The Road to Destination Therapy: Optimizing Long-Term Mechanical Cardiopulmonary Support for Pulmonary Hypertension

项目摘要： 该提案的目标是为慢性、严重 肺动脉高压（PAH）和相关的RV衰竭。重度PAH患者将死于RV 如果没有肺移植，不幸的是，这些患者中的许多人经历了漫长的等待时间， 不稳定，并且由于差的心输出量和终末器官功能障碍而变得不适合移植。防止 为此，我们的团队使用了创新的静脉动脉（VA）ECMO模式作为恢复（BTR）的临时桥梁 或移植（BTT），以支持RV，促进Amphibia，并确保整体的均匀灌注 身体我们的方法导致了极好的存活率，但最好在RV失败之前进行干预， 为患者提供更长时间的支持，并为不符合移植条件的患者提供支持。这个目标 一项建议是扩展和改进我们为PAH患者提供临时ECMO支持的成功方法 进行永久性的治疗支持为了实现这一目标，我们需要更紧凑的便携式ECMO 用于增强移动性的系统，其氧合器具有更慢的凝块形成、更大的耐久性和有限的 血液损伤，以消除输血的需要。我们计划测试一种新的肺辅助设备（PAD） 在绵羊肺动脉高压（PH）/RV衰竭模型中，PAD包括： 两个平行的、高度生物相容的气体交换器模块， 用于BTR或BTT的悬浮泵或用于目标治疗的小型VAD质量泵。流体力学 该装置的设计和表面处理减缓了凝块形成并减少了血液的剪切应力损伤 细胞，允许更长期的支持，最低限度的全身抗凝，无需输血， 终末器官功能障碍患者最初可能在医院得到支持，然后转移到家里， 并每2-3个月返回更换一次气体交换器。对于目标1，我们将确定ECMO的模式 在慢性PH/RV衰竭的绵羊模型中提供最佳RV支持的附件。连接模式 包括：1）右心房（RA）泵入肺动脉（PA），2）右心房泵入左心房（LA），3）无泵 PA至LA，4）泵送RA -无名动脉，5）泵送静脉-静脉（阴性对照）。每例病患的 在检查PAD流速对血流动力学、RV的影响时，将维持支持4小时 功能和PAD功能。这些结果将告知哪种模式对PAH患者最有益。 对于目标2，我们将检查在一个月的支持期间，右心室功能和PAD系统耐久性的变化。 PAD系统或Maquet呼吸机辅助（MC）系统将连接到患有慢性PH/RV的绵羊中 失败一个月。PAD将以目标1确定的最佳配置连接，而 MC系统将使用最佳泵送配置，因为其高阻力排除了PA-LA的使用。我们 假设PAD将延长寿命、便携性，并产生比MC更少的血液损伤， 当在最佳确定的研究中临床使用时，改善生活质量和生存期。

Project Abstract: The goal of this proposal is to develop long-term cardiopulmonary support for patients with chronic, severe pulmonary arterial hypertension (PAH) and associated RV failure. Patients with severe PAH will die of RV failure without lung transplant. Unfortunately many of these patients experience long waiting times, are unstable, and become transplant ineligible, due to poor cardiac output and end-organ dysfunction. To prevent this, our team has used innovative modes of venoarterial (VA) ECMO as a temporary bridge to recovery (BTR) or transplantation (BTT) to support the RV, facilitate ambulation, and ensure uniform perfusion of the whole body. Our approach has led to excellent survival rates, but it would be better to intervene prior to RV failure, to support patients for longer periods, and to offer support to non-transplant eligible patients. The goal of this proposal is to extend and improve our successful approach for temporary ECMO support for PAH patients toward permanent, destination therapy support. To accomplish this, we need more compact portable ECMO systems for enhanced mobility, with oxygenators that have slower clot formation, greater durability, and limited blood damage to eliminate the need for transfusions. We plan to test a new pulmonary assist device (PAD) being developed by our group in a sheep pulmonary hypertension (PH)/RV failure model. The PAD consists of two parallel, highly biocompatible gas exchanger modules that can be driven by conventional magnetically levitated pumps for BTR or BTT or a small, VAD-quality pump for destination therapy. The fluid mechanical design and surface treatments of the device slow clot formation and reduce shear stress damage of blood cells, allowing for longer-term support with minimal systemic anticoagulation, no transfusions, and minimized end-organ dysfunction. Patients could potentially be supported initially in the hospital, transitioned to home, and return for gas exchanger replacements every 2-3 months. For Aim 1, we will determine the mode of ECMO attachment that provides optimal RV support in a sheep model of chronic PH/RV failure. Attachment modes include: 1) pumped right atrium (RA) to pulmonary artery (PA), 2) pumped RA to left atrium (LA), 3) pumpless PA to LA, 4) pumped RA – innominate artery, and 5) pumped venovenous (negative control). In each case, the support will be maintained for 4 hours while examining the effect of PAD flow rate on hemodynamics, RV function, and PAD function. These results will inform which mode(s) could be most beneficial to PAH patients. For Aim 2, we will examine changes in RV function and durability of the PAD system over a month of support. Either the PAD system or a Maquet Cardiohelp (MC) system will be attached in sheep with chronic PH/RV failure for one month. The PAD will be attached in the optimal configuration determined from Aim 1, while the MC system will use the optimal pumped configuration, since its high resistance precludes PA-LA use. We hypothesize that the PAD will improve longevity, portability and create less blood damage than the MC and will improve quality of life and survival when used clinically in an optimally determined study.