The Effect of Nebulized Albuterol on Donor Oxygenation

• Sponsor: Vanderbilt University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00310401
• Collaborator: California Transplant Donor Network (Other), University of California, San Francisco (Other)
• Enrollment: 506
• Location: 1
• Arms: 2
• Duration (Months): 50
• Patients Per Site Per Month: 10.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Brain Death; Organ Donor; Pulmonary Edema	Drug: Albuterol; Drug: Saline	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 506 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Nebulized Albuterol on Donor Oxygenation
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Albuterol Albuterol sulfate 5 mg dissolved in normal saline administered every 4 hours by nebulization	Drug: Albuterol; 5 mg nebulized q4h; Other Names: salbutamol
Placebo Comparator: Saline Saline administered every 4 hours by nebulization	Drug: Albuterol; 5 mg nebulized q4h; Other Names: salbutamol ; Drug: Saline; 1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Donor Oxygenation [Change from enrollment to organ procurement (about ~40h after enrollment)]

   The primary outcome was the change in oxygenation as measured by change in the PaO2/FiO2 ratio from study enrollment to organ procurement

Secondary Outcome Measures

1. Number of Donor Lungs Used for Transplantation [72 hours]

   Number of lungs procured and used for transplantation

2. Lung Compliance [baseline and at organ procurement (about ~40h after enrollment)]

   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)

3. Pulmonary Vascular Resistance [72 hours]

4. Chest X-ray Findings [change from enrollment to organ procurement (about ~40h after enrollment)]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Brain death

• Consent for lung donation and donor research

• Release from coroner or medical examiner

Exclusion Criteria

• Age less than 14 years

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Transplant Donor Network	Oakland	California	United States	94612

Sponsors and Collaborators

• Vanderbilt University Medical Center
• California Transplant Donor Network
• University of California, San Francisco

Investigators

• Principal Investigator: 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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Organ procurement organization participating in this study.

Publications

• 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. Epub 2002 May 17.
• 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. Review.
• 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.
• 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.
• 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. Epub 2005 Jun 4.
• 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.
• 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. Review.
• 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.
• Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev. 2002 Jul;82(3):569-600. Review.
• 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.
• 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.
• 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. Epub 2005 Oct 27.
• 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.
• 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.
• 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.
• Simon RP. Neurogenic pulmonary edema. Neurol Clin. 1993 May;11(2):309-23. Review.
• 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.
• Thabut G, Vinatier I, Stern JB, Lesèche G, Loirat P, Fournier M, Mal H. Primary graft failure following lung transplantation: predictive factors of mortality. Chest. 2002 Jun;121(6):1876-82.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Lorraine B. Ware, Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT00310401
• Other Study ID Numbers: 3U01HL081332-01S1
• First Posted: Apr 3, 2006
• Last Update Posted: Mar 16, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Lorraine B. Ware, Professor of Medicine, Vanderbilt University Medical Center: brain death; organ donor; pulmonary edema; albuterol; hypoxia; lung transplantation; infiltrates
• Additional relevant MeSH terms: Pulmonary Edema; Brain Death; Albuterol

Study Results

Participant Flow

Arm/Group Title	Albuterol	Saline
Arm/Group Description
Period Title: Overall Study
STARTED	260	246
COMPLETED	260	246
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Albuterol	Saline	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	260	246	506
Age (Count of Participants)
<=18 years	14 5.4%	15 6.1%	29 5.7%
Between 18 and 65 years	224 86.2%	217 88.2%	441 87.2%
>=65 years	22 8.5%	14 5.7%	36 7.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43 (16)	42 (15)	42 (16)
Sex: Female, Male (Count of Participants)
Female	99 38.1%	88 35.8%	187 37%
Male	161 61.9%	158 64.2%	319 63%
Region of Enrollment (participants) [Number]
United States	260 100%	246 100%	506 100%

Outcome Measures

1. Primary Outcome

Title	Donor Oxygenation
Description	The primary outcome was the change in oxygenation as measured by change in the PaO2/FiO2 ratio from study enrollment to organ procurement
Time Frame	Change from enrollment to organ procurement (about ~40h after enrollment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Albuterol	Saline
Arm/Group Description	Albuterol 5 mg every 4 hour by nebulization	Saline every 4 hours by nebulization
Measure Participants	260	246
Median (Inter-Quartile Range) [cmH2O]	49	40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Albuterol, Saline
	Comments	Paired T Test was used to compare the change in PaO2/FiO2 ratio from enrollment to procurement between albuterol and saline treated donors
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Paired T Test
	Comments

2. Secondary Outcome

Title	Number of Donor Lungs Used for Transplantation
Description	Number of lungs procured and used for transplantation
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Albuterol	Saline
Arm/Group Description	Albuterol: 5 mg nebulized q4h	Saline: 1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours
Measure Participants	260	246
Count of Participants [Participants]	74 28.5%	78 31.7%

3. Secondary Outcome

Title	Lung Compliance
Description	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)
Time Frame	baseline and at organ procurement (about ~40h after enrollment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Albuterol	Saline
Arm/Group Description	Albuterol: 5 mg nebulized q4h	Saline: 1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours
Measure Participants	260	246
baseline	48 (14)	50 (15)
at organ procurement (mean ~40h after enrollment)	52 (14)	56 (38)

4. Secondary Outcome

Title	Pulmonary Vascular Resistance
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

Insufficient data available to analyze this outcome

Arm/Group Title	Albuterol	Saline
Arm/Group Description	Albuterol: 5 mg nebulized q4h	Saline: 1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours
Measure Participants	0	0

5. Secondary Outcome

Title	Chest X-ray Findings
Description	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).
Time Frame	change from enrollment to organ procurement (about ~40h after enrollment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Albuterol	Saline
Arm/Group Description	Albuterol: 5 mg nebulized q4h	Saline: 1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours
Measure Participants	260	246
Enrollment	4.7 (3.3)	4.6 (3.2)
at organ procurement (about ~40h after enrollment)	5.0 (3.2)	4.4 (2.8)

Adverse Events

Arm/Group Title	Albuterol		Saline
Arm/Group Description
All Cause Mortality
	Albuterol		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Albuterol		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/260 (0%)		0/246 (0%)
Other (Not Including Serious) Adverse Events
	Albuterol		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/260 (0%)		0/246 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.