Role of Cyclohexanone Toxicity in Mediating Congenital Cardiac Surgery Outcomes

环己酮毒性在调节先天性心脏手术结果中的作用

基本信息

批准号：
10444513
负责人：
ALLEN D EVERETT
金额：
$ 72.92万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444513
关键词：
5 year old Adrenal Cortex Hormones Adverse effects Animal Model Animals Attention Attention deficit hyperactivity disorder Biological Assay Blood - brain barrier anatomy Blood Banks Brain Brain Injuries Cardiac Cardiac Surgery procedures Cardiopulmonary Bypass Cardiovascular system Cell Death Cessation of life Chemicals Child Childhood Clinical Clinical assessments Congenital Abnormality Congenital Heart Defects Cyclohexanones Data Development Environment Excision Exposure to Goals Healthcare Heart Diseases Human Hyperactivity IV Fluid In Vitro Industrialization Infant Infusion procedures Intravenous infusion procedures Learning Length of Stay Magnetic Resonance Imaging Maps Measures Mediating Medical Medical Device Memory Metabolism Methods Methylprednisolone Michigan Molecular Morbidity - disease rate Motor Multicenter Trials National Heart, Lung, and Blood Institute Neonatal Neurons Operative Surgical Procedures Organic solvent product Outcome Patients Perioperative Pharmacology Phenotype Placebos Plastics Postoperative Period Prevention strategy Randomized Rattus Rodent Model Role Sampling Serum Slice Solvents Source Structure Survivors Techniques Testing Thrombosis Toxic effect Toxicology Universities Validation Ventilator Zeolites age related cardiac intensive care unit cardiovascular effects cell type cohort congenital heart disorder disability executive function improved improved outcome in vivo in vivo Model innovation molecular sieving mortality motor deficit neonatal brain neonate neurodevelopment neurodevelopmental effect novel perioperative morbidity relating to nervous system success surgery outcome white matter injury

项目摘要

Congenital heart defects (CHD) are the leading cause of birth defect-associated illness and death. Neurodevelopmental delays and disabilities are the most frequent and significant consequence for CHD survivors. Efforts to reduce morbidity and improve outcomes have primarily focused on surgical techniques, cardiopulmonary bypass (CPB) strategies and pharmacologic therapies without much success. Exposure to industrial chemicals in the health care environment are increasingly being recognized as harmful, and maybe a mechanism for these poor outcomes in CHD. Cyclohexanone, is a hazardous organic industrial solvent used principally in health care as a joining compound in the fabrication of plastic medical devices. Cyclohexanone has been shown to leach from IV infusion sets and the CPB circuit and in animal studies, with significant cardiovascular effects. Therefore, our hypothesis is that cyclohexanone derived from medical plastics is associated with adverse cardiovascular and neurodevelopmental outcomes in congenital cardiac surgery. We now have significant and compelling pilot data in neonates undergoing cardiac surgery that there is a) substantial cyclohexanone exposure from IV infusions and CPB and b) with adjusted analysis, cyclohexanone levels were significantly associated with adverse post-operative cardiovascular outcomes, and worse 12 month neurodevelopmental outcomes, thus supporting our hypothesis. Our long-term goal is to develop new prevention strategies and more precise treatments to improve outcomes for neonates undergoing surgery with CPB. We will approach this hypothesis using samples and outcomes from the discovery cohort: the completed NHLBI multicenter Trial NCT01579513, entitled “Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass (MP trial)”, Eric Graham, PI (n=190, randomized to MP (methylprednisolone) therapy or placebo) and the completed external validation cohort the University of Toronto, “Clinical Assessment of Thrombosis in Children After Heart Surgery: The CATCH Study” (NCT01435473), Brian McCrindle and Cedric Manlhiot (PIs) (N=327, <5 years old) and a neonatal cardiac surgery from the University of Michigan (N=59), Mark Russell, PI. With the following Specific Aims we propose to: Aim 1) Determine if serum perioperative cyclohexanone levels are associated with perioperative morbidity, mortality, and neurodevelopmental outcomes. Aim 2) Determine cyclohexanone exposure sources and removal using zeolite molecular sieves. Finally, Aim 3) Determine cyclohexanone neural toxicity, blood brain barrier and learning/memory effects. These Aims describe a paradigm shift in the mechanism of reduced neonatal heart surgery outcomes. Innovation includes discovery of the novel role of the industrial organic solvent contaminant cyclohexanone from medical plastic fabrication on neonatal cardiac surgery clinical outcomes and methods for removal. Reduction of organic solvent exposure from medical plastics offers an immediate and actionable means to improve neonatal cardiac surgical outcomes.

先天性心脏病（CHD）是出生缺陷相关疾病和死亡的主要原因。神经发育迟缓和残疾是冠心病最常见和最严重的后果降低发病率和改善结果的努力主要集中在手术技术上，体外循环（CPB）策略和药物治疗没有取得太大成功。人们越来越认识到医疗保健环境中的工业化学品是有害的，并且可能是 CHD 不良后果的机制环己酮是一种危险的有机工业溶剂。主要用于医疗保健领域，作为塑料医疗器械制造中的连接化合物。已被证明可以从 IV 输液器和 CPB 回路以及动物研究中获得，具有显着的效果因此，我们的假设是源自医用塑料的环己酮具有心血管作用。与先天性心脏手术中不良心血管和神经发育结果相关。现在在接受心脏手术的新生儿中拥有重要且令人信服的试点数据，表明：静脉输注和体外循环中的环己酮暴露，b) 经过调整分析，环己酮水平为与术后不良心血管结局显着相关，并且 12 个月内情况更糟神经发育结果，从而支持我们的假设，我们的长期目标是开发新的预防措施。我们提供策略和更精确的治疗来改善接受 CPB 手术的新生儿的预后。将使用发现队列中的样本和结果来接近这一假设：完成的 NHLBI 多中心试验 NCT01579513，标题为“新生儿心肺皮质类固醇治疗” 旁路（MP 试验）”，Eric Graham，PI（n=190，随机接受 MP（甲基强的松龙）治疗或安慰剂）和多伦多大学完成的外部验证队列，“血栓形成的临床评估” 心脏手术后的儿童：CATCH 研究”(NCT01435473)，Brian McCrindle 和 Cedric Manlhiot (PI) （N=327，<5 岁）和密歇根大学新生儿心脏手术（N=59），Mark Russell，PI。我们建议实现以下具体目标：目标 1) 确定围手术期血清环己酮水平与围手术期发病率、死亡率和神经发育结果相关。目标 2) 确定。环己酮暴露源和使用沸石分子筛去除最后，目标 3) 确定。环己酮神经毒性、血脑屏障和学习/记忆效应描述了一个范例。减少新生儿心脏手术结果的机制发生转变，创新包括新颖的发现。医用塑料制造中的工业有机溶剂污染物环己酮对新生儿的作用心脏手术的临床结果和去除医疗中有机溶剂的方法。塑料提供了一种立即可行的方法来改善新生儿心脏手术的结果。