Keywords
Hypothermia, Transplant, Kidney, Deceased Organ Donors, Kidney-Graft Function
-
Views
-
Downloads
How to cite this article
Kadir S and Al-Khafaji A. Targeted temperature management in deceased organ donors [version 1; peer review: not peer reviewed]. F1000Research 2016, 5:1333 (https://doi.org/10.12688/f1000research.8597.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
Export Citation
Sciwheel
EndNote
Ref. Manager
Bibtex
ProCite
Sente
▬
✚
F1000 Faculty Critique
Targeted temperature management in deceased organ donors
[version 1; peer review: not peer reviewed]
PUBLISHED 10 Jun 2016
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Critical care collection.
Abstract
Corresponding author:
Ali Al-Khafaji
Competing interests:
The authors declare that they have no competing interests.
Grant information:
The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2016 Kadir S and Al-Khafaji A.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Kadir S and Al-Khafaji A. Targeted temperature management in deceased organ donors [version 1; peer review: not peer reviewed]. F1000Research 2016, 5:1333 (https://doi.org/10.12688/f1000research.8597.1)
First published: 10 Jun 2016, 5:1333 (https://doi.org/10.12688/f1000research.8597.1)
Latest published: 10 Jun 2016, 5:1333 (https://doi.org/10.12688/f1000research.8597.1)
Critique of:
Citation
Niemann CU, Feiner J, Swain S Bunting S, Friedman M, Crutchfield M, Broglio K, Hirose R, Roberts JP, Malinoski D. Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function. New England Journal of Medicine 2015; 373 (5): 405–414. PubMed PMID: 26222557. ClinicalTrials.gov number, NCT01680744
Background
There are about 16,000–17,000 renal transplants per year in the United States. Greater than 60% are deceased donor transplants. Up to 50% of these cases are complicated by delayed graft function (DGF), characterized by a requirement for dialysis in the recipient within 7 days after renal transplant. DGF is associated with an increased risk for an acute rejection episode. It is an independent risk factor for decreased graft survival and prolonged. Ischemia–reperfusion injury during the transplantation process is also a major contributing factor to subsequent poor allograft function.
Methods
Intervention was initiated after research authorization was obtained. The investigators randomized donors declared deceased by neurologic criteria (DNC) to normothermia (36.5–37.5C) versus hypothermia (34–35C). The goal was to reach the target temperature within 4 hours of enrollment and maintain temperature until transport to the operating room. The primary outcome measure was DGF. The secondary outcome measures were the rate of individual organs transplanted in each treatment group and the number of organs transplanted from each enrolled donor.
Objective
To investigate the potential benefit and safety of normothermia vs. targeted hypothermia (36.5–37.5 versus 34–35 degrees C) in donors with respect to rates of delayed graft function among transplant recipients.
Setting
Patients who met DNC from two large organ-donation service areas March 20, 2012 and October 17, 2013.
Subjects
394 donors who met DNC criteria were identified by two organ-procurement organizations: Northern California and Nevada- California Transplant Donor Network and Southern California and Nevada One Legacy. Legal statutes do not require informed consent.
Analysis
The initial plan was to enroll 500 donors. This would provide a 90% power to detect a 30% relative difference in the rate of delayed graft function between the study groups. The investigators had a scheduled pre-planned interim analysis for efficacy or futility in the 5th quarter of the study period. The primary outcome sub group comparison utilized the t test and Fisher’s exact. For the secondary outcomes chi-square test was utilized. The preplanned interim analysis used a logistic-regression model for delayed graft function with adjustment for covariates including donor creatinine level at enrollment, organ-procurement agency, donor age, cold-ischemia time and donor type (Standard Criteria Donors versus Extended Criteria Donors). The primary efficacy analysis included all transplanted kidneys with known cold-ischemia time and outcome data on delayed graft function in the recipients.
Results
The interim analysis showed benefit of hypothermia, prompting early termination of the study. 370 total organ donors were enrolled. 180 were randomized to hypothermia, and 190 to normothermia. 572 patients received a kidney transplant. This included 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%). The primary efficacy analysis showed that hypothermia, as compared with normothermia, significantly reduced the odds of delayed graft function (odds ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.92; P=0.02).
In an analysis involving donors who were expanded-criteria donors, hypothermia significantly reduced the odds of delayed graft function in this subgroup - 31.0% in the hypothermia group compared with 56.5% in the normothermia group with the adjusted odds ratio for the development of DGF being 0.31 (95% CI, 0.15 to 0.68; P=0.003).
Among standard-criteria donors, the rate of delayed graft function was lower in the hypothermia group than in the normothermia group (27.3% vs. 33.6%). The odds of delayed graft function were lower though not statistically significant (adjusted odds ratio, 0.71; 95% CI, 0.45 to 1.13; P=0.15).
In terms of secondary outcomes, the overall number of organs transplanted from each donor and the rate of organs transplanted in each treatment group. There were four adverse events in organ donors: one episode of dysrhythmia and one episode of systemic hypertension in the hypothermia group and two episodes of cardiac arrest before organ recovery in the normothermia group.
Conclusions
Targeted temperature control in donors had a statistically and clinically significant protective effect on renal-graft outcomes in recipients.
Abstract adapted from the original provided courtesy of PubMed: A service of the National Library of Medicine and the National Institutes of Health.
Commentary
Renal transplantation accounts for the majority of organ transplanted in the United States each year. Delayed graft function (DGF) incurs a significant negative impact of organ recipients and the health care system1. The frequency of DGF varies from 4 to 10% in living donor transplants and 5 to 50% in deceased donor kidney transplants2. In 1995, Terasaki et al.3 showed that graft survival for living unrelated donation is superior compared to deceased donation. This thought to be due to numerous pathophysiologic changes that occur in brain death that potentially contribute to DGF in the transplanted kidney4.
In this randomized controlled trial, subjects were either warmed to 36.5–37.5 or cooled to 34–35°C with the goal of reaching the target temperature within 4 hours of enrollment. Temperature was maintained until transport to the operating room. The average time between declaration of death and organ recovery was approximately 30 hours. Based on cardiac arrest literature the goal duration of mild hypothermia (34°C) was at least 12 hours with median duration of hypothermia turning out to be 16.9 hours5.
Recipients were not randomly assigned but recipient characteristics that were known to affect kidney-graft survival were balanced between the two treatment groups. The primary analysis adjusted for factors that were known to be associated with DGF such as the creatinine level at the time of consent, age, and cold-ischemia time were all significantly associated with delayed graft function. Hypothermia significantly decreased the rate of DGF (38% lower) when compared to the normothermia group). The trial demonstrated that noninvasive temperature-management aimed at hypothermia in donors decreased the rate of DGF in recipients.
This study is the first randomized controlled trial to employ hypothermia in potential renal donors. The data was collected in a prospective manner. The study investigators were not involved in the outcome assessment process. In the interim analysis the factors associated with DGF such as cold ischemia time, age and baseline creatinine were taken into account making this a well-designed randomized controlled trial.
There are a number of limitations to this study. Health care providers who were caring for the donors were aware of the group assignments which could have introduced bias into care for the donors. Transplant surgeons had the opportunity to contact the PI or Co PI if there were questions concerning donor enrollment. No information on acute rejection or the potential long term effects on graft survival can be deduced currently. In addition, outcomes with respect to other organs were not stated. The investigators excluded hemodynamically unstable and coagulopathic donors which impacts the generalizability of the study. Recipients’ ethnicities are not stated in the analysis. It is known that African –American ethnicity is a risk factor for DGF6. No data is provided on adherence to intervention and how temperature variations were dealt with. The authors did not include details of the fluid management of donors or recipients, for example, chloride liberal versus restrictive7.
The study protocol mentions that subjects were warmed to 36.5–37.5. The method and duration of warming was not included in the protocol. In hypothermia trials passive rewarming was utilized since active rewarming is associated with worse reperfusion injury.
This study was terminated prematurely. A systematic review of randomized trials (RCT) stopped early for benefit by Montori et al. 20058 showed that RCTs that stopped early show implausibly large treatment effects, particularly when the number of events is small. A Systematic Review and Meta-regression Analysis on stopping RCTs early for benefit and the estimation of treatment effects by Bassler et al.9 in 2010 showed that truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies. This renders the current results of this study preliminary. Further trials are therefore required prior to utilizing hypothermia as a standard of practice in this specific patient population.
Recommendation
This is the first RCT to investigate hypothermia in renal donors and measure recipient outcomes. The results of this study must be interpreted with caution based on the aforementioned reasons.
However, therapeutic hypothermia is both simple and incurred no adverse events. It may be applicable in donors who are relatively hemodynamically stable and not coagulopathic. From a practical view point, in the absence of another RCT addressing this issue, one may consider therapeutic hypothermia in potential renal transplant donors.
Download
Export To
metrics
| Views | Downloads | |
|---|---|---|
| F1000Research | - | - |
|
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Citations
CITE
how to cite this article
Kadir S and Al-Khafaji A. Targeted temperature management in deceased organ donors [version 1; peer review: not peer reviewed]. F1000Research 2016, 5:1333 (https://doi.org/10.12688/f1000research.8597.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.
Open Peer Review
Current Reviewer Status:
AWAITING PEER REVIEW
AWAITING PEER REVIEW
Key to Reviewer Statuses
VIEW
HIDE
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Comments on this article Comments (0)