Brain Death, Lung Transplantation, Organ Donors
Conditions
Brief summary
Brain-dead patients who provide authorization for organ donation will be randomized to naloxone or placebo if baseline arterial blood gas (ABG) after initiation of OPO (Organ Procurement Organization) management reveals hypoxemia, as defined by the ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2) below 300 mm Hg, unless they have already been ruled-out for lung recovery. Investigators aim to assess whether naloxone improves oxygenation prior to organ recovery more than placebo.
Detailed description
Naloxone has been used by many OPOs for decades to improve the pulmonary status of brain-dead organ donors (based on anecdotal evidence and small uncontrolled studies). Its efficacy in this population has never been assessed in a controlled clinical trial. The rationale for its use appears to be that it blocks the increase in capillary permeability that occurs with herniation and brain death (as demonstrated in a single sheep study of herniation). Investigators aim to rigorously test this hypothesis in a randomized placebo-controlled trial in brain-dead organ donors who have baseline hypoxemia. The primary outcome will be the acute change in oxygenation (on first follow-up ABG after naloxone as well as the final ABG prior to organ recovery). Investigators will also assess whether treatment results in more lungs being recovered and transplanted, after correcting for baseline variables such as age, blood group, smoking history, and cause of death. This study will be performed under the auspices of the Organ Donation Research Consortium and be carried out by multiple OPOs across the country. Naloxone or blinded placebo (identical syringe filled with saline) will be given after the baseline ABG shows hypoxemia (PFR - PaO2 divided by FiO2, on positive end-expiratory pressure \[PEEP\] of 5 and usually 100% FiO2). Naloxone and placebo will both be co-administered with a neuromuscular blocking agent (e.g. vecuronium, per center protocol) to obviate any increase in spinal reflex movements that may be potentiated by naloxone treatment. All other protocols for organ donor management should be maintained at each OPO and no other study interventions are required. Transplant centers will be informed (through DonorNet) that the organ donor being considered for lung recovery has been enrolled in this blinded clinical trial.
Interventions
DRUGNaloxone
Naloxone 8-mg IV bolus
DRUGNormal saline
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
13 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Brain-dead organ donor being managed by OPO (organ procurement organization) * Lungs being considered for recovery and transplant * Baseline ABG (after authorization) with P/F ratio \< 300
Exclusion criteria
* No authorization for research * Lungs already excluded for transplant (e.g. known chronic obstructive pulmonary disease \[COPD\], human immunodeficiency virus \[HIV\] infection)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation (P/F Ratio) From Baseline to Final Pre-recovery Arterial Blood Gas (ABG) | Baseline and at time of organ recovery, within 72 hours | Change in ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2) from final ABG performed before organ recovery compared to baseline ABG |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Lungs Transplanted | At time of organ recovery (within 72 hours) | Whether one or both lungs were transplanted from this organ donor (dichotomized) |
| Acute Change in Oxygenation (P/F Ratio) | Baseline and ABG at 4-6 hours after intervention | Change in PaO2:FiO2 ratio from ABG at 4-6 hours after randomization compared to baseline prior to randomization |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Naloxone Naloxone 8-mg IV given once after baseline ABG
Naloxone: Naloxone 8-mg IV bolus | 98 |
| Placebo Equivalent volume of saline given once
Normal saline | 101 |
| Total | 199 |
Baseline characteristics
| Characteristic | Placebo | Total | Naloxone |
|---|---|---|---|
| Age, Continuous | 36.8 years STANDARD_DEVIATION 13 | 37 years STANDARD_DEVIATION 13 | 37.4 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 18 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 170 Participants | 87 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 35 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) White | 76 Participants | 153 Participants | 77 Participants |
| Region of Enrollment United States | 101 participants | 199 participants | 98 participants |
| Sex: Female, Male Female | 50 Participants | 90 Participants | 40 Participants |
| Sex: Female, Male Male | 51 Participants | 109 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 101 |
| other Total, other adverse events | 0 / 98 | 0 / 101 |
| serious Total, serious adverse events | 0 / 98 | 0 / 101 |
Outcome results
Primary
Change in Oxygenation (P/F Ratio) From Baseline to Final Pre-recovery Arterial Blood Gas (ABG)
Change in ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2) from final ABG performed before organ recovery compared to baseline ABG
Time frame: Baseline and at time of organ recovery, within 72 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Naloxone | Change in Oxygenation (P/F Ratio) From Baseline to Final Pre-recovery Arterial Blood Gas (ABG) | 81 mm Hg |
| Placebo | Change in Oxygenation (P/F Ratio) From Baseline to Final Pre-recovery Arterial Blood Gas (ABG) | 80 mm Hg |
Secondary
Acute Change in Oxygenation (P/F Ratio)
Change in PaO2:FiO2 ratio from ABG at 4-6 hours after randomization compared to baseline prior to randomization
Time frame: Baseline and ABG at 4-6 hours after intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Naloxone | Acute Change in Oxygenation (P/F Ratio) | 71 mm Hg |
| Placebo | Acute Change in Oxygenation (P/F Ratio) | 33 mm Hg |
Secondary
Number of Participants Who Had Lungs Transplanted
Whether one or both lungs were transplanted from this organ donor (dichotomized)
Time frame: At time of organ recovery (within 72 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Naloxone | Number of Participants Who Had Lungs Transplanted | 19 Participants |
| Placebo | Number of Participants Who Had Lungs Transplanted | 19 Participants |