CTRIP Ex-vivo perfusion and ventilation of lungs to assess transplant suitability

描述（由申请人提供）：肺部疾病是美国第四大死亡原因。肺移植（LTX）可以改善许多肺部疾病患者的生活质量并提高生存率，但由于适用于移植的肺数量不足而受到严重限制。目前，用于移植的肺是从传统的器官捐赠者那里取回的--这些捐赠者遭受了致命的脑损伤，但在脑死亡发生之前进行了插管和通气。由于大多数来自传统器官捐献者的肺不适合移植，美国每年只进行1,400例LTX手术。增加肺供体的数量是可能的，因为肺在移植的实体器官中是独一无二的。具体地，肺在循环停止后的相当长的时间段内保持存活，因为肺组织不依赖于血流进行细胞呼吸。PI已经在动物模型中证明，即使在死亡后数小时内取回，肺在移植后也可以良好地发挥功能。如果肺可以从美国每年300万猝死受害者中的一些人--无心跳供体（NHBDs）--中取出用于LTX，那么肺供体短缺就可以消除。为了使NHBD肺成为一种可行的选择，需要一种可靠的方法来确保死后移植肺的安全性。本提案的目的是：1）。完善体外（离体）肺灌注和通气技术，以可靠地评估肺功能和移植的适用性; 2）.进行初步/可行性临床研究，以证明离体灌注后移植人肺的安全性; 3）.计划一项多中心前瞻性临床试验，以比较来自常规脑死亡器官供体的LTX与使用在离体灌注回路中评估的死亡后从NHBD取回的肺的LTX的有效性，作为第2阶段临床试验;以及4）。开发一种教育工具，以加强紧急医疗服务（EMS）人员的参与，以识别合适的NHBD进行肺捐赠，并促进NHBD的肺捐赠。这种离体灌注方法将允许评估从NHBD取回的肺的LTX的适用性，并且重要的是还将提供在移植前治疗肺以减少缺血-再灌注损伤的机会。因此，这种新的供体来源和离体灌注将不仅提供更多的肺用于移植，而且提供比目前移植的肺更好的肺（更少的移植物功能障碍和改善的存活率）。该项目解决了困扰LTX作为终末期肺病患者治疗的两个主要问题-适合移植的肺太少，以及LTX后移植失败。该项目将彻底改变LTX和终末期肺病的治疗。 公共卫生相关性：这个为期2年的第1阶段项目将完善体外（离体）灌注和移植人肺的技术，以确定它们是否适合移植，并将在试点临床研究中证明离体灌注后移植人肺的安全性。该项目还计划进行一项大型多中心临床试验，使用这种离体肺灌注/通气系统来评估从无心跳供体死后回收的人类肺。这将为移植提供更多的人类肺，这些肺可能比目前从传统脑死亡器官捐赠者移植的肺功能更好，寿命更长。

DESCRIPTION (provided by applicant): Lung disease is the fourth leading cause of death in the U.S. Lung transplant (LTX) could improve quality of life and enhance survival in many lung disease patients, but is severely constrained by an inadequate number of suitable lungs for transplant. Currently, lungs for transplant are retrieved from conventional organ donors - individuals who sustain a lethal brain injury, but who are intubated and ventilated before brain death occurs. Because most lungs from conventional organ donor are not suitable for transplant, only 1,400 LTX procedures are performed annually in the U.S. This Stage 1 Grand Opportunities project will test the hypothesis that the number of lung donors can be dramatically expanded to allow performance of substantially more LTX procedures. Increasing the number of lung donors is possible because the lung is unique among solid organs that are transplanted. Specifically, lungs remain viable for substantial periods of time after circulatory arrest because lung tissue does not rely on blood flow for cellular respiration. The PI has demonstrated in animal models that lungs can function well after transplant, even if retrieved hours after death. If lungs could be retrieved for LTX from some of the 3 million annual U.S. victims of sudden death - non-heart-beating donors (NHBDs) - then the lung donor shortage could be eliminated. To make NHBD lungs a viable option requires a reliable way to ensure safety of transplanting lungs retrieved after death. The aims of this proposal are: 1). to perfect a technique of lung perfusion and ventilation outside the body (ex-vivo) to reliably assess lung function and suitability for transplant; 2). to perform a pilot/feasibility clinical study to demonstrate safety of transplanting human lungs after ex-vivo perfusion; 3). to plan a multi-center prospective clinical trial to compare effectiveness of LTX from conventional brain-dead organ donors with LTX using lungs retrieved from NHBDs after death assessed in an ex-vivo perfusion circuit as a Stage 2 clinical trial; and 4). to develop an educational tool to enhance involvement of Emergency Medical Services (EMS) personnel to identify appropriate NHBDs for lung donation and facilitate lung donation from NHBDs. This ex-vivo perfusion approach will allow assessment of suitability for LTX of lungs retrieved from NHBDs, and importantly will also provide an opportunity to treat lungs before transplant to reduce ischemia-reperfusion injury. Thus, this new donor source and ex-vivo perfusion will not only provide many more lungs for transplant, but lungs that are better (less graft dysfunction and improved survival) than lungs currently being transplanted. This project addresses two major problems that plague LTX as a therapy for patients with end-stage lung disease - far too few suitable lungs for transplant, and graft failure after LTX. This project would revolutionize LTX and the treatment of end-stage lung disease. PUBLIC HEALTH RELEVANCE: This 2-year Stage 1 project will perfect a technique to perfuse and ventilate human lungs outside the body (ex- vivo) to determine if they are suitable for transplant, and will demonstrate safety of transplanting human lungs after ex-vivo perfusion in a pilot clinical study. This project will also plan a large multi-center clinical trial to use this ex-vivo lung perfusion/ventilation system to evaluate human lungs retrieved after death from non-heart- beating donors. This would provide much larger numbers of human lungs for transplant that may function better and last longer than lungs currently being transplanted from conventional brain-dead organ donors.