In this issue of Transplantation Schnuelle et al1 present an analysis of the relationship of spontaneous core body temperature (CBT) of the deceased donor 4 to 20 hours before procurement on 3-year allograft survival after heart transplantation. This is a retrospective secondary analysis of data collected from a randomized controlled trial intended to study donor pretreatment with low dose dopamine.2,3 The original study demonstrated reduced dialysis requirement and improved graft survival after kidney transplantation. In this current post hoc analysis, 99 heart transplant recipients were grouped by tertiles of the donor CBT (lowest, 32-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C). A lower CBT was shown to be associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile P = 0.02 and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93°C; p-0.02) The authors conclude that (a) a lower CBT in the brain-dead donor before procurement may be associated with an unfavorable clinical course after heart transplantation and (b) more research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended.
However, the results presented in the article of Schnuelle et al must be viewed with great caution. There are several major limitations with this analysis and thus proper interpretation of the data is vital. Some of the limitations, mentioned by the authors, include the possibility of incidental observation rather than cause and effect. Because this is a retrospective secondary analysis of data from a prior intervention trial that was not designed to investigate the consequences of donor hypothermia, no causal inference can be made. In addition, temperature readings were not part of protocol measurements, and the sample size was small. The small sample size in particular limits the number of variables that can be appropriately used in the multivariable analysis. There are many donor and recipient variables that could affect the outcome after heart transplantation. Given the small sample size only, a limited number of covariates can be used without overfitting the model. This potential overfitting is a crucial limitation in any interpretation of the multivariate results. In addition, the rationale for the authors choosing the groups by tertiles rather than 2 groups (<36°C and > 36°C) as they did in another retrospective secondary analysis of spontaneous donor hypothermia on graft outcomes after kidney transplantation4 is not entirely clear. There is no difference in the outcome at 3 months but apparent at 3 years only in the heart-alone group. This brings up the question of multiple testing as cardiac transplant was only one of several organs studied and within each group a dopamine and no dopamine arm were included. When looking at specific outcomes in a subgroup where many other subgroups exist, it is of vital importance to correct for multiple testing so as to avoid type 1 error (or false negation of the null hypothesis). Further, causes of death are not discussed let alone whether they are potentially related or unrelated to the initial hypothermia.
We also need to differentiate the effect and implications of spontaneous hypothermia measured in the current study from those in the induced/therapeutic hypothermia studies. The physiology of induced hypothermia is almost assuredly different than spontaneous hypothermia (one may think of the difference of induced hypotension during neurosurgery versus spontaneous drop of blood pressure to see the problem with extrapolating an induced physiologic change to one that occurs spontaneously). In fact, previous studies that were designed to look at induced hypothermia were promising. In a randomized controlled study of brain dead donors assigned to 1 of 2 targeted temperature ranges: 34°C to 35°C (hypothermia) or 36.5°C to 37.5°C (normothermia), rate of delayed graft function was lower in recipients of kidneys from donors in the hypothermia group.5 This study was terminated early, on the recommendation of an independent data and safety monitoring board, after the interim analysis showed the efficacy of induced hypothermia. The rates of individual organs transplanted and the total number of organs transplanted from each donor were the secondary outcomes for this study which were not different between the groups. However, outcomes of transplantation of organs other than kidney are not analyzed or published.
The results of induced hypothermia in brain-dead donors in reducing the rate of delayed graft function following kidney transplantation is promising and warrants further study including nonrenal organ transplantation. Innovative deceased donor intervention strategies to increase both the quality and quantity of organs transplanted are an area of active interest to the transplant community, and further regulatory guidelines are being developed to make this possible. We hope, as a scientific community, we will be judicious and careful in extrapolating the results of the current study, of spontaneous hypothermia in the donor on outcomes following heart transplantation with induced hypothermia.
1. Schnuelle P, Benck U, Kramer BK, et al. Impact of donor core body temperature on graft survival after heart transplantation. Transplantation
2. Schnuelle P, Gottmann U, Hoeger S, et al. Effect of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA
3. Schnuelle P, Schmitt WH, Weiss C, et al. Effects of dopamine donor Pretreatment on graft survival after kidney transplantation: a randomized trial. Clin J Am Soc Nephrol
4. Schnuelle P, Mundt HM, Druschler F, et al. Impact of spontaneous donor hypothermia on graft outcomes after kidney transplantation. Am J Transplant
5. Niemann CU, Feiner J, Swain S, et al. Therapeutic hypothermia in deceased organ donors and kidney-graft function. NEJM