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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.
Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial
Am J Transplant. 2016 Jan;16(1):254-61 doi: 10.1111/ajt.13417.
See all 2 Highlighted Expert Reviews articles matching your criteria
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A Randomized Controlled Trial of Naloxone for Optimization of Hypoxemia in Lung Donors After Brain Death
  • Dhar R
  • Stahlschmidt E
  • Paramesh A
  • Marklin G
Transplantation. 2019 Jul;103(7):1433-1438 doi: 10.1097/TP.0000000000002511.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This muticentre, placebo-controlled study investigated the use of IV naloxone in brain-dead organ donors as a strategy to reduce neurogenic pulmonary oedema. The study demonstrated no difference in the primary outcome of improvement in PaO2:FiO2 ratio, and no difference in transplant rates from the donors recruited. The study is well designed, and it appears that there is no benefit to this intervention in this subset of donors with all-cause hypoxaemia. Interestingly, reversal of hypoxaemia through other donor management protocols was significantly associated with increased chance of transplant, highlighting the importance of interventions to improve this in donors. It should also be noted that no transplant outcomes were assessed: it is important that in any donor intervention the transplant rates and outcomes of all transplanted organs from the donors are documented, as what is good for one organ may be detrimental to the outcomes of another.
Expert Review
Reviewer: Lorraine B. Ware M.D. Professor of Medicine and Pathology, Immunology and Microbiology Vanderbilt University School of Medicine
Conflicts of Interest: No
Clinical Impact Rating 4
Review: Naloxone has been postulated to improve donor oxygenation by reducing the rise in cardiac output that accompanies herniation and leads to neurogenic pulmonary edema. This hypothesis was derived from a sheep model and data from a single uncontrolled human donor study; nonetheless, naloxone has been incorporated into many donor management protocols. To better define the potential utility of naloxone in donor management, Dhar and colleagues tested the effect of IV naloxone in a multicenter prospective randomized controlled clinical trial in 199 hypoxemic deceased organ donors. Contrary to the hypothesis, they found no beneficial effect of naloxone on oxygenation or rate of lung utilization. The findings of this study have two important clinical implications. First, the findings suggest that there is no role for naloxone in management of deceased organ donors; routine use in donor management is not indicated. Second, despite the inherent challenges, it is critical that we continue to design and implement randomized clinical trials in the deceased donor population to better inform the clinical practice of donor management.
Aims: To evaluate whether naloxone is able to improve oxygenation in brain dead (BD) lung donors with hypoxemia.
Interventions: Eligible donors were randomized to naloxone (8 mg IV) or saline placebo as soon as possible after the initial arterial blood gas (ABG). ABGs were collected as per standard Organ Procurement Organizations practices (approx. every 6-8 hours) with a final ABG collected prior to organ procurement.
Participants: 199 lung-eligible BD donors were randomized (naloxone, n=98; placebo, n=101). Eligible patients were age 13-70 years without established lung disease who had hypoxemia, defined as PaO2:FiO2 ratio (PFR) <300 on arterial blood gas (ABG) performed after BD declaration.
Outcomes: The primary outcome was change in PFR from baseline to final ABG. The secondary efficacy outcome was proportion of donors enrolled who had lungs transplanted. Primary analyses were performed using intention-to-treat principles. Outcomes were also evaluated in a per protocol analysis.
Follow Up: Median total time from BD to procurement was 41 hours (IQR 32-47).
BACKGROUND:

Persistent hypoxemia is the principal reason lungs from otherwise eligible brain dead (BD) organ donors are not transplanted. Experimental models and retrospective studies have suggested that naloxone attenuates neurogenic pulmonary edema and reverses hypoxemia after brain death. We undertook a multisite, randomized, placebo-controlled trial to evaluate whether naloxone is able to improve oxygenation in BD donors with hypoxemia.

METHODS:

BD organ donors at 4 organ procurement organizations were randomized in a blinded manner to naloxone 8 mg or saline placebo if lung were being considered for allocation but exhibited hypoxemia (partial pressure of oxygen in arterial blood to fraction of inspired oxygen ratio [PFR] below 300 mm Hg). The primary outcome was change in PFR from baseline to final arterial blood gas. Secondary outcomes included early improvement in PFR and proportion of lungs transplanted.

RESULTS:

A total of 199 lung-eligible BD donors were randomized to naloxone (n = 98) or placebo (n = 101). Groups were comparable at baseline. Both groups exhibited similar improvements in oxygenation (median improvement in PFR of 81 with naloxone versus 80 with saline, P = 0.68), with 37 (39%) versus 38 (40%) exhibiting reversal of hypoxemia. There was no difference in the rate of lungs transplanted (19% in both groups, P = 0.97) although it was significantly higher in those with reversal of hypoxemia (32/69 versus 2/111, P < 0.001).

CONCLUSIONS:

Naloxone does not improve oxygenation more than placebo in hypoxemic organ donors. However, reversal of hypoxemia was a powerful predictor of lung utilization regardless of drug therapy. Further organ procurement organization-led research is needed to assess optimal interventions to improve oxygenation in BD donors with hypoxemia.
Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial
  • Ruttens D
  • Verleden SE
  • Vandermeulen E
  • Bellon H
  • Vanaudenaerde BM
  • et al.
Am J Transplant. 2016 Jan;16(1):254-61 doi: 10.1111/ajt.13417.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This manuscript reports a long-term, retrospective analysis of an RCT comparing prophylactic azithromycin to placebo in lung transplant recipients. Azithromycin has anti-inflammatory and immunomodulatory properties and was shown in an earlier analysis to improve freedom from bronchiolitis obliterans early after lung transplant. Since then, the classification of chronic lung allograft dysfunction (CLAD) has been revised and the authors here provide a retrospective analysis of the 7-year follow-up of the patients in the trial, using the new CLAD classification. The analysis demonstrates a significant reduction in the incidence of CLAD (and improved CLAD free survival time) with prophylactic azithromycin. Long-term pulmonary function and functional exercise capacity were also significantly better in the treatment arm. Data regarding tacrolimus levels are missing from the manuscript – there are some case reports of interaction between azithromycin and tacrolimus, and erratic tacrolimus levels have been shown to be predictive for development of CLAD. This is a relatively small, retrospective analysis and so should be regarded as exploratory, but nonetheless provides some evidence of a role for prophylactic azithromycin in these patients.
Expert Review
Reviewer: Professor Stuart C. Sweet, Washington University, St. Louis, MO, USA
Conflicts of Interest: No
Clinical Impact Rating 4
Review: The article by Ruttens and colleagues provides additional follow-up details 7 years after enrolment of the final patient from a cohort who participated in a randomized, controlled trial of prophylactic azithromycin (AZI) therapy in lung transplant recipients. Using an intention to treat analysis, the original study population was analysed using the updated allograft dysfunction (CLAD) classification. The key findings of the study included the observation that CLAD-free survival was longer in the azithromycin group, pulmonary function and exercise capacity were better in the azithromycin group (these differences were felt to have developed in the first 2 years of follow-up) and no overall difference in graft survival (felt to be related to the use of open label AZI in both the treatment and placebo groups). No AZI significant side effects were noted. Although this is a single centre study limited by retrospective design of the longer term follow-up, it suggests that centres should consider whether the potential benefit of using AZI prophylaxis in lung transplant recipients may outweigh the potential risks. These findings will benefit from confirmation in a multicentre study, ideally with inclusion of mechanistic analyses.
Aims: To evaluate the long-term effects of prophylactic azithromycin therapy post lung transplantation in view of the recently updated classification system for chronic lung allograft dysfunction (CLAD).
Interventions: Participants were randomized to receive either azithromycin (250mg) three times per week, or placebo.
Participants: 83 single-lung, bilateral lung or heart–lung transplant recipients >18 years of age, previously included in a randomized controlled trial of azithromycin versus placebo*
Outcomes: Outcomes measured were CLAD, graft loss, pulmonary function and functional exercise capacity.
Follow Up: 7 years

Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx.