Giving unstable brain-dead heart donors intravenous levothyroxine did not lead to more hearts being transplanted, a randomized trial showed.
In hemodynamically unstable potential donors, administering the thyroid hormone supplement after brain death did not significantly improve donor heart utilization compared with saline placebo, with transplantation rates of 54.9% and 53.2%, respectively (adjusted risk ratio 1.01, 95% CI 0.97-1.07), reported Rajat Dhar, MD, of Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, and colleagues.
The prespecified recipient safety outcome — graft survival at 30 days after transplantation — occurred in 97.4% of transplanted hearts in the levothyroxine group and 95.5% in the saline group (P<0.001 for noninferiority). However, severe hypertension and tachycardia occurred in excess in the levothyroxine group, Dhar and colleagues noted in the New England Journal of Medicine.
“Neither weaning from vasopressor therapy nor ejection fraction on echocardiography was better with levothyroxine than with normal saline, findings that suggest a lack of physiological benefit of levothyroxine on donor cardiovascular function,” they wrote. “These results provide evidence that thyroid hormone administration does not improve donor stability or organ-transplantation rates.”
In the trial, 12 of the 15 participating organ-procurement organizations (OPOs) had been using levothyroxine as part of their standard protocols for years. With the present results, several organizations have stopped using thyroid hormone in this setting, Dhar said in a statement.
Intravenous levothyroxine has been widely used in deceased donor care due to the theory that neurohormonal insufficiency after brain death leads to myocardial energy depletion and shock, and hormone supplementation should widen the net of usable organs. However, this was supported only by observational data.
“The few randomized trials that have evaluated administration of thyroid hormone to donors have focused on intermediate outcomes such as donor hemodynamics and were underpowered to evaluate organ utilization,” Dhar and team wrote. “Despite little high-quality evidence, consensus guidelines continue to recommend thyroid hormone in hemodynamically unstable or heart-eligible donors.”
“We found good evidence that this intervention we’ve been using for 40 years doesn’t work,” Dhar said in a press release. “It’s vital that we explore questions like this to ensure we are doing all we can for patients who need organs — and to ensure that they receive the most benefit possible from the generous people who choose to donate organs.”
Dhar and colleagues acknowledged that blinding was not feasible in their trial. Open-label use of levothyroxine was allowed after 12 hours and used in a minority of the control group. Moreover, they noted their trial did not test the more active thyroid hormone (T3 or triiodothyronine).
In an accompanying editorial, Kiran Khush, MD, MAS, of Stanford University School of Medicine in California, noted that “even so, [this study] provides the most definitive data to date about donor thyroid hormone replacement therapy. The results have major clinical implications for OPOs around the country.”
Khush cited data from the United Network for Organ Sharing suggesting that 48% of all potential organ donors and 55% of donors with left ventricular dysfunction were treated with levothyroxine from 2015 to 2022. Nearly half the OPOs nationwide routinely administer thyroid hormone during donor care, he added.
The present study included 852 hemodynamically unstable potential heart donors (mean age 36 years, over 30% women). Participants were randomly assigned to open-label infusion of IV levothyroxine (30 μg/hour for 12+ hours) or saline placebo within 24 hours of death according to neurologic criteria. The median time from declaration of brain death to levothyroxine or saline administration was 8 hours.
In addition to the main results of the trial, there were no differences between the levothyroxine and saline groups in terms of vasopressor requirements, donor ejection fraction, and number of organs transplanted (four per donor in both groups).
“It is very unusual to have a study of deceased organ donors of this size and with such sufficient rigor, but we believed the 4-year, multicenter research was critical to definitively answer this key question to enable better organ donor management,” said study co-author Gary Marklin, MD, also of Washington University School of Medicine, in the press release.
The researchers said their patient sample was representative of the target population, and their findings may be generalizable to hemodynamically unstable heart donors.
The trial was supported by Mid-America Transplant with internal support from each organ procurement organization.
Dhar disclosed consulting to Marinus Pharmaceuticals and Mid-America Transplant.
Khush reported receiving research funding from the NIH and consulting to the Scientific Registry for Transplant Recipients.
New England Journal of Medicine
Source Reference: Dhar R, et al “Intravenous levothyroxine for unstable brain-dead heart donors” N Engl J Med 2023; DOI: 10.1056/NEJMoa2305969.
New England Journal of Medicine
Source Reference: Khush KK “The importance of randomized, controlled trials in the care of organ donors” N Engl J Med 2023; DOI: 10.1056/NEJMe2311964.