Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function

  • Practice changing study
New England Journal of Medicine. 2015;373(5):405-14

Abstract

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 35degreeC (hypothermia) or 36.5 to 37.5degreeC (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

Reviewer: Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England, UK.
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 of 5)
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.

Methodological quality

Jadad score : 3
Allocation concealment : YES
Data analysis : MODIFIED INTENTION TO TREAT
Research notes : The author Niemann, C. confirmed the paper was centrally randomised and therefore had adequate allocation concealment

Study details

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 35⁰C) or normothermia (36.5 to 37.5⁰C).
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

Metadata

Funding : Non-industry funding
Publication type : Randomised Controlled Trial
Trial registration : ClinicalTrials.gov - NCT01680744
Organ : Kidney
Language : English
Author email : claus.niemann@ucsf.edu