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

描述(申请人提供)：肺部疾病是美国第四大死因。肺移植(LTX)可以改善许多肺部疾病患者的生活质量和提高存活率，但严重制约了适合移植的肺的数量不足。目前，供移植的肺是从传统的器官捐赠者那里提取的，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呼吸。由于大多数来自传统器官捐赠者的肺不适合移植，美国每年只进行1400例LTX手术。这个第一阶段的大机遇项目将检验这样一个假设，即肺捐赠者的数量可以大幅扩大，以允许进行更多的LTX手术。增加肺捐赠者的数量是可能的，因为肺在移植的实体器官中是独一无二的。具体地说，肺在循环停止后仍能存活很长一段时间，因为肺组织不依赖血液流动进行细胞呼吸。PI已经在动物模型中证明了肺在移植后可以很好地发挥作用，即使在死亡后几个小时被取回。如果能从每年300万美国猝死受害者中的一些人-非心脏跳动捐赠者(NHBD)-那里提取肺用于LTX，那么肺捐赠者的短缺就可以消除。要使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取回的肺移植的安全性。这项建议的目的是：1)。完善体外(体外)肺灌流和换气技术，以可靠地评估肺功能和移植的适宜性；进行中试/可行性临床研究，以证明体外灌流后移植人肺的安全性；计划一项多中心前瞻性临床试验，以比较来自传统脑死亡器官捐赠者的LTX与使用死后从NHBD取回的肺的LTX的有效性，作为第二阶段临床试验在体外灌流电路中进行评估；开发一种教育工具，以加强紧急医疗服务人员的参与，以确定适合肺捐赠的非HBD，并促进从NHBD进行肺捐赠。这种体外灌流方法将能够评估从NHBD取回的肺的LTX的适合性，重要的是，还将提供在移植前治疗肺的机会，以减少缺血再灌注损伤。因此，这种新的供体来源和体外灌流不仅将为移植提供更多的肺，而且还将提供比目前移植的肺更好的肺(更少的移植功能障碍和更高的存活率)。该项目解决了困扰LTX作为终末期肺部疾病患者治疗方法的两个主要问题--适合移植的肺太少，以及LTX后移植失败。该项目将对LTX和终末期肺部疾病的治疗产生革命性影响。 公共卫生相关性：这个为期两年的第一阶段项目将完善一项技术，以在体外(体外)灌流和通风人类肺，以确定它们是否适合移植，并将在一项试点临床研究中展示体外灌流后移植人类肺的安全性。该项目还将计划一项大型的多中心临床试验，使用这种体外肺灌流/通风系统来评估死后从非心脏跳动捐赠者那里获取的人肺。这将为移植提供更多数量的人类肺，这些肺可能比目前从传统脑死亡器官捐赠者那里移植的肺功能更好，持续时间更长。

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.