Naloxone for Optimizing Hypoxemia Of Lung Donors (NO-HOLDS)

Randomized Placebo-controlled Trial of Intravenous Naloxone to Improve Oxygenation in Hypoxemic Lung-Eligible Brain-Dead Organ Donors

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.

Study Overview

• Status: Completed
• Conditions: Brain Death; Lung Transplantation; Organ Donors
• Intervention / Treatment: Drug: Normal saline; Drug: Naloxone

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.

• Study Type: Interventional
• Enrollment (Actual): 199
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80246
      • Donor Alliance
  • Louisiana
    • Metairie, Louisiana, United States, 70002
      • Louisiana Organ Procurement Agency
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Mid-America Transplant Services
  • Ohio
    • Columbus, Ohio, United States, 43212
      • Lifeline of Ohio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Naloxone; Naloxone 8-mg IV given once after baseline ABG	Drug: Naloxone; Naloxone 8-mg IV bolus; Other Names: Narcan
SHAM_COMPARATOR: Placebo; Equivalent volume of saline given once	Drug: Normal saline; Other Names: saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline and at time of organ recovery, within 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Had Lungs Transplanted	Whether one or both lungs were transplanted from this organ donor (dichotomized)	At time of organ recovery (within 72 hours)
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	Baseline and ABG at 4-6 hours after intervention

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

General Publications

• Dhar R, Stahlschmidt E, Paramesh A, Marklin G. A Randomized Controlled Trial of Naloxone for Optimization of Hypoxemia in Lung Donors After Brain Death. Transplantation. 2019 Jul;103(7):1433-1438. doi: 10.1097/TP.0000000000002511.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2015
• Primary Completion (ACTUAL): September 22, 2017
• Study Completion (ACTUAL): September 25, 2017

Study Registration Dates

• First Submitted: October 1, 2015
• First Submitted That Met QC Criteria: October 19, 2015
• First Posted (ESTIMATE): October 20, 2015

Study Record Updates

• Last Update Posted (ACTUAL): July 31, 2020
• Last Update Submitted That Met QC Criteria: July 16, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Death; Unconsciousness; Consciousness Disorders; Coma; Brain Death; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxone
• Other Study ID Numbers: ODRC-001