Brain Death, Heart Failure
Conditions
Keywords
Organ donor
Brief summary
This randomized controlled trial will evaluate whether intravenous thyroxine infusion given to brain-dead organ donors who are eligible to donate hearts for 12 hours will result in more hearts transplanted than saline placebo
Detailed description
Background: Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid stimulating hormone) may contribute to hemodynamic instability and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy. Methods: This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12-hours or saline placebo. The primary study hypothesis is that thyroxine treatment results in more hearts transplanted. Additional outcome measures are time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography. Discussion: This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment for organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether treatment increases hearts transplanted and/or provides other hemodynamic benefits.
Interventions
DRUGThyroxine
Infusion prepared by mixing 500 μg of drug in 500-ml of normal saline (i.e. concentration of 1 μg/ml) and enclosing the bag in an opaque sleeve. Infusion started at 30 μg/hour (30 ml/hour) for twelve hours.
DRUGSaline
The placebo will be a 500-ml bag of normal saline (without active drug) also enclosed in an opaque sleeve. This infusion will also be started at 30 ml/hour for twelve hours.
Sponsors
Mid-America Transplant
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Declared dead by neurologic criteria (brain dead) * Authorization for organ donation and research * On one or more vasopressors and/or inotropes
Exclusion criteria
* Brain death declared more than 24 hours prior * Only vasopressor is vasopressin * Weight \< 45 kg (100 lbs) * Known coronary artery disease or history of myocardial infarction * Known valvular heart disease * Prior sternotomy or cardiac surgery * Donor at VA hospital * Received intravenous or oral thyroxine within past month * Known HIV+ status * Other reason donor is unable to receive study drug (determined by on-site personnel)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Graft Function | 30 days | 30-day graft survival of hearts transplanted from study donors, obtained from SRTR recipient registry |
| Heart Transplanted | One week | Whether heart is transplanted into living recipient |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weaned Off Vasopressors | 12 hours | Weaned off vasopressors within twelve hours |
| Time to Order Echo | 72 hours | Time till hemodynamic stability permits ordering initial echocardiogram |
| Lungs Transplanted | 72 hours | Whether the lungs were transplanted into a living recipient |
| Ejection Fraction | 72 hours | Left ventricular ejection fraction measured on first echocardiography |
| Time Till Off Vasopressors | 72 hours | Time in hours from randomization to when weaned off vasopressors (except vasopressin) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Organs Transplanted | One week | Total number of organs transplanted (incl. lungs, liver, kidneys, heart, pancreas) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Thyroxine Intravenous thyroxine infusion
Thyroxine: Infusion prepared by mixing 500 μg of drug in 500-ml of normal saline (i.e. concentration of 1 μg/ml) and enclosing the bag in an opaque sleeve. Infusion started at 30 μg/hour (30 ml/hour) for twelve hours. | 419 |
| Saline Placebo Intravenous saline infusion
Saline: The placebo will be a 500-ml bag of normal saline (without active drug) also enclosed in an opaque sleeve. This infusion will also be started at 30 ml/hour for twelve hours. | 419 |
| Total | 838 |
Baseline characteristics
| Characteristic | Saline Placebo | Total | Thyroxine |
|---|---|---|---|
| Age, Continuous | 36 years STANDARD_DEVIATION 10 | 36 years STANDARD_DEVIATION 10 | 36 years STANDARD_DEVIATION 11 |
| Blood Group A | 148 Participants | 282 Participants | 134 Participants |
| Blood Group AB | 8 Participants | 19 Participants | 11 Participants |
| Blood Group B | 49 Participants | 99 Participants | 50 Participants |
| Blood Group O | 214 Participants | 438 Participants | 224 Participants |
| Cause of Death Anoxia | 195 Participants | 357 Participants | 162 Participants |
| Cause of Death Other | 6 Participants | 17 Participants | 11 Participants |
| Cause of Death Stroke / Cerebrovascular | 79 Participants | 166 Participants | 87 Participants |
| Cause of Death Trauma | 117 Participants | 260 Participants | 143 Participants |
| Race/Ethnicity, Customized Asian, Pacific-Islander, other | 7 Participants | 23 Participants | 16 Participants |
| Race/Ethnicity, Customized Black | 49 Participants | 124 Participants | 75 Participants |
| Race/Ethnicity, Customized Hispanic | 63 Participants | 123 Participants | 60 Participants |
| Race/Ethnicity, Customized White, non-Hispanic | 278 Participants | 530 Participants | 252 Participants |
| Region of Enrollment United States | 419 Participants | 838 Participants | 419 Participants |
| Sex: Female, Male Female | 153 Participants | 280 Participants | 127 Participants |
| Sex: Female, Male Male | 247 Participants | 523 Participants | 276 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 419 / 419 | 419 / 419 |
| other Total, other adverse events | 51 / 419 | 16 / 419 |
| serious Total, serious adverse events | 2 / 419 | 3 / 419 |
Outcome results
Primary
Graft Function
30-day graft survival of hearts transplanted from study donors, obtained from SRTR recipient registry
Time frame: 30 days
Population: Only out of those hearts that were transplanted (not all study participants)
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Thyroxine | Graft Function | 224 hearts |
| Saline Placebo | Graft Function | 213 hearts |
Comparison: Non-inferiority analysis for thyroxine vs salinep-value: <0.00195% CI: [-2.3, 6]Regression, Logistic
Primary
Heart Transplanted
Whether heart is transplanted into living recipient
Time frame: One week
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thyroxine | Heart Transplanted | 230 Participants |
| Saline Placebo | Heart Transplanted | 223 Participants |
Comparison: 80% power to detect a 10% increase in hearts transplantedp-value: 0.5795% CI: [0.97, 1.07]Chi-squared, Corrected
Secondary
Ejection Fraction
Left ventricular ejection fraction measured on first echocardiography
Time frame: 72 hours
Population: only those who had echocardiography performed after study start
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thyroxine | Ejection Fraction | 59 percentage of ejection fraction | Standard Deviation 11 |
| Saline Placebo | Ejection Fraction | 58 percentage of ejection fraction | Standard Deviation 12 |
Secondary
Lungs Transplanted
Whether the lungs were transplanted into a living recipient
Time frame: 72 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thyroxine | Lungs Transplanted | 163 Participants |
| Saline Placebo | Lungs Transplanted | 149 Participants |
Secondary
Time Till Off Vasopressors
Time in hours from randomization to when weaned off vasopressors (except vasopressin)
Time frame: 72 hours
Population: out of those who began study infusion on vasopressors
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thyroxine | Time Till Off Vasopressors | 22 hours |
| Saline Placebo | Time Till Off Vasopressors | 25 hours |
Secondary
Time to Order Echo
Time till hemodynamic stability permits ordering initial echocardiogram
Time frame: 72 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thyroxine | Time to Order Echo | 12 hours |
| Saline Placebo | Time to Order Echo | 13 hours |
Secondary
Weaned Off Vasopressors
Weaned off vasopressors within twelve hours
Time frame: 12 hours
Population: out of those who began the study infusion still on vasopressors (i.e. some had been weaned off prior to infusion)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thyroxine | Weaned Off Vasopressors | 143 Participants |
| Saline Placebo | Weaned Off Vasopressors | 152 Participants |
Other Pre-specified
Total Organs Transplanted
Total number of organs transplanted (incl. lungs, liver, kidneys, heart, pancreas)
Time frame: One week
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thyroxine | Total Organs Transplanted | 4 organs |
| Saline Placebo | Total Organs Transplanted | 4 organs |