In response to the editorial by Reddy and Kaplan,1 we offer the following reply. The study cohort used here was not part of the randomized dopamine trial, which investigated the effect of donor dopamine on dialysis requirement after kidney transplantation. The heart transplant cohort was established post hoc, after the renal trial was completed. Its intention was to explore safety aspects of cardiac transplants from multiorgan donors enrolled in the dopamine trial.2 Naturally, the heart transplant cohort considered a completely different patient group. Applying Cox regression, we found a significant inverse association of the metric value of the donor's spontaneous temperature 4 to 20 hours before procurement, and heart allograft failure with a P value less than 0.02, which was likewise robust in multivariable analysis.3 The probability that this finding resulted from multiple testing is low, because we investigated in the same study cohort, apart from dopamine, only the donor's body temperature. Furthermore, with Bonferroni adjustment, the significance level of our observation was below the desired α = 0.025 for negation of the null hypothesis.
We feel that comparing physiology of induced hypotension during neurosurgery with spontaneous hypotension, which Reddy and Kaplan used for an argument by analogy, barely meets the facts in the brain-dead donor. Brain death is completely an unphysiological state, and spontaneous hypothermia is a common feature due to decoupling of the lower brain stem integrating neuronal perception and regulation of the body temperature. The investigators of the hypothermia trial clearly stated in the methods section of the original report4: “…Donors who were assigned to therapeutic hypothermia were either allowed to spontaneously reach a body temperature of 34°C to 35°C or were cooled with the use of forced-air systems or passive cooling devices, according to the system that was available in each facility...”. Hence, the trial compared outcome after kidney transplantation according to the targeted range of the donor's body temperature, irrespective of whether the desired temperature occurred spontaneously or resulted from active cooling. Against this background, and given the profound advantageous effect on initial graft function after kidney transplantation, there is little evidence supporting that organs from hypothermic brain-dead donors behave very differently depending on the temperature management applied.
We fully agree with Reddy and Kaplan that the trial of therapeutic hypothermia is promising and therefore warrants further study including nonrenal transplants. Reducing delayed graft function after transplantation is unquestionably a major achievement, because it is burdensome.5 It is also clear that restriction of safety assessments to hemodynamic and respiratory stability in the donors and the numbers of organs transplanted are not sufficient to assess the quality of nonrenal organs conditional on the trial intervention. The easiest way to complete the current debate on whether a low temperature of the donor may be harmful for the cardiac allograft is to evaluate and publish the outcomes of nonrenal transplants from multiorgan donors enrolled in the Niemann trial. This would certainly enhance the value of the trial and facilitate a broad implementation in clinical transplantation.
1. Reddy KS, Kaplan B. Donor hypothermia and organ transplantation. Transplantation
. Published online August 6, 2018. doi: 10.1097/TP.0000000000002399.
2. Benck U, Hoeger S, Brinkkoetter PT, et al. Effects of donor pre-treatment with dopamine on survival after heart transplantation: a cohort study of heart transplant recipients nested in a randomized controlled multicenter trial. J Am Coll Cardiol
3. Schnuelle P, Benck U, Krämer BK, et al. Impact of donor core body temperature on graft survival after heart transplantation. Transplantation
. Published online July 10, 2018. doi: 10.1097/TP.0000000000002337.
4. Niemann CU, Feiner J, Swain S, et al. Therapeutic hypothermia in deceased organ donors and kidney-graft function. N Engl J Med
5. Gill J, Dong J, Rose C, et al. The risk of allograft failure and the survival benefit of kidney transplantation are complicated by delayed graft function. Kidney Int