Treatment of Pulmonary Edema in Organ Donors

项目摘要： 与肝脏和肾脏的利用率大于85%相比，美国的供体肺利用率为 不到15%，对供体肺的需求远远超过可用的供应。最常见的原因 供肺低氧血症和/或肺浸润。由于肺水肿是一种 脑损伤患者肺浸润和低氧血症的常见可逆原因， 治疗器官捐献者的肺水肿应该会导致更高的供体肺利用率。雾化β- 2肾上腺素能受体激动剂增加肺泡液体清除率，减轻肺水肿 人类的肺。我们的研究小组最近报告说，大多数人类捐赠的肺， 排斥移植的患者有显著的肺水肿，并对β-2肾上腺素能激动剂有反应， 肺泡液体清除率增加。β-2肾上腺素能激动剂也具有有效的抗炎和抗炎作用。 内皮和肺上皮保护作用，这可能对脑死亡器官供体有益。基于 根据这一令人信服的证据，目标1提出检验这样一种假设，即雾化β-2 在500例脑死亡器官捐献者中进行的随机、盲法安慰剂对照试验中， 通过增强肺水肿清除改善供体氧合，并将改善供体肺 采购费率。在目标2中，这些肺中对β-2激动剂治疗的反应机制将是 测定在目标3中，研究了可能改变肺液体平衡的遗传因素的潜在作用， 将测试对雾化的β-2激动剂的反应。针对临床研究中发现的障碍， 在最近的NHLBI肺移植研讨会上，该提案致力于推动临床肺移植领域的发展， 一项新的、大规模的、足够有力的、多中心的研究， 廉价的治疗，以提高供体肺的利用率。如果有效，沙丁胺醇治疗可以迅速在捐助者 转化为广泛的临床应用。此外，测试沙丁胺醇对供体氧合的影响， 供体肺的利用也可能为沙丁胺醇在其他形式的急性肺动脉炎中的临床试验铺平道路。 肺水肿如心源性肺水肿、神经源性肺水肿、急性肺损伤和急性肺损伤。 呼吸窘迫综合征项目叙述： 目前的供体肺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， 提高供体肺的质量和可用性。拟议中的研究将测试一种广泛使用的， 安全的吸入治疗，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.