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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088263-05
Application #
8213425
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Harabin, Andrea L
Project Start
2008-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$400,606
Indirect Cost
$133,556
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Singer, Jonathan P; Peterson, Eric R; Snyder, Mark E et al. (2014) Body composition and mortality after adult lung transplantation in the United States. Am J Respir Crit Care Med 190:1012-21
Ware, L B; Landeck, M; Koyama, T et al. (2014) A randomized trial of the effects of nebulized albuterol on pulmonary edema in brain-dead organ donors. Am J Transplant 14:621-8
Shah, R J; Wickersham, N; Lederer, D J et al. (2014) Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation. Am J Transplant 14:446-52
Shah, Rupal J; Diamond, Joshua M; Cantu, Edward et al. (2013) Latent class analysis identifies distinct phenotypes of primary graft dysfunction after lung transplantation. Chest 144:616-22
Shah, R J; Bellamy, S L; Lee, J C et al. (2013) Early plasma soluble receptor for advanced glycation end-product levels are associated with bronchiolitis obliterans syndrome. Am J Transplant 13:754-9
Bastarache, Julie A; Diamond, Joshua M; Kawut, Steven M et al. (2012) Postoperative estradiol levels associate with development of primary graft dysfunction in lung transplantation patients. Gend Med 9:154-65
Polosukhin, Vasiliy V; Degryse, Amber L; Newcomb, Dawn C et al. (2012) Intratracheal bleomycin causes airway remodeling and airflow obstruction in mice. Exp Lung Res 38:135-46
Sims, Michael W; Beers, Michael F; Ahya, Vivek N et al. (2011) Effect of single vs bilateral lung transplantation on plasma surfactant protein D levels in idiopathic pulmonary fibrosis. Chest 140:489-96
Rey, Michael M; Ware, Lorraine B; Matthay, Michael A et al. (2011) Informed consent in research to improve the number and quality of deceased donor organs. Crit Care Med 39:280-3

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