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

• 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
• 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

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)是导致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CHD最常见和最重要的后果 幸存者。减少发病率和改善预后的努力主要集中在外科技术上， 体外循环(CPB)策略和药物治疗效果不佳。暴露于 医疗保健环境中的工业化学品越来越多地被认为是有害的，也许 冠心病预后不良的机制。环己酮，是一种有害的有机工业溶剂 主要用于医疗保健，作为塑料医疗器械制造中的连接化合物。环己酮有 在动物研究中，静脉输液器和CPB循环中显示出渗出，具有显著的意义 对心血管的影响。因此，我们的假设是，从医用塑料中提取的环己酮 与先天性心脏手术的心血管和神经发育不良结局有关。我们 现在在接受心脏手术的新生儿中有重要和令人信服的试点数据，有大量的 从静脉输液和体外循环中暴露环己酮和b)经调整分析，环己酮水平为 与术后心血管不良结局显著相关，更糟糕的是12个月 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 改善体外循环手术新生儿预后的策略和更精确的治疗。我们 我将使用来自发现队列的样本和结果来接近这一假设：完成的NHLBI 多中心试验NCT01579513，题为“接受心肺手术的新生儿的皮质类固醇治疗” 搭桥(MP试验)“，Eric Graham，Pi(n=190，随机接受MP(甲基强的松龙)治疗或安慰剂治疗)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：捕捉研究》(NCT01435473)，Brian McCrindle和Cedric Manlhiot(PI) 来自密歇根大学的新生儿心脏外科手术(N=59)，马克·罗素，PI。 我们提出以下具体目标：目的1)测定围术期血清环己酮水平 与围手术期的发病率、死亡率和神经发育结局有关。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 环己酮的神经毒性、血脑屏障和学习/记忆效应。这些目标描述了一个范例 新生儿心脏手术结果减少的机制转变。创新包括对小说的发现 医用塑料制造过程中工业有机溶剂污染物环己酮对新生儿的影响 心脏手术的临床结果和摘除方法。减少来自医疗机构的有机溶剂接触 整形手术为改善新生儿心脏手术结果提供了一种即时和可行的手段。