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The Continued Need for Clinical Trials in Deceased Organ Donor Management

Niemann, Claus U. MD1,2; Matthay, Michael A. MD1,3; Ware, Lorraine B. MD4

doi: 10.1097/TP.0000000000002512
Commentaries
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1 Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA.

2 Department of Surgery, University of California San Francisco, San Francisco, CA.

3 Department of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA.

4 Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN.

Received 23 October 2018.

Accepted 24 October 2018.

The authors declare no conflicts of interest.

C.U.N., M.A.M., and L.B.W. conceptualized the content. C.U.N., M.A.M., and L.B.W. prepared the article.

Correspondence: Claus U. Niemann, MD, Division of Transplantation, Department of Anesthesia and Perioperative Care, Department of Surgery, University of California San Francisco, 4th Floor, Box 0648, 500 Parnassus MUE, San Francisco, CA 94143-0648. (Claus.Niemann@ucsf.edu).

In this issue of Transplantation, Dhar et al1 describe the results of a study that compared naloxone to placebo in deceased organ donors with the goal to improve oxygenation. The rationale for this study was based in part on the observation that naloxone reduced neurogenic pulmonary edema in the sheep when administered during experimental elevation of intracranial pressure to 100 mm Hg by mitigating the increase in cardiac output triggered by herniation.2 The sheep study generated the hypothesis that a decrease in cardiac output might decrease lung vascular pressures and thus reduce the hydrostatic forces contributing to pulmonary edema. In addition to the sheep study, a single uncontrolled human donor study also suggested that naloxone might improve oxygenation in deceased donors.3 Based on this uncontrolled study, naloxone has been widely incorporated into donor management protocols. However, the results of the current randomized trial showed no beneficial effect of naloxone treatment on oxygenation in deceased organ donors. The negative findings of the current trial should make it clear that naloxone is not an effective therapy to improve oxygenation during donor management.

One limitation in this trial is that deceased donors were enrolled a median of 9 hours after declaration of brain death, suggesting that naloxone was administered several hours after the catecholamine surge triggered by herniation and perhaps outside the window for any potential benefit. Although it would be of interest to test the effect of naloxone on lung edema and oxygenation when administered before and during herniation in patients with severe brain injury, such a clinical trial would be outside the purview of deceased donor intervention research.

As noted in the summary of the ventilator protocols, 3 of the 4 OPOs in the current trial routinely use albuterol or levalbuterol every 4 hours in donor management. In a large randomized clinical trial of inhaled albuterol versus placebo in 506 deceased organ donors, albuterol had no beneficial effect on oxygenation, severity of pulmonary edema, or lung utilization, indicating that there is no role for aerosolized beta-2 agonists in routine donor management.4 It is critical that both positive and negative findings from clinical trials inform medical practice, and more work is needed in the field of donor management to ensure that the best evidence is incorporated into clinical practice.

Another major challenge in donor management research is the heterogeneity in donor management practices across the 58 organ procurement organizations (OPOs) in the United States. This heterogeneity is highlighted by marked differences in ventilator protocols used by the 4 OPOs that participated in the naloxone trial. Like most aspects of donor management, there is a paucity of clinical trials to guide ventilator management in deceased organ donors. Although a European trial suggested that an open lung protective ventilatory strategy improved oxygenation and lung utilization in deceased donors, the study intervention was short (6 h) and does not readily translate to the US donor management environment.5 A randomized trial of an open lung protective ventilatory strategy versus conventional ventilation for the duration of donor management in 400 deceased organ donors in Northern California (NCT#03439995) is currently enrolling and should provide evidence that is more applicable to donor management in the United States.

We commend the investigators for completing the naloxone trial in a very challenging research environment. The difficulty of conducting rigorous research in this area has been discussed in more depth in several recent publications.6-8

As pointed out by the authors, the trial is one of the few prospective trials ever conducted in deceased organ donors. Some of the challenges of donor intervention research are well illustrated in the current trial.

A major difficulty in conducting this type of research is related to appropriate communication with transplant centers receiving organs from deceased donors that were involved in interventional trials. This applies not only to the target organ of the intervention (here the lung) but also the nontargeted organs (heart, liver, kidneys, and pancreas). The struggle for appropriate communication is evident in the current trial. Similarly, when do intended recipients of all affected organs need to be notified of ongoing research in the deceased organ donor and what is the threshold for informed consent from the recipient, if any? Several elements of the approval process in the current study are not well outlined, but it appears that the institutional review board at one site (presumably one of the participating academic centers) determined that human subjects were not involved in the research and participating OPOs considered the intervention as minimal risk based on the fact that the naloxone is already used by many OPOs and is within the current standard of care.

Although the trial design and possible stopping rules (ie, interim analysis) are not clear, it appears that a pragmatic trial design was chosen, in that other aspects of donor care were not protocolized. This is a valid approach when attempting to demonstrate efficacy or futility across different healthcare settings with variable OPO practices. Despite the negative findings, the study highlights the importance of research in the neglected field of donor management, a field that has been neglected mostly because of lack of regulatory clarity and infrastructure. In the United States, the Donor Intervention Research Panel recently sent its recommendations to the Department of Health Resources and Service Administration, and a subsequent very detailed report by the National Academy of Medicine provides some much-needed guidance9 that hopefully will pave the way for an increase in rigorous clinical trials in the deceased donor population.

The report by the National Academy of Medicine outlined several principles for receiving approval for deceased organ donor-based interventional trials and communicating them to the broader donation and transplantation community of practice, including human subjects research protection where applicable, as well as dissemination of information to potential transplant recipient sites.

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REFERENCES

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