Multicenter, parallel-group, randomized trial

N= 838

To evaluate the hypothesis that intravenous levothyroxine would increase the rate of hearts transplanted from hemodynamically unstable brain-dead organ donors being considered for heart donation

Levothyroxine (n= 419)

Placebo (n= 419)

Deceased patients aged 14 to 55 years with authorization for organ donation, declared dead according to neurologic criteria, weight ≥45 kg, hemodynamic instability after fluid resuscitation

Hearts not considered for transplantation due to known heart disease or if thyroid hormone was received within the past month

Subjects were randomized within 24 hours after declaration of death to IV levothyroxine (30 μg/hour for a minimum of 12 hours) or placebo (normal saline). Baseline free T4 levels were obtained before the start of levothyroxine or saline infusion and before organ procurement. The levothyroxine dose could be decreased or discontinued based on prespecified hemodynamic variables (hypertension, tachycardia, or arrhythmias, defined in the trial protocol). Extension of levothyroxine infusion beyond 12 hours was permitted at the discretion of each organ-procurement organization (OPO). Open-label use of levothyroxine was discouraged but permitted in the control group and only after the 12 hours of saline infusion was completed. 

Primary: Transplantation of the donor heart

Secondary: Number of organs transplanted per donor, lungs transplanted, liver transplanted, number of kidneys transplanted per donor, weaning from vasopressor therapy, time to wean off vasopressors, time until first echocardiogram was ordered, donor ejection fraction, adverse events, graft survival at 30 days

Placebo (n= 419)

Race/ethnic group

White, non-Hispanic

Black

Hispanic or Latino

Asian, Pacific Islander, or other

252/403 (63%)

75/403 (19%)

60/403 (15%)

16/403 (4%)

278/397 (70%)

49/397 (12%)

63/397 (16%)

7/397 (2%)

Blood group

O

A

B

AB

224 (53%)

134 (32%)

50 (12%)

11 (3%)

214 (51%)

148 (35%)

49 (12%)

8 (2%)

Coexisting conditions

Hypertension

Diabetes

Cigarette use

Cocaine use

98/403 (24%)

38/403 (9%)

58/403 (14%)

92/403 (23%)

104/397 (26%)

31/397 (8%)

76/397 (19%)

105/397 (26%)

Cause of death

Anoxia

Stroke

Trauma

Other

162/403 (40%)

87/403 (22%)

143/403 (35%)

11/403 (3%)

195/397 (49%)

79/397 (20%)

117/397 (29%)

6/397 (2%)

Left ventricular ejection fraction, %

First echocardiogram

Maximum of all echocardiograms

59 ± 11

60 ± 9

58 ± 12

60 ± 10

1.0 (-0.6 to 2.7)^b

0.5 (-0.9 to 2.0)^b

More donors had adverse events in the levothyroxine group than in the saline group.

Significant differences were observed in the number of cases of severe hypertension (26 vs. 5, p<0.001) and tachycardia (16 vs. 3, p= 0.003).

The incidence of serious adverse events was similar in the two groups.

In hemodynamically unstable brain-dead potential heart donors, intravenous levothyroxine infusion did not result in significantly more hearts being transplanted than saline infusion.

The study was well-designed with a large sample size and multicenter approach, providing robust data on the efficacy of levothyroxine in this context. However, the lack of blinding and the allowance for open-label use of levothyroxine in the control group could introduce bias. Additionally, the study did not find a significant benefit of levothyroxine, which challenges current practices based on observational data. The findings are limited to the specific population of hemodynamically unstable brain-dead donors and may not be generalizable to other donor populations.

Hemodynamic Effects of High-dose Levothyroxine and Methylprednisolone in Brain-dead Potential Organ Donors

Randomized controlled trial

N= 199 (intent-to-treat population [ITT])

To determine whether high-dose levothyroxine (T4), high-dose methylprednisolone (MP), or the combination of both, administered early in donor management, would improve donor hemodynamics, allowing substantial reduction in vasopressor support

Levothyroxine (n= 49)

Methylprednisolone (n= 50)

Combination (n= 51)

Control (n= 49)

Adult donors aged 18–70 years with valid authorization for organ donation

Pediatric donors

Adult donors were randomized to receive high-dose levothyroxine, high-dose methylprednisolone, both, or no hormonal therapy. Standard donor management protocols were followed. Vasopressor requirements were assessed at baseline, 4 hours, and at procurement using the vasoactive-inotropic score (VIS). Crossover to the combination group was allowed for poor cardiac function or high vasopressor requirements. Hormone and cytokine levels were measured at baseline and procurement.

Levothyroxine regimen: 20 μg IV followed by continuous infusion at 50 μg/h, titrated to a maximum dose of 200 μg/h, to minimize vasopressor support. Once stable, the dose was down-titrated to 50 μg/h or the lowest dose possible to support appropriate
hemodynamics.

Methylprednisolone regimen: 30 mg/kg (maximum 2 g) with a repeated dose of 15 mg/kg (maximum 1 g) 12 h after the first dose. 

Combination regimen: Received both levothyroxine and methylprednisolone in the doses noted above. 

Primary: Difference in vasopressor requirement to maintain goal hemodynamics among the 4 treatment groups (vasoactive-inotropic score [VIS)

Secondary: Change in thyroid hormone levels, cortisol levels, and inflammatory markers (PP population), number, types, and proportion of organs procured versus consented, transplant rates, and recipient outcomes

Combination (n= 51)

Race

White/Caucasian

Black

Hispanic/Latino

Other

24 (49%)

23 (47%)

2 (4%)

0 (0%)

31 (62%)

16 (32%)

3 (6%)

0 (0%)

31 (61%)

16 (31%)

4 (8%)

0 (0%)

29 (59%)

15 (31%)

3 (6%)

2 (4%)

0.535

Cause of death

CVA/stroke

Head trauma

Anoxia

CNS tumor

Other

21 (43%)

17 (35%)

9 (18%) 

2 (4%) 

0 (0%) 

30 (60%) 

15 (30%)

4 (8%) 

0 (0%) 

1 (2%) 

24 (47%)

17 (33%) 

9 (18%) 

0 (0%) 

1 (2%) 

19 (39%)

24 (49%)

6 (12%)

0 (0%) 

0 (0%) 

0.213

Levothyroxine (n= 49)

1.6 ± 2.6

162 (53%)

Organ-specific yield

Heart
Lung
Liver
Kidney
Pancreas
Intestine

11 (28%)
20 (24%)
42 (86%)
82 (84%)
7 (26%)
0 (0%)

15 (38%)
26 (29%)
40 (82%)
83 (88%)
8 (32%)
0 (0%)

18 (47%)
29 (32%)
43 (84%)
92 (90%)
8 (27%)
0 (0%)

21 (51%)
40 (43%)
44 (94%)
87 (91%)
9 (26%)
0 (0%)

0.155
0.045
0.362
0.413
0.950
-

128 (79%)

In the ITT analysis, the VIS declined modestly in all but the levothyroxine group.

Relative reductions in VIS were similar in the per-protocol (PP; N= 182) analysis, although the levothyroxine group was no longer significantly different from the control group (p= 0.455).

Thyroid levels: In the PP population, no significant changes in the methylprednisolone and control groups; with the exception of TSH, the infusion of T4 significantly increased all thyroid levels.

Cortisol levels: In the PP population, no significant changes in the levothyroxine and control groups

Inflammatory markers: In the PP population, no significant treatment effect of steroid administration.

The only significant difference among groups was the proportion of lungs recovered in the control group compared with the levothyroxine group in the ITT analysis. This finding was not present in the PP analysis.

No adverse effects on organ yield, transplantation rates, or recipient outcomes were reported. No differences were found in patient or graft survival among the treatment groups.

High-dose methylprednisolone alone or in combination with levothyroxine allowed for significant reduction in vasopressor support in organ donors. Levothyroxine alone offered no advantage in reducing vasopressor support. Organ yield, transplantation rates, and recipient outcomes were not adversely affected.

The study is the largest randomized trial of combination hormonal replacement therapy to date, providing significant insights into donor management. However, it is underpowered for organ yield and recipient outcomes, and the lack of blinding may have introduced bias. The study's findings remain relevant despite the delay in reporting.

Levothyroxine therapy before brain death declaration increases the number of solid organ donations

Retrospective observational study

N= 77

To evaluate the impact of early levothyroxine therapy (LT; before the declaration of brain death) on the number of solid organs procured per donor

Early LT group (n= 37)

Late LT group (n= 40)

Trauma patients who progressed to brain death, consented for organ donation, received LT, and donated solid organs

Patients who did not receive LT

Retrospective analysis of trauma patients who progressed to brain death. Patients were categorized as early levothyroxine if treatment was initiated before declaration of brain death and late levothyroxine if initiated after declaration; the timing and use of levothyroxine were at the discretion of the attending surgeon. Brain death was determined by the attending physician based on physical examination and a brain perfusion scan. 

Primary: Number of solid organs donated

Secondary: Need for vasopressors, units of blood products

Early LT (n= 37)

Early LT (n= 37)

Not assessed

The early use of LT and aggressive blood product resuscitation was associated with a significantly higher number of solid organs donated per donor. Early LT reduces vasopressors and fresh frozen plasma (FFP) requirements. Earlier use of LT before the declaration of brain death may be considered in potential organ donors.

The study highlights the potential benefits of early levothyroxine therapy in increasing organ donation rates. However, the retrospective design and small sample size may limit the generalizability of the findings. The lack of a standardized protocol for levothyroxine administration and the reliance on the discretion of attending surgeons may introduce variability in the results. Further prospective studies are needed to confirm these findings and establish standardized protocols for early levothyroxine therapy in organ donation.

Hormone Replacement before brain death increases organ donation rate after catastrophic brain injury: An EAST multicenter trial

Multicenter, prospective, observational trial

N= 1,184

To investigate which hormones, when replaced either alone or in combination, in catastrophic brain injury (CBI) patients before brain death, are associated with organ donation, and which combinations of hormones are most beneficial for preserving organ donation potential

Hormone replacement therapy (HRT) group (n= 704)

Non-HRT group (n= 480)

Adult (≥18 years old) trauma patients who suffered a traumatic mechanism CBI and expired in-hospital because of brain death or circulatory death caused by their head injury between January 1, 2022 and June 15, 2025

Primary: Organ donation rate

Secondary: Tissue donation rate, organ donation rates by specific hormones and hormone combinations administered

Non-HRT (n= 480)

Known comorbidities

None

Atrial fibrillation

Cancer

COPD

ESRD

CHF

Diabetes

Liver disease

234 (33.2%)

34 (4.8%)

29 (4.1%) 

28 (4.0%) 

18 (2.6%)

30 (4.3%)

91 (12.9%) 

15 (2.1%) 

98 (20.4%)

54 (11.2%)

44 (9.2%) 

38 (7.9%)

10 (2.1%)

38 (7.9%) 

72 (15.0%)

16 (3.3%) 

< 0.001

< 0.001

< 0.001

0.006

0.740

0.012

0.352

0.277

Non-HRT (n= 480)

HRT patients had significantly higher rates of acute kidney injury (15.8% vs. 9.8%, p= 0.004) and acute respiratory distress syndrome (4.5% vs. 1.5%, p= 0.006), with no difference in venous thromboembolism (1.6% vs. 1.7%, p= 1.000).

When administered to CBI patients before brain death, HRT is associated with significantly increased odds of organ donation. A standardized protocol incorporating HRT should be utilized across trauma centers to maximize organ donation in patients who have suffered nonsurvivable head trauma.

The study is strengthened by its multicenter nature and large study population, making it the largest study on the topic of CBI management. However, there is potential for coding errors and/or missing data due to its retrospective nature. Variability in hormone dosage and frequency, as well as differences in donor management protocols across centers, may have impacted the results. Additionally, demographic differences between the HRT and non-HRT cohorts could signal unaccounted confounders.

A Randomized Trial of Intravenous Thyroxine for Brain-Dead Organ Donors With Impaired Cardiac Function

Randomized trial

N= 28 (intent-to-treat population)

To evaluate whether intravenous thyroxine (T4) improves cardiac function in brain-dead donors with impaired ejection fraction (EF)

T4 infusion (n= 17)

Control (n= 11)

Brain-dead organ donors aged 18-50 who were managed at a single-organ procurement organization (OPO) recovery center, and transferred within 12 hours of brain death

Known coronary artery disease or structural heart disease, hepatitis C or HIV infection, received open-label T4 prior to screening

Donors underwent protocolized fluid resuscitation and were weaned off vasopressors. Those with EF <60% were randomized to T4 infusion (20 mg IV bolus followed by 10 mg/h) or no T4 for 8 hours. Transthoracic echocardiography (TTE) was performed before and after infusion.

Primary: Improvement in left ventricular ejection fraction (LVEF)

Secondary: Proportion of hearts transplanted

T4 (n= 17)

T4 (n= 17)

10 (5-15)

10 (59%)

In the per-protocol analysis, improvement in LVEF was also not greater in those receiving T4.

No specific adverse events related to T4 infusion were reported

In this small randomized study of brain death donors with impaired cardiac function, T4 infusion did not result in greater cardiac recovery. A larger randomized trial comparing T4 to placebo appears warranted but would require collaboration across multiple OPOs.

The study was limited by its small sample size and the fact that many in the T4 group did not receive the full intervention due to hemodynamic instability. The study's findings are not generalizable without further research across multiple OPOs.

A Randomized Trial Comparing Triiodothyronine (T3) with Thyroxine (T4) for Hemodynamically Unstable Brain-Dead Organ Donors

Randomized trial

N= 37

To determine whether T3 infusion would improve cardiac performance, hemodynamic stability, and result in more hearts transplanted than standard T4 therapy in hemodynamically unstable heart-eligible brain-dead (BD) organ donors

T3 (n= 16)

T4 (n= 21)

BD organ donors (aged <18 or >50 years old) managed at a single OPO's independent organ recovery center within the study period (January 2015 to June 2017) who were being evaluated for heart transplantation

Known CAD or structural heart disease; hepatitis C or HIV; could not be randomized within 12 hours of BD; received open-label T4 prior to screening

All eligible subjects underwent standardized fluid resuscitation. All other donor management followed the standardized OPO
protocols.

Donors were randomized to T3 or T4 infusion for eight hours. T4 was started with a 20 μg bolus followed by infusion at 10 μg/hour, increased to 20 μg/hour if needed. T3 was started with a 4 μg bolus followed by 2 μg/hour. Infusions were continued for eight hours but could be discontinued if hypertension or tachycardia developed.

Hemodynamic parameters and echocardiographic profiles were recorded before and after infusion.

Primary: Improvement of LVEF

Secondary: Proportion of hearts transplanted, improvement in hemodynamic parameters, change in fT3 and fT4 levels

T4 (n= 21)

T4 (n= 21)

Infusion of T3 does not appear to confer significant hemodynamic or cardiac benefits over T4 for hemodynamic unstable BD organ donors.

The study is limited by its small sample size and potential baseline imbalances between groups. While it provides valuable insights into the comparative effectiveness of T3 and T4, the lack of significant differences in primary outcomes suggests that larger studies are needed to confirm these findings. The study's focus on a specific donor population may limit generalizability, and the open-label use of T4 in the T4 group could have influenced results. Further research is needed to explore the benefits of thyroid hormone therapy versus placebo in this context.

The Role of Thyroid Hormone Administration in Potential Organ Donors

Prospective, before-and-after clinical study

N= 19

To assess the use of levothyroxine sodium therapy in brain-dead potential organ donors to reverse hemodynamic instability and prevent cardiovascular collapse, leading to more available organs for transplantation

All patients (n= 19)

Patients with traumatic and nontraumatic intracranial lesions, candidates for organ donation following brain death declaration, admitted to the surgical intensive care unit during September 1, 1999, through August 31, 2000

Patients with hemodynamic stability

Patients were resuscitated with fluids, inotropic agents, and vasopressors. If patients remained unstable, they received a bolus of 50% dextrose, 2 g methylprednisolone sodium succinate, 20 U insulin, and 20 µg levothyroxine sodium, followed by a continuous infusion of levothyroxine sodium at 10 µg/h. Hemodynamic and metabolic data were collected hourly prior to and after levothyroxine administration until organ donation or until life support was discontinued.

Primary: Reduction in vasopressor requirements before and after levothryoxine

Secondary: Hemodynamic profile before and after levothyroxine, increase in organ donation, prevention of cardiovascular collapse

All patients (n= 19)

Cause of brain death

Trauma

Non-trauma

16

3

All patients (n= 19)

Ten (53%) of the 19 patients were completely weaned off vasopressors.

Ten of the 19 patients underwent successful organ donation for a total of 33 organs. Organs were not harvested from the remaining 9 patients due to family refusal.

No patient suffered cardiovascular collapse.

Three patients developed severe hypertension (systolic blood pressure ≥180 mmHg), which resolved once levothyroxine therapy was discontinued.

Levothyroxine therapy plays an important role in the management of hemodynamically unstable potential organ donors by decreasing vasopressor requirements and preventing cardiovascular collapse. This may result in an increase in the quantity and quality of organs available for transplantation.

The study lacks a control group, which limits the strength of the conclusions. The absence of thyroid hormone level measurements before and after treatment is another limitation. The relatively high dose of levothyroxine used and the lack of post-transplantation follow-up are additional limitations. Despite these, the study provides valuable insights into the potential benefits of levothyroxine therapy in increasing organ availability for transplantation.

The Impact of Early Hormonal Therapy in Catastrophic Brain-Injured Patients and Its Effect on Organ Procurement

Retrospective study

N= 53

To evaluate the impact of early hormonal therapy (HT) on organ procurement from catastrophic brain-injured patients

HT before brain death (BD) (n= 32)

HT after BD (n= 21)

Catastrophic brain-injured patients admitted to LAC+USC Medical Center from January 2006 through December 2008 who progressed to brain death, consented for organ donation, and underwent successful organ procurement

Patients who did not receive hormonal therapy

Patients were divided into two groups: those who received hormonal therapy (HT) before BD declaration and those who received HT after BD declaration. Data collected included demographics, clinical characteristics, and organ procurement outcomes. Hormonal therapy consisted of IV methylprednisolone, insulin, D50, and levothyroxine.

Primary: Number of organs procured

Secondary: Vasopressor requirements, duration of vasopressor use

HT After BD (n= 21)

HT Before BD (n= 32)

For all individual organs, procurement rates were higher among patients receiving HT before BD; this was statistically significant for heart (56.2 vs 28.6%, p= 0.048) and lungs (37.5% vs 4.8%, p= 0.008). 

Patients receiving HT before BD also required high doses of vasopressors less frequently and for a shorter duration; this was statistically significant for vasopressin (34.4 vs 71.4%, p= 0.008; and 13.0 ± 8.5 vs 35.8 ± 36.5 hours, p= 0.020).

Early hormonal replacement therapy, initiated before significant vasopressor use or BD declaration, may increase the yield of organs from our current donor pool and warrants further study.

The study is limited by its retrospective design and the potential influence of other aspects of the aggressive donor management protocol. The lack of functional data on the procured organs is another limitation. However, the study provides valuable insights into the potential benefits of early hormonal therapy in increasing organ procurement rates.