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.

先天性心脏缺陷（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CHD最常见和最重要的后果 幸存者降低发病率和改善结局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太大的成功。暴露于 卫生保健环境中的工业化学品越来越被认为是有害的， CHD不良结局的机制。环己酮，是一种危险的有机工业溶剂， 主要用于医疗保健，作为塑料医疗器械制造中的连接化合物。环己酮具有 在动物研究中显示从IV输液器和CPB回路中浸出， 心血管影响因此，我们的假设是，来自医用塑料的环己酮是 与先天性心脏手术中不良心血管和神经发育结局相关。我们 目前，在接受心脏手术的新生儿中有重要且令人信服的试点数据， IV输注和CP B和B）中的环己酮暴露量以及调整后的分析， 与不良术后心血管结局显著相关，12个月时更差 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 策略和更精确的治疗，以改善接受CPB手术的新生儿的结局。我们 我将使用来自发现队列的样本和结果来探讨这一假设：已完成的NHLBI 多中心试验NCT 01579513，标题为“皮质类固醇治疗新生儿心脏病” 旁路（MP试验）"，Eric Graham，PI（n=190，随机分配至MP（甲基强的松龙）治疗组或安慰剂组）， 已完成的外部验证队列，多伦多大学，“血栓形成的临床评估， 心脏手术后的儿童：CATCH研究”（NCT 01435473），Brian McCrindle和Cedric Manlhiot（PI） （N=327，<5岁）和密歇根大学的新生儿心脏手术（N=59），Mark Russell，PI。 我们提出以下具体目的：目的1）确定血清围手术期环己酮水平 与围手术期发病率、死亡率和神经发育结局相关。目标2）确定 环己酮暴露源和使用沸石分子筛去除。第三步：确定 环己酮神经毒性、血脑屏障和学习/记忆影响。这些目标描述了一个范例 降低新生儿心脏手术结果的机制的转变。创新包括发现小说 医用塑料制品中工业有机溶剂污染物环己酮对新生儿的影响 心脏手术的临床结局和切除方法。减少医疗器械中的有机溶剂暴露 整形外科为改善新生儿心脏手术结果提供了一种直接可行的方法。