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| Name | Class |
|---|---|
| California Transplant Donor Network | NETWORK |
| University of California, San Francisco | OTHER |
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The purpose of this study is to test the effectiveness of albuterol versus placebo with the following specific aims: a) Treatment of brain dead organ donors with albuterol will reduce pulmonary edema, improve donor oxygenation, and increase the number of lungs available for transplantation, b) Developing a blood test to predict the development of primary graft dysfunction in lung transplant recipients, and c) treating brain dead organ donors with albuterol will decrease markers of primary graft dysfunction and lead to improved lung transplant recipient outcomes and to higher rates of lungs suitable for transplantation.
The donor lung utilization rate in the United States remains 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 hypoxemia and infiltrates in patients with brain injury, strategies to treat pulmonary edema in organ donors should lead to improved donor oxygenation and higher rates of donor lung utilization. Inhaled beta-2 agonists increase the rate of alveolar fluid clearance and reduce pulmonary edema in both animal and human lungs. In addition, our group has recently reported that the majority of human donor lungs that are rejected for transplantation have measurable pulmonary edema and respond to beta-2 agonists with increased rates of alveolar fluid clearance. Based on this compelling scientific evidence, we propose to test the efficacy of an inhaled beta-2 agonist to increase the rate of alveolar fluid clearance and reduce pulmonary edema in brain dead organ donors with the following specific aims:
Specific Aim 1: To test the effect of aerosolized albuterol on donor oxygenation in a multicenter, randomized, double-blinded, placebo-controlled trial in 500 brain dead organ donors managed over a 2 year period by the California Transplant Donor Network (CTDN).
Hypothesis 1a: Treatment of brain dead organ donors with aerosolized albuterol will improve donor oxygenation and increase the donor lung utilization rate compared to treatment with placebo.
Hypothesis 1b: Treatment of brain dead organ donors with aerosolized albuterol will reduce the severity of pulmonary edema in procured lungs compared to treatment with placebo.
Specific Aim 2: To develop and validate a panel of biological markers that can predict and diagnose acute lung injury due to primary graft dysfunction in lung transplant recipients.
Hypothesis 2a: A panel of plasma biological markers measured in brain dead organ donors that includes markers of inflammation, coagulation, endothelial injury and lung epithelial injury will predict the development of primary graft dysfunction in the lung recipient.
Hypothesis 2b: Treatment of brain dead organ donors with inhaled beta-2 agonists will lead to reductions in levels of a panel of biological markers of inflammation, coagulation, endothelial injury, and lung epithelial injury that will be associated with increased donor lung utilization and improved recipient outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Albuterol | Experimental | Albuterol sulfate 5 mg dissolved in normal saline administered every 4 hours by nebulization |
|
| Saline | Placebo Comparator | Saline administered every 4 hours by nebulization |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Albuterol | Drug | 5 mg nebulized q4h |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Donor Oxygenation | The primary outcome was the change in oxygenation as measured by change in the PaO2/FiO2 ratio from study enrollment to organ procurement | Change from enrollment to organ procurement (about ~40h after enrollment) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Donor Lungs Used for Transplantation | Number of lungs procured and used for transplantation | 72 hours |
| Lung Compliance | Static compliance of the respiratory system using plateau pressure (Pplat) measured at end-inspiration and calculated using the equation static compliance = tidal volume/(Pplat - PEEP) |
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Inclusion Criteria:
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Lorraine B Ware, M.D. | Vanderbilt University Medical Center | Principal Investigator |
| Michael A Matthay, M.D. | University of California, San Francisco | Principal Investigator |
| Megan Landeck, RN, BSN, APC | California Transplant Donor Network | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| California Transplant Donor Network | Oakland | California | 94612 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15113353 | Background | Ojo AO, Heinrichs D, Emond JC, McGowan JJ, Guidinger MK, Delmonico FL, Metzger RA. Organ donation and utilization in the USA. Am J Transplant. 2004;4 Suppl 9:27-37. doi: 10.1111/j.1600-6135.2004.00396.x. | |
| 7474001 | Background | Rogers FB, Shackford SR, Trevisani GT, Davis JW, Mackersie RC, Hoyt DB. Neurogenic pulmonary edema in fatal and nonfatal head injuries. J Trauma. 1995 Nov;39(5):860-6; discussion 866-8. doi: 10.1097/00005373-199511000-00009. |
| Label | URL |
|---|---|
| Organ procurement organization participating in this study. | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Albuterol | |
| FG001 | Saline |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Albuterol | |
| BG001 | Saline | |
| BG002 | Total |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Donor Oxygenation | The primary outcome was the change in oxygenation as measured by change in the PaO2/FiO2 ratio from study enrollment to organ procurement | Posted | Median | Inter-Quartile Range | cmH2O | Change from enrollment to organ procurement (about ~40h after enrollment) |
|
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Albuterol |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lorraine B. Ware M.D. | Vanderbilt University | 615 322 8614 | lorraine.ware@vanderbilt.edu |
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| ID | Term |
|---|---|
| D001926 | Brain Death |
| D011654 | Pulmonary Edema |
| D000860 | Hypoxia |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D003128 | Coma |
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| ID | Term |
|---|---|
| D000420 | Albuterol |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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| Saline | Drug | 1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours |
|
|
| baseline and at organ procurement (about ~40h after enrollment) |
| Pulmonary Vascular Resistance | 72 hours |
| Chest X-ray Findings | Chest radiographs were scored using a radiographic score that scored each quadrant for extent of radiographic infiltrates on a scale of 0 to 4, then summed each quadrant for a total score from 0 (no infiltrates) to 16 (extensive infiltrates in all 4 radiographic quadrants). | change from enrollment to organ procurement (about ~40h after enrollment) |
| 8316188 | Background | Simon RP. Neurogenic pulmonary edema. Neurol Clin. 1993 May;11(2):309-23. |
| 12087129 | Background | Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev. 2002 Jul;82(3):569-600. doi: 10.1152/physrev.00003.2002. |
| 12381777 | Background | Ware LB, Fang X, Wang Y, Sakuma T, Hall TS, Matthay MA. Selected contribution: mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung. J Appl Physiol (1985). 2002 Nov;93(5):1869-74. doi: 10.1152/japplphysiol.00252.2002. |
| 12241936 | Background | Ware LB, Wang Y, Fang X, Warnock M, Sakuma T, Hall TS, Matthay M. Assessment of lungs rejected for transplantation and implications for donor selection. Lancet. 2002 Aug 24;360(9333):619-20. doi: 10.1016/s0140-6736(02)09774-x. |
| 11124490 | Background | Bhorade SM, Vigneswaran W, McCabe MA, Garrity ER. Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation. J Heart Lung Transplant. 2000 Dec;19(12):1199-204. doi: 10.1016/s1053-2498(00)00215-1. |
| 7776671 | Background | Sundaresan S, Semenkovich J, Ochoa L, Richardson G, Trulock EP, Cooper JD, Patterson GA. Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs. J Thorac Cardiovasc Surg. 1995 Jun;109(6):1075-9; discussion 1079-80. doi: 10.1016/S0022-5223(95)70190-7. |
| 14570373 | Background | Whiting D, Banerji A, Ross D, Levine M, Shpiner R, Lackey S, Ardehali A. Liberalization of donor criteria in lung transplantation. Am Surg. 2003 Oct;69(10):909-12. |
| 10517756 | Background | Verghese GM, Ware LB, Matthay BA, Matthay MA. Alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema. J Appl Physiol (1985). 1999 Oct;87(4):1301-12. doi: 10.1152/jappl.1999.87.4.1301. |
| 11371404 | Background | Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001 May;163(6):1376-83. doi: 10.1164/ajrccm.163.6.2004035. |
| 2252240 | Background | Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1250-7. doi: 10.1164/ajrccm/142.6_Pt_1.1250. |
| 10051282 | Background | Ware LB, Golden JA, Finkbeiner WE, Matthay MA. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med. 1999 Mar;159(3):980-8. doi: 10.1164/ajrccm.159.3.9802105. |
| 9887124 | Background | Campbell AR, Folkesson HG, Berthiaume Y, Gutkowska J, Suzuki S, Matthay MA. Alveolar epithelial fluid clearance persists in the presence of moderate left atrial hypertension in sheep. J Appl Physiol (1985). 1999 Jan;86(1):139-51. doi: 10.1152/jappl.1999.86.1.139. |
| 8049807 | Background | Sakuma T, Okaniwa G, Nakada T, Nishimura T, Fujimura S, Matthay MA. Alveolar fluid clearance in the resected human lung. Am J Respir Crit Care Med. 1994 Aug;150(2):305-10. doi: 10.1164/ajrccm.150.2.8049807. |
| 12023995 | Background | Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, Scherrer U. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med. 2002 May 23;346(21):1631-6. doi: 10.1056/NEJMoa013183. |
| 16254268 | Background | Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med. 2006 Feb 1;173(3):281-7. doi: 10.1164/rccm.200508-1302OC. Epub 2005 Oct 27. |
| 12107675 | Background | Atabai K, Ware LB, Snider ME, Koch P, Daniel B, Nuckton TJ, Matthay MA. Aerosolized beta(2)-adrenergic agonists achieve therapeutic levels in the pulmonary edema fluid of ventilated patients with acute respiratory failure. Intensive Care Med. 2002 Jun;28(6):705-11. doi: 10.1007/s00134-002-1282-x. Epub 2002 May 17. |
| 12588712 | Background | de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med. 2003 Feb 15;167(4):490-511. doi: 10.1164/rccm.200207-670SO. |
| 12829889 | Background | Avlonitis VS, Fisher AJ, Kirby JA, Dark JH. Pulmonary transplantation: the role of brain death in donor lung injury. Transplantation. 2003 Jun 27;75(12):1928-33. doi: 10.1097/01.TP.0000066351.87480.9E. |
| 14555551 | Background | Christie JD, Kotloff RM, Pochettino A, Arcasoy SM, Rosengard BR, Landis JR, Kimmel SE. Clinical risk factors for primary graft failure following lung transplantation. Chest. 2003 Oct;124(4):1232-41. doi: 10.1378/chest.124.4.1232. |
| 12065352 | Background | Thabut G, Vinatier I, Stern JB, Leseche G, Loirat P, Fournier M, Mal H. Primary graft failure following lung transplantation: predictive factors of mortality. Chest. 2002 Jun;121(6):1876-82. doi: 10.1378/chest.121.6.1876. |
| 16210116 | Background | Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D; ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2005 Oct;24(10):1454-9. doi: 10.1016/j.healun.2004.11.049. Epub 2005 Jun 4. No abstract available. |
| 15477105 | Background | de Perrot M, Snell GI, Babcock WD, Meyers BF, Patterson G, Hodges TN, Keshavjee S. Strategies to optimize the use of currently available lung donors. J Heart Lung Transplant. 2004 Oct;23(10):1127-34. doi: 10.1016/j.healun.2003.09.010. No abstract available. |
Total of all reporting groups
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Participants |
|
|
|
| Secondary | Number of Donor Lungs Used for Transplantation | Number of lungs procured and used for transplantation | Posted | Count of Participants | Participants | 72 hours |
|
|
|
| Secondary | Lung Compliance | Static compliance of the respiratory system using plateau pressure (Pplat) measured at end-inspiration and calculated using the equation static compliance = tidal volume/(Pplat - PEEP) | Posted | Mean | Standard Deviation | ml/cmH2O | baseline and at organ procurement (about ~40h after enrollment) |
|
|
|
| Secondary | Pulmonary Vascular Resistance | Insufficient data available to analyze this outcome | Posted | 72 hours |
|
|
| Secondary | Chest X-ray Findings | Chest radiographs were scored using a radiographic score that scored each quadrant for extent of radiographic infiltrates on a scale of 0 to 4, then summed each quadrant for a total score from 0 (no infiltrates) to 16 (extensive infiltrates in all 4 radiographic quadrants). | Posted | Mean | Standard Deviation | units on a scale | change from enrollment to organ procurement (about ~40h after enrollment) |
|
|
|
| 0 |
| 260 |
| 0 |
| 260 |
| EG001 | Saline | 0 | 246 | 0 | 246 |
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| D014474 |
| Unconsciousness |
| D003244 | Consciousness Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D003643 | Death |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D000588 |
| Amines |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |