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

CTRIP 肺离体灌注和通气以评估移植适宜性

• 批准号: 7939804
• 负责人: Thomas M. Egan
• 金额: $ 74.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939804
• 关键词: Accident and Emergency department; Address; Animal Model; Attitude; Blood flow; Brain Death; Brain Injuries; Cardiac Death; Categories; Cause of Death; Cell Respiration; Cessation of life; Clinical Data; Clinical Research; Clinical Trials; Educational Intervention; Emergency medical service; Ensure; Environmental air flow; Europe; Functional disorder; Future; Goals; Heart; Hospitals; Hour; Human; Human Resources; Individual; Knowledge; Laboratories; Learning; Lung; Lung diseases; Methods; Multi-Institutional Clinical Trial; Organ; Organ Donations; Organ Donor; Organ Transplantation; Patients; Performance; Perfusion; Plague; Procedures; Process; Protocols documentation; Quality of life; Reperfusion Injury; Research Ethics Committees; Research Infrastructure; Respiratory physiology; Retrieval; Safety; Solid; Source; Staging; Structure of parenchyma of lung; Sudden Death; System; Techniques; Testing; Therapeutic; Time; Tissue Donations; Transplantation; United States; compare effectiveness; ex vivo perfusion; experience; graft failure; improved; improved functioning; instrument; novel; pre-clinical; prospective; public health relevance; success; tool

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.

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，但由于适合移植的肺数量不足而受到严重限制。目前，用于移植的肺来自传统的器官捐献者——那些遭受致命脑损伤的人，但在脑死亡发生之前，他们被插管和通气。由于大多数来自传统器官供体的肺不适合移植，在美国每年只有1400例肺移植手术。这个第一阶段的大机会项目将测试一个假设，即肺供体的数量可以大幅增加，从而允许更多的肺移植手术的进行。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。具体来说，肺在循环停止后仍能存活相当长的一段时间，因为肺组织不依赖血流进行细胞呼吸。PI已经在动物模型中证明，肺在移植后可以正常工作，即使在死后数小时恢复。如果能从美国每年300万猝死患者——非心脏跳动供体（NHBDs）中的一些人身上提取肺来进行LTX治疗，那么肺供体短缺就可以消除。为了使非hbd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)完善体外肺灌注通气技术，以可靠地评估肺功能和移植的适宜性；2)开展中试/可行性临床研究，以证明体外灌注后人体肺移植的安全性；3)计划开展一项多中心前瞻性临床试验，比较常规脑死亡器官供体的LTX与NHBDs死亡后取肺的LTX的有效性，作为一项ii期临床试验，在离体灌注回路中评估；（四）发展教育工具，加强紧急医疗服务人员的参与，以甄别合适的非本地居民捐肺，并促进非本地居民捐肺。这种离体灌注方法将允许评估从NHBDs中取出的肺进行LTX的适用性，重要的是，也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体外灌注不仅可以提供更多的肺供移植，而且比目前移植的肺更好（移植物功能障碍更少，生存率更高）。该项目解决了两个主要问题，困扰LTX作为终末期肺病患者的治疗方法——适合移植的肺太少，以及LTX后移植失败。这个项目将彻底改变LTX和终末期肺病的治疗。