Plastic Chemicals in Pediatric Cardiopulmonary Bypass: Evaluating Cardiac Toxicity and Investigating Clinical Alternatives

项目摘要 邻苯二甲酸酯是一种增塑剂，用于使硬质聚氯乙烯（PVC）塑料变软。医疗 据报道，邻苯二甲酸酯含量在产品重量的20-80%之间，具体取决于产品类型。 然而，人们对其安全性提出了质疑。PVC中最常用的邻苯二甲酸酯增塑剂 邻苯二甲酸二（2-乙基己基）酯（DEHP）。接受心脏手术的患者涉及使用 心肺旁路（CPB）回路暴露于血液制品、回路 导管、旁路插管和气管内导管。尽管塑料有着不可估量的好处， 人们越来越关注邻苯二甲酸酯化学品暴露的潜在健康风险。因此，有一个 迫切需要开发和采用更安全的替代品用于儿科CPB。拟议研究 该项目将通过评估DEHP对儿童心脏的心脏毒性作用来满足这一需求， 调查潜在的缓解策略，以减少对有毒邻苯二甲酸酯化学品的暴露。目标1将 评估邻苯二甲酸酯增塑剂对人类小儿心脏电生理和收缩力的直接影响。 目标2将确定潜在缓解策略的有效性，以减少邻苯二甲酸酯暴露， 心脏结局。后者将包括研究市售DEHP的心脏安全性特征- 免费替代品和使用细胞洗涤去除心肺组织中邻苯二甲酸酯增塑剂的效用 分流液该提案的结果将在很大程度上适用于心脏病学领域，具有潜在的 为在医疗器械生产中使用邻苯二甲酸酯增塑剂的监管决策提供信息。这 这对于用于治疗经历了以下情况的脆弱新生儿和婴儿的医疗设备尤其重要： 体外循环这个应用程序包含一个三年的培训计划，将进一步我的科学 开发，通过建立在我的申办者的专业知识（Posnack博士，具有心脏病方面的专业知识 电生理学和心脏毒性）和共同申办者（具有临床前模型经验的Ishibashi博士， 小儿心脏手术）。我还将受益于更广泛的合作者群体，他们将提供以下方面的见解： 临床相关性和实验技术。这份培训计划将扩大我对以下问题的科学理解： 儿科心血管生理学、增塑剂毒性和临床相关模型，同时支持我的未来 他的目标是在一家顶级儿童医院领导一个转化研究实验室。

Project Summary Phthalates are a type of plasticizer that are used to make rigid polyvinyl chloride (PVC) plastic flexible. In medical devices, phthalate levels have been reported to be between 20-80% of a product’s weight depending on the type of device; however, questions have arisen over their safety. The most common phthalate plasticizer used in PVC medical devices is di(2-ethylhexyl) phthalate (DEHP). Patients undergoing cardiac surgery involving the use of a cardiopulmonary bypass (CPB) circuit are exposed to significant levels of DEHP from blood products, circuitry tubing, bypass cannulas, and endotracheal tubes. Despite the immeasurable benefits of plastics – there is increasing concern over the potential health risks of phthalate chemical exposures. Accordingly, there is an urgent need to develop and adopt safer alternatives to be used in pediatric CPB. The proposed research project will address this need by evaluating the cardiotoxic effects of DEHP on the pediatric heart and investigating potential mitigation strategies to reduce exposure to toxic phthalate chemicals. Aim 1 will assess the direct effects of phthalate plasticizers on human pediatric cardiac electrophysiology and contractility. Aim 2 will determine the efficacy of potential mitigation strategies to reduce phthalate exposure and improve cardiac outcomes. The latter will include investigating the cardiac safety profile of commercially available DEHP- free alternatives and the utility of using cell washing to remove phthalate plasticizers from cardiopulmonary bypass fluids. The results of this proposal will largely be applicable to the fields of cardiology, with the potential to inform regulatory decision making over the use of phthalate plasticizers in medical device manufacturing. This is particularly important for medical devices that are used to treat vulnerable neonates and infants undergoing cardiopulmonary bypass. This application contains a three-year training plan that will further my scientific development, by building upon the expertise of my Sponsor (Dr. Posnack with expertise in cardiac electrophysiology and cardiotoxicity) and co-Sponsor (Dr. Ishibashi with experience in preclinical models and pediatric cardiac surgery). I will also benefit from a broader group of collaborators, who will provide insight into clinical relevance and experimental techniques. This training proposal will expand my scientific understanding of pediatric cardiovascular physiology, plasticizer toxicity, and clinically relevant models while supporting my future goal to lead a translational research laboratory at a top children’s hospital.