Brain metabolism and neuroprotection in cardiopulmonary bypass

体外循环中的脑代谢和神经保护

基本信息

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
项目类别：
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

项目摘要

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），最常见的重大出生缺陷，影响每千名活产8例（估计每年30-40,000名儿童）。冠心病儿童通常需要手术干预。心脏手术不可或缺的支持技术包括心肺旁路（CPB）和深度低温循环停滞（DHCA）。这些程序可能会导致这些脆弱的小儿患者有害影响。发现DHCA的早期，热情的使用，特别是在新生儿中，由于发现与长期暴露有关的明显神经系统发病率而缓解了。接受CPB和DHCA进行心脏手术的儿童在到达学龄前儿童和学龄后接受了新生儿和婴儿的评估。 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扫描；（ii）术后癫痫发作约为11％；（iii）中风，在大约9％的术后MRI中证明。因此，找到将减少CPB和DHCA的神经系统后遗症并保护大脑免受损伤的条件非常重要。在心脏搭桥期间，改善治疗和预防策略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了解。这项研究将继续研究负责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作用，以及在Bypass恢复期间的体温过低。在这一系列实验中，我们将使用常用的临床DHCA和CPB策略来表征脑损伤模式，并通过研究新兴的神经保护状态（体温过低32-34C）和临床适用的药物（GCSF，Topiramate，单独或组合）来扩展神经保护的潜力。我们将发现神经保护暴露的时间，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。这些发现将有助于定义所选机制的贡献，通过这种机制，可能会发生DHCA，CPB和再灌注引起的低氧性缺血性脑损伤，并可能会发生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学疲劳。公共卫生相关性：在心脏手术中幸存下来的新生儿面临着各种神经系统缺陷，包括全球认知功能障碍，视觉空间疾病，良好和严重的运动控制受损，执行/计划功能受损和注意力缺陷多功能障碍。这项研究将通过手术程序确定脑损伤的机制，并批判性地评估温和的体温过低以及两种有前途的保护剂，粒细胞菌落刺激因子（GCSF）（GCSF）和托托型托型和托托型，既可以单独又是一起，以供它们在保护大脑免受手术免受手术免受手术伤害的能力方面的功效。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
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
影响因子：
0
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