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; 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）是与先天缺陷相关疾病和死亡的主要原因。 神经发育延迟和疾病对冠心病是最频繁，最重大的后果 幸存者。降低发病率和改善结果的努力主要集中于手术技术， 心肺旁路（CPB）策略和药理学疗法，没有太大的成功。接触 医疗保健环境中的工业化学物质越来越被认为是有害的，也许是 这些冠心病预后的机制。环己酮是一种危险的有机工业解决方案 主要是在卫生保健中作为塑料医疗设备的加入。环己酮具有 被证明可以从IV输注集和CPB电路和动物研究中步行，具有显着的 心血管效应。因此，我们的假设是从医学塑料中得出的环己酮是 与先天性心脏手术中的心血管和神经发育结果不良相关。我们 现在，在接受心脏手术的新生儿中有大量且引人注目的飞行员数据，有a）大量 从IV输注和CPB和B）进行调整的分析中，环己酮暴露于环己酮，环己酮水平为 与不良后心血管结局显着相关，而12个月则更糟 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 策略和更精确的治疗方法，以改善接受CPB手术的新生儿的结局。我们 将使用发现队列的样本和结果来解决这一假设：已完成的NHLBI 多中心试验NCT01579513，标题为“正在经历心肺的新生儿的皮质类固醇治疗 旁路（MP试验）”，Eric Graham，PI（n = 190，随机分为MP（甲基苯甲甲酮）疗法或安慰剂）和 完成的外部验证队列多伦多大学，“血栓形成的临床评估 心脏手术后的孩子：捕获研究”（NCT01435473），Brian McCrindle和Cedric Manlhiot（PIS） （n = 327，<5岁）和密歇根大学（n = 59）的新生儿心脏手术，马克·罗素（Mark Russell），pi。 以以下特定目标，我们建议：目标1）确定血清周期性环己酮水平是否水平 目标2）确定 使用沸石分子筛的环己酮暴露源和去除。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。这些目的描述了范式 新生儿心脏手术结果降低的机制的转移。创新包括发现小说 在新生儿对工业有机溶剂污染物环己酮的作用 心脏手术临床结果和去除方法。减少医疗的有机偿付能力暴露 塑料提供了一种直接且可行的手段来改善新生儿心脏外科手术结果。