Brain Death, Organ Donor, Pulmonary Edema
Conditions
Keywords
brain death, organ donor, pulmonary edema, albuterol, hypoxia, lung transplantation, infiltrates
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.
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.
Interventions
DRUGAlbuterol
5 mg nebulized q4h
DRUGSaline
1.0 cc diluted with saline in identical fashion to study drug and administered by nebulizer every 4 hours
Sponsors
California Transplant Donor Network
University of California, San Francisco
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Donor Lungs Used for Transplantation | 72 hours | Number of lungs procured and used for transplantation |
| 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) |
| Pulmonary Vascular Resistance | 72 hours | — |
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Albuterol | 260 |
| Saline | 246 |
| Total | 506 |
Baseline characteristics
| Characteristic | Saline | Albuterol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 14 Participants | 29 Participants |
| Age, Categorical >=65 years | 14 Participants | 22 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 217 Participants | 224 Participants | 441 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 15 | 43 years STANDARD_DEVIATION 16 | 42 years STANDARD_DEVIATION 16 |
| Region of Enrollment United States | 246 participants | 260 participants | 506 participants |
| Sex: Female, Male Female | 88 Participants | 99 Participants | 187 Participants |
| Sex: Female, Male Male | 158 Participants | 161 Participants | 319 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 260 | 0 / 246 |
| serious Total, serious adverse events | 0 / 260 | 0 / 246 |
Outcome results
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
Time frame: Change from enrollment to organ procurement (about ~40h after enrollment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albuterol | Donor Oxygenation | 49 cmH2O |
| Saline | Donor Oxygenation | 40 cmH2O |
Comparison: Paired T Test was used to compare the change in PaO2/FiO2 ratio from enrollment to procurement between albuterol and saline treated donorsp-value: 0.98Paired T Test
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).
Time frame: change from enrollment to organ procurement (about ~40h after enrollment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol | Chest X-ray Findings | Enrollment | 4.7 units on a scale | Standard Deviation 3.3 |
| Albuterol | Chest X-ray Findings | at organ procurement (about ~40h after enrollment) | 5.0 units on a scale | Standard Deviation 3.2 |
| Saline | Chest X-ray Findings | Enrollment | 4.6 units on a scale | Standard Deviation 3.2 |
| Saline | Chest X-ray Findings | at organ procurement (about ~40h after enrollment) | 4.4 units on a scale | Standard Deviation 2.8 |
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)
Time frame: baseline and at organ procurement (about ~40h after enrollment)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol | Lung Compliance | baseline | 48 ml/cmH2O | Standard Deviation 14 |
| Albuterol | Lung Compliance | at organ procurement (mean ~40h after enrollment) | 52 ml/cmH2O | Standard Deviation 14 |
| Saline | Lung Compliance | baseline | 50 ml/cmH2O | Standard Deviation 15 |
| Saline | Lung Compliance | at organ procurement (mean ~40h after enrollment) | 56 ml/cmH2O | Standard Deviation 38 |
Secondary
Number of Donor Lungs Used for Transplantation
Number of lungs procured and used for transplantation
Time frame: 72 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Albuterol | Number of Donor Lungs Used for Transplantation | 74 Participants |
| Saline | Number of Donor Lungs Used for Transplantation | 78 Participants |
Secondary
Pulmonary Vascular Resistance
Time frame: 72 hours
Population: Insufficient data available to analyze this outcome