injury; Neurons; Newborn Infant; Nursery Schools; Operative Surgical Procedures; Outcome; Oxygen; Pathway interactions; Patients; Pattern; Periventricular Leukomalacia; Pharmaceutical Preparations; Phosphorylation; Physicians; Plasma; Postoperative Period; Prevention strategy; Procedures; Process; Protective Agents; Proteins; Protocols documentation; Quality of life; Recovery; Reperfusion Therapy; Research; Rewarming; STAT3 gene; School-Age Population; Seizures; Series; Signal Transduction; Speech; Stroke; Survivors; Techniques; Temperature; Testing; Therapeutic; Time; Visual Spatial Disorder; Visuospatial; Weaning; base; brain metabolism; caspase-3; cell injury; congenital heart disorder; defined contribution; executive function; extracellular; fluoro jade; genetic regulatory protein; improved; inhibitor/antagonist; intravenous administration; motor control; natural hypothermia; neonate; neuroprotection; pressure; protective effect; receptor; research study; topiramate; tyrphostin AG-490; visual motor; white matter damage; white matter injury

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.

描述（由申请人提供）：先天性心脏病（CHD）是最常见的重大出生缺陷，影响每1000例活产8例（估计每年有30- 40，000名儿童）。患有CHD的儿童通常需要手术干预。心脏手术的辅助技术包括体外循环（CPB）和深低温停循环（DHCA）。这些程序可能会对这些脆弱的儿科患者产生不利影响。DHCA的早期，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神经系统发病率所缓和。在新生儿和婴儿时期接受过CPB和DHCA心脏手术的儿童在达到学龄前和学龄后进行评估。这些儿童被发现具有独特的神经障碍模式，其特征是认知障碍、执行功能受损、表达性言语和语言异常、视觉空间和视觉运动技能受损、注意力缺陷/多动障碍、运动迟缓和学习障碍。这些障碍的神经病理学基础包括（i）术后脑室周围白质软化，在超过50%的术后MRI扫描中可见;（ii）在约11%中出现的术后癫痫发作;以及（iii）在约9%的术后MRI中证实的中风。因此，寻找减少CPB和DHCA神经系统后遗症并保护大脑免受损伤的条件是非常重要的。心脏搭桥术期间脑损伤的治疗和预防策略的改进的进一步进展取决于对DHCA如何影响导致细胞死亡的关键细胞神经病理过程的理解。本研究将继续研究DHCA依赖性神经元损伤的机制，并确定两种有前途的化合物GCSF和托吡酯的神经保护效果，以及旁路术后恢复期间的低温。在这一系列实验中，我们将用临床常用的DHCA和CPB策略表征脑损伤模式，并通过研究新兴的神经保护策略（低温32- 34 C）和临床适用的药物（GCSF，托吡酯），单独或联合使用来扩展神经保护的潜力。我们将发现神经保护性暴露的时机、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DHCA，CPB和再灌注诱导的缺氧缺血性脑损伤可能发生的选定机制的贡献，以及评估临床适用的神经保护策略，这些策略有可能显着改善婴儿和儿童的神经功能结局。公共卫生关系：心脏手术后幸存的新生儿面临各种神经功能缺损，包括整体认知功能障碍、视觉空间障碍、精细和粗大运动控制受损、执行/计划功能受损和注意力缺陷多动障碍。本研究将确定脑损伤的外科手术的机制，并严格评估亚低温以及两个有前途的保护剂，粒细胞集落刺激因子（GCSF）和托吡酯单独和联合使用，为他们的有效性，在保护脑免受手术造成的损伤。

项目成果

Reporting guidelines for health care simulation research: extensions to the CONSORT and STROBE statements.

• DOI: 10.1186/s41077-016-0025-y
• 发表时间: 2016
• 期刊: Advances in simulation (London, England)
• 作者: Cheng A;Kessler D;Mackinnon R;Chang TP;Nadkarni VM;Hunt EA;Duval-Arnould J;Lin Y;Cook DA;Pusic M;Hui J;Moher D;Egger M;Auerbach M;International Network for Simulation-based Pediatric Innovation, Research, and Education (INSPIRE) Reporting Guidelines Investigators
• 通讯作者: International Network for Simulation-based Pediatric Innovation, Research, and Education (INSPIRE) Reporting Guidelines Investigators

Effect of perfusion flow rate on tissue oxygenation in newborn piglets during cardiopulmonary bypass.

体外循环期间灌注流量对新生仔猪组织氧合的影响。

• DOI: 10.1016/s0003-4975(02)04342-4
• 发表时间: 2003
• 期刊: The Annals of thoracic surgery
• 作者: Schears,Gregory;Schultz,StevenE;Creed,Jennifer;Greeley,WilliamJ;Wilson,DavidF;Pastuszko,Anna
• 通讯作者: Pastuszko,Anna

Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet.

• DOI: 10.1007/s11064-014-1399-7
• 发表时间: 2014-11
• 期刊: NEUROCHEMICAL RESEARCH
• 影响因子: 4.4
• 作者: Pastuszko, Peter;Schears, Gregory J.;Greeley, William J.;Kubin, Joanna;Wilson, David F.;Pastuszko, Anna
• 通讯作者: Pastuszko, Anna