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.
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is a very interesting study of the influence of information about organ donation in 18 year-olds in the State of Illinois in the USA. The outcome assessed was the number who registered as an organ donor at the time that their driver licence renewal requests were sent out. All brochures were sent by US mail to the recipients, 60,000 in all. The four different brochures were short and related to the organ donor, to the organ recipient, to individuals awaiting organ transplant or to a combination of all of these. The recipients were randomised to receive one of the four brochures and each brochure was accompanied by an identical personal letter from the Secretary of State for Illinois. The number of registrations as an organ donor that occurred as a result of the direct mailing was also compared with a response to an internet approach. The combination brochure got the greatest response compared to those based on the organ donor, organ recipient, and waiting list patients. Furthermore, the campaign revealed that individuals were more likely to register after a postal mail approach than an internet approach. Thus, direct mailing efforts were an effective approach to promote organ and tissue donation registration in 18 year olds, and also suggest that a brochure that embraces the organ donor, the organ recipient and the waiting list patient, was the most successful in increasing registration.
Expert Review
Reviewer:
Ms Linda Wright, Department of Surgery & Joint Centre for Bioethics, University of Toronto, Canada
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Knowing a person's donation wishes is important in increasing organ donation (OD) from deceased donors. This is an informative paper on the "marketing" of OD by both method of registration and content of information to Illinois residents. The finding that more subjects registered by hard copy through the US mail rather than the Internet is instructive. It is unclear how much the letter accompanying the brochures influenced readers. The finding of higher rates of registration among those who received brochures providing information on donors, recipients and waitlisted patients, rather than on only one of these groups of people increases our knowledge of what information enables donor registration. Understanding why this is the case would be even more helpful, as would research to determine the outcome of the same variables in other populations. An ethical issue here relates to informed consent to donate. For informed decision making, potential registrants need accurate, objective information. Balancing facts with persuasive messaging requires careful attention to wording and tone. This paper furthers our knowledge on several dimensions, but leaves questions about the actual wording of the message in this initiative.
Aims:
To evaluate the most effective framing strategy to employ when promoting organ donation registration.
Interventions:
Participants were randomised to receive one of four brochures featuring, organ donors (group 1), recipients (group 2), individuals on the waiting list (group 3), or a combination of organ donors, recipients and individuals on the waiting list (group 4).
Participants:
60,000 18 year old Illinois residents with a driver’s license or a state ID
Outcomes:
The primary measured outcome was organ donation registration rate. Costs per registration and overall, online and US postal mail effectiveness were also measured.
Follow Up:
Unclear
BACKGROUND:
This study extends previous direct-mail campaigns by evaluating the effectiveness of a marketing campaign promoting organ donation message strategies from the vantage point of organ donors, organ recipients, individuals on the waiting list, or a combination of these three frames.
METHODS:
Illinois residents were randomly assigned to one of four organ donation brochures disseminated via U.S. postal mail. Registrations occurred via the Internet and U.S. postal mail.
RESULTS:
Individuals register at a greater rate following exposure to the combination framed message compared to organ donor, organ recipient, and waiting list narratives. The campaign revealed that individuals are more likely to register via U.S. postal mail than the Internet.
CONCLUSION:
Direct-mail marketing efforts were shown to be an effective approach to promote organ and tissue donation registrations. The results demonstrated a preference for the combination framed brochure. The results are discussed with an emphasis on the practical implications of utilizing direct-mail marketing efforts to promote organ donation among young adults.
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England, UK.
Conclusion:
This is a fascinating study with significant implications for preservation studies. The authors show that organ donors after brain death subjected to mild cooling had significantly less DGF than donors subjected to conventional normothermia before organ retrieval. In fact the DMC stopped the study on the basis that efficacy had been demonstrated before completion of recruitment. The effect was much more striking in expanded criteria donors. What does this mean in terms of ongoing trials of machine preservation after organ retrieval in kidney transplantation? Would the two approaches be complementary or would ongoing trials need to be repeated in organ donors who have been mildly cooled before retrieval of the kidneys? Certainly this study has provided food for thought in the preservation world!
Expert Review
Reviewer:
Dr Gabriel C Oniscu, Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
This is a significant study in the area of donor management. A simple intervention - mild cooling of the donor from 37°C (±0.5°C) to 34.5°C (±0.5°C) resulted in a significant reduction in the delayed graft function (DGF) in the transplanted kidneys. Overall there was an 11% improvement in DGF with the greatest beneficial effect in the recipients of extended criteria donors (24.5% reduction in DGF). The magnitude of the effect is comparable with that noted in machine preservation studies (compared with cold storage). There is much additional information required prior to generalise these findings (outcome for the other transplanted organs, duration of cooling, optimal cooling temperature, mechanism of action). However, this study could potentially change clinical practice through a simple and low-cost intervention that leads to a significant improvement in the function of the transplanted organs. This study raises many questions for the future practice in transplantation, in particular with regards to the place and role of sophisticated technology for preservation and organ perfusion in the context of simple solutions such as the one implemented in this trial. Therefore there is a clear need for further studies to replicate these findings and understand the mechanisms responsible for these astonishing results.
Aims:
To test the benefit of targeted hypothermia in organ donors before organ recovery on delayed graft function in kidney recipients.
Interventions:
Deceased organ donors after declaration of death were randomised to undergo either hypothermia (34 to 35°C) or normothermia (36.5 to 37.5°C).
Participants:
394 donors aged ≥ 18 years
Outcomes:
The primary outcome measured was delayed graft function (the need for dialysis in the first week posttransplant). Secondary outcomes were the rate of individual organs transplanted in each treatment group and the number of organs transplanted from each enrolled donor.
Follow Up:
1 week
BACKGROUND:
Delayed graft function, which is reported in up to 50% of kidney-transplant recipients, is associated with increased costs and diminished long-term graft function. The effect that targeted mild hypothermia in organ donors before organ recovery has on the rate of delayed graft function is unclear.
METHODS:
We enrolled organ donors (after declaration of death according to neurologic criteria) from two large donation service areas and randomly assigned them to one of two targeted temperature ranges: 34 to 35°C (hypothermia) or 36.5 to 37.5°C (normothermia). Temperature protocols, which were initiated after authorization was obtained for the organ to be donated and for the donor's participation in the study, ended when organ donors left the intensive care unit for organ recovery in the operating room. The primary outcome was delayed graft function in the kidney recipients, which was defined as the requirement for dialysis during the first week after transplantation. Secondary outcomes were the rates of individual organs transplanted in each treatment group and the total number of organs transplanted from each donor.
RESULTS:
The study was terminated early, on the recommendation of an independent data and safety monitoring board, after the interim analysis showed efficacy of hypothermia. At trial termination, 370 organ donors had been enrolled (180 in the hypothermia group and 190 in the normothermia group). A total of 572 patients received a kidney transplant (285 kidneys from donors in the hypothermia group and 287 kidneys from donors in the normothermia group). Delayed graft function developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and in 112 recipients of kidneys from donors in the normothermia group (39%) (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.92; P=0.02).
CONCLUSIONS:
Mild hypothermia, as compared with normothermia, in organ donors after declaration of death according to neurologic criteria significantly reduced the rate of delayed graft function among recipients. (Funded by the Health Resources and Services Administration; ClinicalTrials.gov number, NCT01680744.).
CET Conclusion