Does the use of double hormone replacement therapy for trauma patient organ donors improve organ recovery for transplant

Abstract

BACKGROUND

With an ongoing demand for transplantable organs, optimization of donor management protocols, specifically in trauma populations, is important for obtaining a high yield of viable organs per patient. Endocrine management of brain-dead potential organ donors (BPODs) is controversial, leading to heterogeneous clinical management approaches. Previous studies have shown that when levothyroxine was combined with other treatments, including steroids, vasopressin, and insulin, BPODs had better organ recovery and survival outcomes were increased for transplant recipients.

AIM

To determine if levothyroxine use in combination with steroids in BPODs increased the number of organs donated in trauma patients.

METHODS

A retrospective review of adult BPODs from a single level 1 trauma center over ten years was performed. Exclusion criteria included patients who were not solid organ donors, patients who were not declared brain dead (donation after circulatory death), and patients who did not receive steroids in their hospital course. Levothyroxine and steroid administration, the number of organs donated, the types of organs donated, and demographic information were recorded. Univariate analyses were performed with P < 0.05 considered to be statistically significant.

RESULTS

A total of 88 patients met inclusion criteria, 69 (78%) of whom received levothyroxine and steroids (ST/LT group) vs 19 (22%) receiving steroids without levothyroxine (ST group). No differences were observed between the groups for gender, race, pertinent injury factors, age, or other hormone therapies used (P > 0.05). In the ST/LT group, 68.1% (n = 47) donated a high yield (3-5) of organ types per donor compared to 42.1% (n = 8) in the ST group (P = 0.038). There was no difference in the total number of organ types donated between the groups (P = 0.068).

CONCLUSION

This study suggests that combining levothyroxine and steroid administration increases high-yield organ donation per donor in BPODs in the trauma patient population. Limitations to this study include the retrospective design and the relatively small number of organ donors who met inclusion criteria. This study is unique in that it mitigates steroid administration as a confounding variable and focuses specifically on the adjunctive use of levothyroxine.

Key Words: Organ donation; Trauma; Brain death; Levothyroxine; Hormone replacement therapy; Steroids; Organ donor; Retrospective

Core Tip: The present study considers the impact of combination endocrine management on the number of solid organs donated in brain-dead organ donors. Specifically, we focused on the use of steroids alone or steroids and levothyroxine in organ donors of the trauma patient population from a single level 1 trauma center. We showed a significant association between a high yield of organs donated per donor and the use of combination hormone replacement therapy as compared to steroids alone. These data complement published literature on combination endocrine management and highlight the role of levothyroxine on the number of organs recovered per organ donor.

INTRODUCTION

Aggressive organ donor management has been shown to yield positive outcomes for organ donation[1-4]. With an ongoing demand for transplantable organs, optimization of donor management protocols, specifically in trauma populations, is important for obtaining a high yield of viable organs per patient. Hormone replacement therapy is an area of intensive care protocols that the Society of Critical Care Medicine has advised, however there is little evidence supporting its efficacy[1,4,5]. Hormone therapy may preserve the potential for organ donation in patients that have experienced non-survivable catastrophic brain injuries or after brain death declaration, but protocols for implementing these interventions are ill-defined[1,6]. The value of combination steroid and thyroid hormone replacement in hemodynamically stable or unstable patients is still under debate, as studies looking at the beneficial effects of these interventions show mixed results[4,7].

The goal of this study was to assess the role of double hormone replacement therapy, including steroid and levothyroxine administration, in organ donation outcomes (organs transplanted per donor). Steroids are routinely utilized for potential brain-dead organ donors in the trauma population. However, the current literature lacks in consistently controlling for steroid use when comparing outcomes between combination therapies[1,4,8,9]. We hypothesized that levothyroxine with steroids administered in trauma patients with catastrophic brain injuries or confirmed brain death would increase the number of organs donated.

MATERIALS AND METHODS

A retrospective review of adult patients who were eligible for organ donation from a level 1 trauma center between July 2012 and March 2021 was performed. The trauma registry was used to find patients meeting the inclusion criteria. Inclusion criteria were as follows: Patients 18 years of age or older who were declared brain dead, were solid organ donors and were administered steroids (methylprednisolone, hydrocortisone, or both) during their hospital course. These patients underwent chart review using electronic medical records and records from the associated organ procurement organization. Exclusion criteria were patients younger than 18 years of age, patients who were not solid organ donors, patients who were not declared brain dead (such as patients who donated after circulatory death), and patients who did not receive steroids (methylprednisolone, hydrocortisone, or both) in their hospital course (Figure 1). Brain death determination was made using two confirmatory brain death exams and, in some cases, ancillary tests including cerebral perfusion scans. The Institutional Review Board approved this study, and a waiver of informed consent was obtained. There were no set trauma intensive care unit guidelines for management of potential organ donors, and management was left to the discretion of the attending physician.

Figure 1 Study design flowchart showing inclusion criteria and final groups. Excluded patients are signified by the unmet criteria in the dark gray box.

Demographic data such as age, race, and gender were collected. Pertinent injury factors were recorded, including injury severity score, type of injury (blunt or penetrating), and presence of traumatic brain injury (TBI). A donated organ was defined as any organ recovered by the organ procurement organization. The type of solid organs donated, including lungs, kidneys, heart, liver, and pancreas, were recorded. The types of solid organs donated were then summed to range between 1-5 organ types per donor. For example, two donated kidneys would still only be counted as one type. A high yield of organs recovered per donor was defined as 3-5 organ types donated by an individual donor.

Data on treatment for other endocrine disorders, such as diabetes insipidus (DI) and hyperglycemia, were also collected. DI treatment was identified as desmopressin or vasopressin administration following suspected DI due to polyuria (> 2.5-3 mL/h/kg), hypernatremia (> 150 mEg/L), high serum osmolarity (> 295 mOsm/L), and/or low urine osmolarity (< 200 mOsm/L)[10]. Insulin requirement was recorded as hyperglycemia treatment.

Patients were then divided into two groups: Those receiving levothyroxine plus steroids (ST/LT group) vs those only receiving steroids without levothyroxine (ST group). Data was analyzed using statistic analysis system (SAS) version 9.4 (SAS Institute Inc, Cary, NC, United States). Variables collected are reported as either median and minimum and maximum for not normally distributed count variables or proportions for categorical variables. Univariable analyses were conducted to compare demographic and clinical donors’ characteristics and donated organs between two groups (ST vs ST/LT) using the χ² test or the exact test when comparing proportions and the Mann-Whitney U test when comparing medians. A two-sided P value less than 0.05 indicated statistical significance.

RESULTS

Study population

Of the patients reviewed, a total of eighty-eight organ and tissue donors met the study inclusion criteria (Figure 1). Of these organ donors, 78% received levothyroxine and steroids (ST/LT group, n = 69) vs 22% receiving steroids alone (ST group, n = 19).

Study demographics

No significant differences were observed between the two groups in the reported patients’ demographical and clinical characteristics (Table 1). Patients’ ages ranged from 18 years-75 years old in the ST group and 20 years-75 years old in the ST/LT group, with the majority in each being male (68.4% vs 81.2%, P = 0.232, respectively). In the ST compared to the ST/LT group, 31.6% vs 46.4% were African American/Black, 57.9% vs 43.5% were Caucasian/White, and 10.5% vs 10.1% were of a different racial background, respectively (P = 0.483). Regarding clinical characteristics of the patients, the median injury severity score was 25 (4–54) in the ST group and 29 (9-75) in the ST/LT group (P = 0.911). Blunt injuries occurred in 73.7% (n = 14) of the ST group patients and 60.9% of the ST/LT group patients, with 26.3% and 39.1%, respectively, having penetrating injuries (P = 0.304). In the ST group, 84.2% of patients had a TBI, and in the ST/LT group, 94.2% had a TBI (P = 0.169). Other than LT and ST, endocrine protocols used were insulin administration for hyperglycemia treatment and desmopressin or vasopressin administration for DI treatment. Insulin was administered in 57.9% of ST group patients and 55.1% of ST/LT patients (P = 0.826). Finally, DI was treated in 31.6% of ST group patients and 40.6% of ST/LT group patients (P = 0.476) (Table 1).

Table 1 Demographic and clinical characteristics of adult donors by hormone therapy usage, n (%).

Item	ST (n = 19)	ST/LT (n = 69)		P value
Age (yr), median (min–max)	36 (20–75)	32 (18–75)		0.214
Gender				0.232
Male	68.4 (13)	81.2 (56)
Female	31.6 (6)	18.8 (13)
Race				0.483
African American/Black	31.6 (6)	46.4 (32)
Caucasian/White	57.9 (11)	43.5 (30)
Other	10.5 (2)	10.1 (7)
Injury type				0.304
Blunt	73.7 (14)	60.9 (42)
Penetrating	26.3 (5)	39.1 (27)
ISS, median (min–max)	25 (4–54)	29 (9–75)		0.911
TBI	84.2 (16)	94.2 (65)		0.169
Insulin	57.9 (11)		55.1 (38)	0.826
DI	31.6 (6)		40.6 (28)	0.476

ISS: Injury severity score; TBI: Traumatic brain injury; DI: Diabetes insipidus treated; ST/LT: Levothyroxine and steroids; ST: Steroids.

Organ donation

Organ donation summaries for the patients are reported in Table 2. The median number of organ types donated [median (min-max)] was not significantly different between the two groups and were 2 (1-5) for the ST group and 3 (1-5) for the ST/LT group (P = 0.068, Table 2). A significantly higher proportion of patients with a high yield of organs (3-5 organ types per donor) was observed in the ST/LT group compared to the ST group (68.1% vs 42.1%, P = 0.038, Table 2). No individual organ type was donated at a significantly higher proportion between the treatment groups (P > 0.05, Table 2). Furthermore, although non-statistically significant, all organs were donated at a numerically higher proportion for the ST/LT group compared to the ST group, except for kidneys, which had a very high donation rate (> 90% in both treatment groups, Table 2).

Table 2 Donated organs by hormone therapy usage, n (%).

Item	ST (n = 19)	ST/LT (n = 69)	P value
Total number, median (min-max)	2 (1–5)	3 (1–5)	0.068
Donation of 3 or more organs	42.1 (8)	68.1 (47)	0.038
Organ type
Heart	42.1 (8)	59.4 (41)	0.179
Kidney	94.7 (18)	91.3 (63)	0.624
Liver	79.0 (15)	92.8 (64)	0.079
Lung	21.1 (4)	39.1 (27)	0.144
Pancreas	26.3 (5)	36.2 (25)	0.419

Total number of organ types donated of five: Heart, liver, lung, kidney, and/or pancreas. ST/LT: Levothyroxine and steroids; ST: Steroids.

DISCUSSION

Meeting the demand for transplantable organs remains an ongoing challenge, making the optimization of interventional protocols, specifically in trauma populations, an essential part of maximizing the number of organs obtained per patient. Steroids are routinely used for potential brain-dead organ donors in the trauma population. However, the current literature lacks in consistently controlling for steroid use when comparing outcomes between combination therapies[4,8,11,12].

The present study compared steroids in adjunct with levothyroxine to steroids alone in brain-dead potential organ donors (BPODs) and found an increase in high-yield organ donation per donor (i.e., 3-5 organ types donated per donor) in the ST/LT group compared to the ST group. There was no difference in the total number donated or the number of individual organs donated between the groups. Notably, there was no decrease in organs donated in the ST/LT group compared to the ST group, suggesting there was no identifiable negative association of LT treatment in this cohort of organ donors in the trauma patient population.

The history of research on including levothyroxine as an intervention for potential organ donors has been mixed[1,7]. For a recent review of the literature on levothyroxine’s role in hormone replacement therapy, see Turco et al[5], 2019. In short, circulating levothyroxine was shown to decrease after brain death in several studies, and pre-clinical studies indicated a potential role of levothyroxine replacement in maintaining perfusion of organs via increased hemodynamic stability[5,13]. Following these findings, numerous clinical studies ranging from small prospective to large retrospective studies identified levothyroxine alone or in combination hormone replacement therapy as beneficial in regards to donor hemodynamic status or organ retrieval rates and outcomes[11,12,14,15]. Clinical trials studying levothyroxine, however, have failed to elucidate a beneficial effect of levothyroxine therapy on the organs of brain-dead donors[7,16-19]. Limitations to these studies include inconsistent outcome measures and, in the case of randomized controlled trials (RCTs), small numbers of hemodynamically unstable patients[19,20]. In addition, quality RCTs evaluating the benefit of combination hormone replacement therapy are lacking[21]. An ongoing multicenter randomized controlled trial including 800 brain-dead, hemodynamically unstable organ donors may clarify whether heart donation, heart function, and/or vasopressor requirements are impacted specifically by intravenous thyroxine treatment[22]. However, as organ procurement organizations are allowed to continue their other individual standard donor management protocols, it is not yet clear how or whether the contributions of other hormone replacement therapies, such as steroids, will be considered[22]. Still, a comparative study showed evidence that levothyroxine intervention before brain death was beneficial in increasing the number of organs donated[23]. One other study identified the timing of hormone replacement therapy as an important factor after catastrophic brain injury, but few studies have been able to give clear guidance on when hormone intervention should be initiated[6]. Timing, then, may also impact the findings in RCTs based on whether levothyroxine treatment was initiated before or after brain death and how long the patients were exposed to the treatment. Similarly, understanding the optimal timing of levothyroxine administration in relation to when steroid interventions are started will aid in determining appropriate endocrine protocols for BPODs in the trauma patient population. In summary, the proper usage of levothyroxine or combination replacement therapy in catastrophic brain injury or after brain death is still under debate. Still, previous literature, as well as the present study, highlight the potential benefits of LT and combination therapy in increasing organ donation after brain death.

While the present study did not focus on stability parameters of the patient population, prospective studies may be able to better differentiate the impact of levothyroxine and steroid therapies on stable compared to unstable patients. Study limitations include its retrospective and single-center nature. Other potential confounders of the results include the vasopressor requirements, cardiovascular stability, timing of hormone therapy administration, and length of time on the therapy. Future prospective studies controlling for these factors may elucidate other important aspects of treating potential organ donors in cases of imminent or confirmed brain death. With multiple cohort studies indicating significant impacts of combination therapy, more clinical trials with sufficient power investigating combination instead of single therapy are warranted.

CONCLUSION

In conclusion, this retrospective study showed an increase in high-yield organ donation per donor when levothyroxine was adjunctively administered with steroids in BPODs as compared to BPODs administered steroids alone. These results, along with previous reports from RCTs, call for further investigation of the use of levothyroxine in adjunct with steroids for the management of brain-dead organ donors.