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

项目摘要： 这项提议的目标是为慢性、重症患者发展长期的心肺支持。 肺动脉高压(PAH)和相关的RV衰竭。重度PAH患者将死于轮状病毒 如果没有肺移植就会失败。不幸的是，这些患者中的许多人都经历了漫长的等待时间， 不稳定，由于心输出量差和终末器官功能障碍而不符合移植条件。为了防止 为此，我们的团队使用了创新的静脉动脉(VA)ECMO模式作为恢复的临时桥梁(BTR)。 或移植(BTT)，以支持RV，方便行走，并确保整体均匀灌流 尸体。我们的方法已经导致了极高的存活率，但最好是在房车故障之前进行干预， 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。这样做的目的是 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 转向永久性的、目的地治疗支持。要做到这一点，我们需要更紧凑的便携式ECMO 用于增强移动性的系统，其氧合器具有较慢的凝块形成、更高的耐用性和有限的 血液损伤，消除了输血的需要。我们计划测试一种新的肺辅助装置(PAD) 本课题组建立了绵羊肺动脉高压(PH)/RV衰竭模型。该衬垫由以下部分组成 两个平行的、高度生物兼容的气体交换模块，可以由传统的磁力驱动 用于btr或btt的悬浮泵，或用于目的地治疗的小型VAD级泵。流体机械 减缓血液凝块形成和减少剪应力损伤的装置的设计和表面处理 细胞，允许更长期的支持，最小限度的全身抗凝，不输血，最大限度地减少 终末器官功能障碍。患者最初可能会在医院得到支持，然后过渡到家里， 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 在绵羊慢性PH/RV衰竭模型中提供最佳RV支持的附件。依恋模式 包括：1)右心房(RA)到肺动脉(PA)，2)RA到左心房(LA)，3)无泵 PA至LA，4)泵送RA无名动脉，5)泵送静脉(阴性对照)。在每种情况下， 支持将维持4小时，同时检查垫流速对血流动力学的影响，RV 功能，和Pad功能。这些结果将告诉我们，哪种模式(S)对PAH患者最有利。 对于目标2，我们将检查在一个月的支持期间房车功能和PAD系统耐用性的变化。 PAD系统或MAQUET心脏帮助(MC)系统将用于患有慢性PH/RV的绵羊 失败了一个月。焊盘将以目标1确定的最佳配置连接，而 MC系统将使用最佳抽水配置，因为其高阻阻碍了PA-LA的使用。我们 假设与MC相比，PAD将提高寿命、便携性，并造成更少的血液损伤 在临床上应用于最佳确定的研究时，可提高生活质量和存活率。

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.