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)塑料变得灵活。在医学上 据报道，邻苯二甲酸盐水平在产品重量的20%-80%之间，具体取决于产品的类型 然而，它们的安全性也出现了问题。聚氯乙烯中最常用的邻苯二甲酸酯增塑剂 医疗器械是邻苯二甲酸二(2-乙基己基)酯(DEHP)。接受心脏手术的患者使用 体外循环(CPB)回路暴露于血液产品、回路 插管、旁路插管和气管内插管。尽管塑料有不可估量的好处，但还有 人们越来越关注邻苯二甲酸盐化学物质暴露的潜在健康风险。相应地，有一种 迫切需要开发和采用更安全的替代品用于儿科CPB。拟议的研究 该项目将通过评估DEHP对儿童心脏和心脏的心脏毒性效应来满足这一需求 研究潜在的缓解策略，以减少对邻苯二甲酸盐有毒化学品的暴露。目标1将 评估邻苯二甲酸酯增塑剂对儿童心脏电生理和收缩性能的直接影响。 目标2将确定潜在缓解策略的有效性，以减少邻苯二甲酸盐暴露并改善 心脏结果。后者将包括调查商用DEHP的心脏安全性概况- 细胞洗涤法去除心肺组织中邻苯二甲酸酯类增塑剂的应用 旁路液体。这项提议的结果将在很大程度上适用于心脏病学领域，具有潜在的 为在医疗器械制造中使用邻苯二甲酸酯增塑剂的监管决策提供信息。这 对于用于治疗易受伤害的新生儿和婴儿的医疗设备尤其重要 心肺转流术。这份申请书包含了一个为期三年的培训计划，它将使我的科学 发展，建立在我的赞助人(Posnack博士，心脏方面的专业知识)的专业知识基础上 电生理学和心脏毒性)和共同发起人(石桥博士，在临床前模型和 儿科心脏手术)。我还将受益于更广泛的合作者小组，他们将提供对 临床相关性和实验技术。这个培训方案将扩大我对 支持我未来的儿科心血管生理学、塑化剂毒性和临床相关模型 目标是在一家顶级儿童医院领导一个翻译研究实验室。

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.