Final Pre-clinical Studies for a Ventricular Assist Device for Infants

摘要 婴幼儿需要机械循环支持以搭桥移植或 复苏仍然具有挑战性。一岁以下的人群几乎没有选择，尽管他们是最大的。 儿童移植的年龄组和有最高的等待名单死亡率。尽管成人VAD是 有时在较大的儿童中使用，泵的大小和输出不匹配是显著的限制。柏林 心脏EXCOR VAD是唯一被批准用于大约6岁以下患者的设备，但 血栓栓塞症和神经功能障碍的发生率是成人VAD的10倍。加尔维克号 2015儿科VAD处于早期临床测试阶段，但它在婴儿和右心方面的使用存在局限性 支持。这项提议的目标是完成宾夕法尼亚州立大学婴儿的临床前测试 心室辅助装置(VAD)，这将是一个更安全的VAD的左或右支持。婴儿VAD已经被 在35项动物研究中作为左心室辅助装置(LVAD)进行了测试，并证明了良好的 生物兼容性。尽管有一种积极的方案，几乎没有抗凝作用，但有 临床上没有明显的血栓栓塞症或终末性器官功能障碍。宾夕法尼亚州立大学婴儿VAD是 气动脉动装置。尽管在成年人中脉动型VAD已经被连续流泵所取代， 在婴儿中采用脉动法有其优点。这些包括血栓栓塞症的低风险和 低水平抗凝的泵血栓形成，插管灵活，用于LVAD、RVAD或BiVAD 支架，泵输出的自动预载敏感控制，生理脉动，无净零点或 在低泵速时通过VAD的负血流，这在旋转泵中发生，并且没有 获得性血管性血友病综合征。我们建议完成所需的研究，以便向 FDA正在进行早期可行性研究计划。具体目标是： 目标1.完成VAD和套管的设计控制和制造工艺开发， 包括用于RVAD的新进气插管。 目的2.完成便携式气动驱动器的设计，为前期可行性研究提供支持。 目的3.在LVAD、RVAD和BiVAD中执行最终泵和驱动器的体外验证测试 配置以显示血流动力学性能和可接受的溶血。 目标4.证明最终泵的安全性(可接受的低血栓栓塞率和正常运行 在高流量(3)和低流量(3)范围内的LVAD和RVAD配置中的驱动器。 目标5.完成预IDE文档，设计EFS临床方案，召开预分组会议 与FDA合作，并准备一份IDE提交。

ABSTRACT The situation for infants and young children requiring mechanical circulatory support for bridge to transplant or recovery remains challenging. The under one year of age group has few options, although they are the largest age group for pediatric transplantation and have the highest waitlist mortality. Although adult VADs are sometimes used in larger children, the pump size and output mismatch are significant limitations. The Berlin Heart EXCOR VAD is the only device approved for patients under approximately 6 years of age, but thromboembolism and neurologic dysfunction occur at a rate 10 times higher than in adult VADs. The Jarvik 2015 Pediatric VAD is in early clinical testing but there are limitations to its use in infants and for right heart support. The objective of this proposal is to complete the pre-clinical testing of the Penn State Infant Ventricular Assist Device (VAD) which will be a safer VAD for left or right support. The Infant VAD has been tested as a Left Ventricular Assist Device (LVAD) in 35 animal studies, and has demonstrated excellent biocompatibility. Despite an aggressive protocol in which there has been little to no anticoagulation, there has been no clinically evident thromboembolism or end organ dysfunction. The Penn State Infant VAD is a pneumatic pulsatile device. Although pulsatile VADs have been replaced by continuous flow pumps in adults, there are advantages to the pulsatile approach in infants. These include a low risk of thromboembolism and pump thrombosis with low levels of anticoagulation, flexibility in cannulation for LVAD, RVAD or BiVAD support, automatic preload–sensitive control of pump output, physiologic pulsatility, the absence of net zero or negative blood flow through the VAD at low pump speed which occurs in rotary pumps, and absence of acquired von Willebrand syndrome. We propose to complete the studies required for an IDE submission to the FDA under the Early Feasibility Study program. The specific aims are: Aim 1. Complete design controls and manufacturing process development for the VAD and cannulae, including a new inlet cannula for the RVAD. Aim 2. Complete the design of the portable pneumatic Driver to support an Early Feasibility Study. Aim 3. Perform in vitro verification testing of the final pump and driver in the LVAD, RVAD, and BiVAD configurations to demonstrate hemodynamic performance and acceptable hemolysis. Aim 4. Demonstrate safety (acceptably low thromboembolism and normal operation) of the final pump and driver in the LVAD and RVAD configurations in the high flow (3) and low flow ranges (3). Aim 5. Complete the pre-IDE documentation, design the EFS clinical protocol, hold a pre-sub meeting with FDA, and prepare an IDE submission.