Treatment of Pulmonary Edema in Organ Donors

项目总结： 与超过85%的肝脏和肾脏利用率相比，美国的供体肺利用率是 不到15%，而且对供体肺的需求远远超过了可用的供应。最常见的原因是 不能利用供体肺的原因是供体低氧血症和/或肺浸润性病变。因为肺水肿是一种 脑损伤患者中常见的可逆的肺浸润性和低氧血症的原因，治疗策略 治疗器官捐赠者的肺水肿应该会导致更高的供体肺利用率。雾化的贝塔- 两种肾上腺素能激动剂均可增加两种动物肺泡液的清除率并减轻肺水肿 和人类的肺。我们的研究小组最近报告说，大多数人类供体肺是 排斥移植有严重的肺水肿，并对β2肾上腺素能激动剂有反应 肺泡液清除率增加。β-2肾上腺素能激动剂也有强大的抗炎和 可能有益于脑死亡器官供者的内皮和肺上皮保护作用。基座 根据这一令人信服的证据，Aim 1建议测试喷雾剂Beta-2给药的假设 激动剂(沙丁胺醇)在500名脑死亡器官捐赠者中进行的随机、盲法安慰剂对照试验 通过促进肺水肿的清除来改善供体氧合，并将改善供体肺 采购率。在目标2中，这些肺对β-2激动剂治疗的反应机制将是 下定决心。在目标3中，可能改变肺液平衡的遗传因素的潜在贡献以及 将测试对雾化β-2激动剂的反应。为了应对临床研究中发现的障碍 通过最近的NHLBI关于肺移植的研讨会，这一建议努力推动临床肺领域 一项新的、大型的、动力充足的、多中心的简单、安全和 廉价的治疗以提高供体肺的利用率。如果有效，沙丁胺醇在捐赠者中的治疗可能会迅速 转化为广泛的临床应用。此外，沙丁胺醇对供体氧合和 供体肺的利用也可能为沙丁胺醇治疗其他形式的急性肺病的临床试验铺平道路 心源性肺水肿、神经源性肺水肿、急性肺损伤和急性 呼吸窘迫综合征。项目说明： 目前供体肺的供应不足以满足日益增长的需求。精心设计 迫切需要研究具有科学说服力的捐助者管理战略，以 提高供肺的质量和可获得性。拟议的研究将测试一种广泛使用的、 安全，吸入治疗，以确定是否可以改善供体肺功能。

Project Summary: Compared to liver and kidney utilization rates of greater than 85%, the donor lung utilization rate in the U.S. is less than 15%, and the demand for donor lungs far exceeds the available supply. The most common reasons for failure to utilize donor lungs are donor hypoxemia and/or pulmonary infiltrates. Since pulmonary edema is a common, reversible cause of pulmonary infiltrates and hypoxemia in patients with brain injury, strategies to treat pulmonary edema in organ donors should lead to higher rates of donor lung utilization. Aerosolized beta- 2 adrenergic agonists increase the rate of alveolar fluid clearance and reduce pulmonary edema in both animal and human lungs. Our research group has recently reported that the majority of human donor lungs that are rejected for transplantation have significant pulmonary edema and respond to beta-2 adrenergic agonists with increased rates of alveolar fluid clearance. Beta-2 adrenergic agonists also have potent anti-inflammatory and endothelial and lung epithelial protective effects that may be beneficial in the brain dead organ donor. Based on this compelling evidence, Aim 1 proposes to test the hypothesis that administration of an aerosolized beta-2 agonist (albuterol) in a randomized, blinded placebo controlled trial in 500 brain dead organ donors will improve donor oxygenation by enhancing clearance of pulmonary edema and will improve donor lung procurement rates. In Aim 2, the mechanisms of the response to beta-2 agonist therapy in these lungs will be determined. In Aim 3, the potential contribution of genetic factors that may modify lung fluid balance and the response to aerosolized beta-2 agonists will be tested. In response to the barriers to clinical research identified by a recent NHLBI Workshop on lung transplantation, this proposal strives to move the field of clinical lung transplantation forward with a novel, large, adequately powered, multicenter study of a simple, safe and inexpensive therapy to improve donor lung utilization. If effective, albuterol therapy in donors could be rapidly translated into widespread clinical use. In addition, testing of the effect of albuterol on donor oxygenation and donor lung utilization may also pave the way for clinical trials of albuterol in other forms of acute pulmonary edema such as cardiogenic pulmonary edema, neurogenic pulmonary edema, acute lung injury and the acute respiratory distress syndrome. Project Narrative: The current supply of donor lungs is inadequate to meet the growing demand. Well designed studies of scientifically compelling donor management strategies are urgently needed to improve the quality and availability of donor lungs. The proposed studies will test a widely used, safe, inhaled therapy to determine whether donor lung function can be improved.