The GOLD Study: Goal of Open Lung Ventilation in Donors

描述(申请人提供)：尽管肝脏和肾脏的利用率在80%-90%之间，但美国移植的供肺利用率约为20%，供肺远远供不应求。供体肺短缺导致等待肺移植的时间长，等待肺移植的患者死亡率高。不能利用供体肺进行移植的最常见原因是供体低氧血症和肺浸润性病变。尽管脑死亡器官供体普遍采用机械通气，但机械通气模式对供体肺功能障碍的潜在贡献尚未得到充分研究，在脑死亡器官供体的管理过程中呼吸机设置的选择在很大程度上是经验性的。在我们最近完成的雾化吸入沙丁胺醇与安慰剂的506例器官捐献者的随机临床试验中，放射学肺不张的程度是供体氧合不良和肺利用率降低的主要预测因素。一种开放式肺保护性呼吸机(OLPV)旨在通过最大限度地增加肺招募来减少肺不张，同时将肺损伤降至最低，已在其他临床环境中改善了结果，包括急性肺损伤患者和有急性肺损伤风险的患者，以及在欧洲器官捐赠者中进行的一项小型研究。然而，大多数美国器官捐赠者仍然采用传统的机械通气策略，呼气末正压(PEEP)水平较低，潮气量较高。因此，我们建议前瞻性地检验在供体管理期间采用OLPV策略的器官供者与传统的高潮气量和低PEEP策略相比将改善供体肺的利用和氧合的假设，并探讨人类呼吸机相关肺损伤的细胞和分子机制。在目标1中，我们将在加州移植供体网络管理的1400名供体的随机临床试验中，测试OLPV策略与传统呼吸机策略对供体肺利用、供体氧合、肺不张和受者结局的影响。在Aim 2的翻译研究中，我们将通过(1)肺泡-毛细血管屏障对蛋白质的通透性、(2)肺水肿的程度、(3)组织学分级以及(4)是否通过减少肺上皮损伤和细胞凋亡来确定OLPV的保护作用是否通过减轻肺上皮损伤和细胞凋亡来确定OLPV策略对离体人肺的肺损伤的影响。AIM 1临床试验的完成将产生很大的影响，提供重要的新信息，可能改变美国的供体管理，并导致供体肺利用率的提高，减少肺移植的等待时间，并降低等待肺移植的死亡率。拟议的研究建立在我们的研究团队与加州移植捐赠者网络合作开发的捐赠者临床试验的全面和独特的基础设施上。目标2中的拟议研究将通过研究OLPV对大量切除的人类肺这一新资源的保护作用的机制，进一步加强拟议研究的影响。

DESCRIPTION (provided by applicant): Despite liver and kidney utilization rates in the 80-90% range, the donor lung utilization rate for transplantation in the United States is approximately 20%, and the demand for donor lungs far exceeds the supply. This donor lung shortage leads to long waiting times for lung transplantation and a high mortality in patients awaiting lung transplantation. The most common reason for failure to utilize donor lungs for transplantation is donor hypoxemia and pulmonary infiltrates. Although brain dead organ donors are universally mechanically ventilated, the potential contribution of the mode of mechanical ventilation to donor lung dysfunction has not been adequately studied and the choice of ventilator settings during management of the brain dead organ donor is largely empiric. In our recently completed randomized clinical trial of nebulized albuterol versus placebo in 506 organ donors, the extent of radiographic lung atelectasis was a major predictor of poor donor oxygenation and lower rates of lung utilization. An open lung protective ventilator (OLPV) that aims to reduce atelectasis by maximizing lung recruitment while minimizing lung injury has improved outcomes in other clinical settings including patients with and at risk for acute lung injury and in a small study in European organ donors. However, most U.S. organ donors are still ventilated with a conventional ventilation strategy with low levels of positive end-expiratory pressure (PEEP) and higher tidal volumes. Therefore, we propose to prospectively test the hypothesis that ventilation of organ donors with an OLPV strategy during the donor management period will improve donor lung utilization and oxygenation compared to a conventional higher tidal volume and lower PEEP strategy and to investigate the cellular and molecular mechanisms of human ventilator-associated lung injury. In Aim 1, we will test the effect of an OLPV strategy compared to a conventional ventilator strategy on donor lung utilization, donor oxygenation, atelectasis and recipient outcomes in a randomized clinical trial i 400 donors managed by the California Transplant Donor Network. In translational studies in Aim 2, we will test the effect of an OLPV strategy on lung injury in the excised human lung as measured by (1) alveolar- capillary barrier permeability to protein, (2) the extent of pulmonary edema, (3) histologic grading and (4) also determine whether the protective effects of OLPV are mediated through reductions in lung epithelial injury and apoptosis. Completion of the clinical trial in Aim 1 will have a high impact, providing significant new information that could transform donor management in the United States and lead to increased rates of donor lung utilization, decreased wait times for lung transplantation, and reduced mortality while awaiting lung transplantation. The proposed studies build on the comprehensive and unique infrastructure for donor clinical trials that our team of investigators has developed in collaboration with the California Transplant Donor Network. The proposed studies in Aim 2 will further enhance the impact of the proposed studies by studying the mechanisms of the protective effect of OLPV in large numbers of excised human lungs, a novel resource.