IV Thyroxine in Brain Dead Organ Donors

Blog Written by Dr Jose Chacko

Intravenous levothyroxine for unstable brain-dead heart donors.

Dhar R, Marklin GF, Klinkenberg WD, et al. N Engl J Med 2023;389:2029-38.

Background

Neurohormonal insufficiency, especially thyroid deficiency, is thought to occur following brain death, leading to depletion of myocardial energy reserves, and shock (1).  Observational studies suggest that the rate of heart and total organ transplants may be higher among donors who receive thyroid hormone, with improved graft function in recipients (2). Based on this hypothesis, hormonal resuscitation is considered a crucial aspect of the care of potential organ donors, particularly if they are hemodynamically unstable. Previous randomized controlled trials have evaluated the hemodynamic impact of hormonal resuscitation in organ donors, but were underpowered to assess organ utilization (3). Consensus guidelines recommend administration of thyroid hormone in hemodynamically unstable, heart-eligible donors (4). However, hormonal resuscitation may be associated with early allograft failure (5). The present study aimed to evaluate the effect of intravenous levothyroxine on the rate of hearts transplanted from hemodynamically unstable brain-dead organ donors (6).

Population and design

The study was conducted across 15 organ procurement organizations (OPOs) in the US and included brain-dead patients with authorization for organ donation. Eligible organ donors were randomized in a 1:1 ratio to receive levothyroxine or normal saline as a placebo.

Inclusion criteria

• Age between 14–55 years
• Declaration of death according to neurologic criteria
• Body weight of 45 kg or more
• Hemodynamic instability, defined as support with one or more vasopressors or inotropes, following fluid resuscitation (vasopressin for the management of diabetes insipidus was not considered to be circulatory support).

Excluded

• Donor hearts not considered for transplantation due to pre-existing heart disease
• Treatment with thyroid hormone within the previous month

Base line free T4 levels were obtained before randomization. Donors were randomly allocated to receive levothyroxine or saline infusion in a 1:1 ratio within 24 hours of declaration of brain death. Randomization was stratified by site, in blocks of 30.

Levothyroxine group

Levothyroxine was administered as an infusion at 30 μg per hour for 12 hours. The dose could be decreased or discontinued based on prespecified hemodynamic variables (hypertension, tachycardia, or arrhythmias). Levothyroxine infusion could be prolonged beyond 12 hours at the discretion of each OPO. Open label use of levothyroxine was discouraged; however, it was permitted in the control group after the 12 hours of saline infusion.

Control group

Donors in the control group received normal saline infusion at 30 ml/hour.

Sample size

The authors hypothesized that levothyroxine administration would result in an increase in the number of hearts transplanted by 10 percentage points. A sample size of 800 donors provided the trial with a minimum of 80% power to detect this treatment effect from a baseline of 35%. Transplant of 320 hearts provided 78% power to assess noninferiority of graft outcome at a one-sided alpha of 0.025, applying a noninferiority margin of 6 percentage points.

Results

Among 3259 organ donors who were screened, 852 were enrolled and underwent randomization.

The mean donor age was 36 years, and predominantly men. The median time from the declaration of brain death to commencement of the study infusion was 8.6 hours in the levothyroxine group and 7.5 hours in the saline group. Vasopressor and inotropic support were similar in both groups. The baseline free T4 level was 1.0 ng/dl in both groups. The dose of levothyroxine was weaned down in 47 (11%) patients and discontinued before 12 hours in 58 patients (14%). The median free T4 level at organ recovery was 1.4 ng/dl in the levothyroxine group and 1.0 ng/dl in the saline group (increase by 40%).

Half the donors in the levothyroxine group received the infusion beyond the pre-specified 12-hour period. In the saline group, 12% of donors received open-label levothyroxine after the 12-period.

Primary outcomes

There was no significant difference in the rate of hearts transplanted between the levothyroxine and saline groups (54.9% vs. 53.2%, adjusted risk ratio: [1.01 (95% CI, 0.97 to 1.07; P = 0.57)]. Graft survival at 30 days was 97.4% in the levothyroxine group and 95.5% in the saline group, establishing non-inferiority (absolute difference, 1.9 percentage points; 95% CI,

−2.3–6.0; P<0.001 for noninferiority). There was no difference observed in the rate of hearts transplanted in predefined subgroups of patients based on the duration between time to declaration of brain death to the time to commencement of infusion (≤12 hours vs. >12 hours) or based on the ejection fraction (≤50% vs. >50%).

Post hoc analysis revealed that the absence of treatment effect was consistent in subgroups of patients based on free T4 levels, vasopressor support at baseline, and donor cause of death.

Secondary outcomes

There was no significant difference between groups in the median number of organs transplanted [4 (3–5) in both groups].  The number of lungs, liver, and kidneys that were transplanted was also similar in both groups. The dose of vasopressors and the rate at which they were weaned down were also similar in both groups.

Adverse events

Serious adverse events were few and similar in both groups (0.5% vs. 0.7%). Severe hypertension and tachycardia were more common in the levothyroxine group.

Study conclusion

The study did not demonstrate a benefit of treatment with intravenous levothyroxine treatment in the number of hearts transplanted, or donor cardiac function at 30 days. Hemodynamic stability was similar in both groups. The study suggests a lack of physiological effect levothyroxine on donor cardiovascular function. Levothyroxine did not impact hemodynamic stability in the donor; besides, transplantation rates were also similar.

Limitations

• Unblinded
• Open label use allowed – 12% had open label levothyroxine in the saline group
• Most donors were not profoundly hypothyroid – may have limited potential benefit; however, no benefit was seen even in the subgroup with low free T4 levels
• No centralized interpretation of donor echocardiogram
• Concomitant therapies were not standardized