More and Better Lungs: Ex-Vivo Perfusion of Lungs from Non-Heart-Beating Donors

描述(申请人提供)：肺部疾病是美国第三大死因。肺移植可以改善许多肺部疾病患者的生活质量，提高患者的存活率。然而，肺移植受到传统器官捐赠者合适肺移植数量不足的严重限制-这些捐赠者遭受致命的脑损伤，但在脑死亡发生之前进行孵化和通风。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1700例肺移植。然而，在循环停止后，肺组织仍然活着。在动物模型中，该项目的PI表明，肺在移植后可以正常工作，即使在死亡后几个小时被取回。在美国，每年有超过75万人是猝死的受害者；如果能从其中一些人--非心脏跳动捐赠者(NHBD)--那里取出肺进行移植，那么肺捐赠者的短缺就可以消除。PI进行了体外肺灌流(EVLP)，以确定最初拒绝接受传统器官捐赠者移植的人肺的适宜性。EVLP后移植这些肺的安全性最近已被证明。这项拟议的第二阶段临床试验将证明通过EVLP评估死后从NHBD取回的肺移植的安全性和有效性。我们将实现这一特定目标：证明使用EVLP评估的NHBD取回的肺移植与传统脑死亡器官捐赠者的肺移植相比并不逊色。我们将从人口众多的北卡罗来纳州韦克县(Wake)的马斯特里赫特1类和2类NHBD以及目标急诊室获得肺。我们将应用已建立的EVLP和体外CT扫描方法来评估移植的适宜性。可接受的肺将根据IRB批准的方案在北卡罗来纳大学和杜克大学进行移植。结果将与同期接受传统器官捐赠者肺移植的患者进行比较。 由于NHBD的肺没有因长时间的脑死亡而受损，从NHBD中提取的肺可能不仅要丰富得多，而且可能比目前从传统脑死亡捐赠者身上移植的肺更好。及时从NHBD中取出肺部需要EMS、执法、法医和OPO人员的协调。通过北卡罗来纳州卫生与公众服务部部长办公室，我们开始与州机构的领导层进行对话，以促进及时从NHBDS中取出肺部。我们将使用非营利性公司美国肺脏银行的专家来分析从宣布死亡到取回肺部的时间流指标。我们将与北卡罗来纳州政府机构一起制定实践和政策，以提高从NHBD中成功取出肺的产量，这些做法和政策可以在北卡罗来纳州和全美实施。一个辅助项目将确定NHBD肺是否适合进行EVLP评估的代谢组生物标记物，以及与肺移植后功能不良相关的生物标记物。研究的成功完成将给肺移植和终末期肺部疾病患者的护理带来革命性的变化。

DESCRIPTION (provided by applicant): Lung disease is the third leading cause of death in the United States. Lung transplant could improve quality of life and enhance survival in many lung disease patients. However, lung transplantation is severely limited by an inadequate number of suitable lungs for transplant from conventional organ donors - individuals who sustain a lethal brain injury, but who are incubated and ventilated before brain death occurs. Because most lungs from conventional organ donors are not suitable for transplant, only 1,700 lung transplants are performed annually in the U.S. However, lung tissue remains viable after circulatory arrest. In animal models, the PI of this project showed that lungs can function well after transplant, even if retrieved hours after death. Each year, more than 750,000 people in the U.S. are victims of sudden death; if lungs could be retrieved for transplant from some of these people - non-heart-beating donors (NHBDs) - the lung donor shortage could be eliminated. The PI has performed ex-vivo lung perfusion (EVLP) to determine suitability of human lungs initially turned down for transplant from conventional organ donors. Safety of transplanting these lungs after EVLP has recently been demonstrated. This proposed Phase 2 clinical trial will demonstrate safety and efficacy of transplant of lungs retrieved from NHBDs after death, assessed by EVLP, We will accomplish this Specific Aim: To demonstrate non-inferiority of lung transplant using lungs retrieved from NHBDs assessed by EVLP compared to lung transplant from conventional brain dead organ donors. We will obtain lungs from Maastricht Category 1 and 2 NHBDs in a large-population North Carolina county (Wake) and from targeted emergency rooms. We will apply established methods of EVLP and ex-vivo CT scan to evaluate suitability for transplant. Acceptable lungs will be transplanted at UNC and Duke under IRB-approved protocols. Outcomes will be compared to patients contemporaneously transplanted with lungs from conventional organ donors. Because lungs from NHBDs have not been injured by a prolonged interval of brain death, lungs retrieved from NHBDs may not only be much more plentiful; they may be superior to lungs currently being transplanted from conventional brain-dead donors. Timely retrieval of lungs from NHBDs requires coordination of EMS, law enforcement, medical examiners, and OPO personnel. Through the Office of the N.C. Secretary of Health and Human Services, we commenced a dialogue with leadership of state agencies to facilitate timely lung retrieval from NHBDs. We will use experts at Lung Banks of America, a not-for-profit corporation, to analyze time flow metrics from declaration of death to lung retrieval. With N.C. state government agencies, we will develop practices and policies to improve the yield of successful lung retrieval from NHBDs that can be implemented in N.C. and across the U.S. An ancillary project will determine metabolomic biomarkers for suitability of NHBD lungs for EVLP assessment, and biomarkers associated with poor function after lung transplant. Successful study completion will revolutionize lung transplant and the care of patients with end-stage lung disease.