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Original Clinical Science—General

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

Van Bakel, Adrian B. MD, PhD1; Hino, Sheryl A. RN2; Welker, Darla RN2; Morella, Kristen MPH3; Gregoski, Mathew J. PhD, MS3; Craig, Michael L. MD1; Crumbley, Arthur J. MD4; Sade, Robert M. MD4

Author Information
doi: 10.1097/TP.0000000000004072

Abstract

INTRODUCTION

The persistent shortage of organs for transplantation has led to relative stagnation of the number of solid organ transplants performed, and increased numbers of patients awaiting transplantation.1 Efforts to increase the supply of transplantable organs include aggressive management of potential organ donors, aimed at restoring and maintaining physiological homeostasis after brain death.

Brain death is accompanied by known hemodynamic, hormonal, and inflammatory changes, which will ultimately cause deterioration of end-organ function, diminishing their suitability for transplantation. A variable decline in pituitary hormones results in reduced levels of cortisol, thyroid hormone (TH), and vasopressin2-4 and an increase in proinflammatory cytokines5,6 that can exacerbate hemodynamic instability. Although blood pressure may be supported by catecholamine vasopressors, these substances, especially in high doses, may have detrimental effects on potentially transplantable organs.

Several reviews of large databases report improvement in both number and quality of organs after hormonal supplementation, most notably with the combination of TH, corticosteroids, and vasopressin.7-10 Other studies have failed to conclusively demonstrate a benefit of hormonal replacement therapy (HRT) on hemodynamics, cardiac function, or on numbers of organs procured.11-13 The primary aim of this study was to determine whether high-dose levothyroxine (T4), high-dose methylprednisolone (MP), or the 2 hormones combined, administered early in the course of donor management, would improve donor hemodynamics, allowing substantial reduction in vasopressor support.

PATIENTS AND METHODS

Adult (aged 18–70 y) donors with valid authorization for organ donation were included in the study. Following authorization, organ procurement organization personnel, all of whom had critical care nursing experience, managed the donors. Standard donor management protocols were followed, including aggressive volume resuscitation and weaning of vasoactive drugs. A pulmonary artery catheter monitored hemodynamics. Administration of blood products maintained hemoglobin at >10 mg/dL and platelet count >50 000/µL. Intravascular volume management and vasoactive drugs maintained mean arterial pressure (MAP) between 60 and 100 mm Hg, central venous pressure between 4 and 8 mm Hg, pulmonary capillary wedge pressure between 6 and 15 mm Hg, and cardiac index (CI) at ≥2.5 L/min/m2. MAP was the primary determinant of vasopressor titration.

A computer-based protocol randomized consecutive donors to 1 of 4 treatment groups. (1) Levo received T4, 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. (2) MP received MP 30 mg/kg (maximum 2 g) with a repeated dose of 15 mg/kg (maximum 1 g) 12 h after the first dose. (3) Combo received both T4 and MP in doses noted above. (4) Control received no T4 or MP.

All donors received glucose 50 g plus regular insulin 20 units IV before initiation of HRT. Vasopressin 0.01 to 0.1 U/min was given intravenously for control of diabetes insipidus (threshold urine volume, >200 mL/h), titrated to maintain urine output 30 to 200 mL/h. Following 4 h of management on assigned treatment, crossover to Combo was allowed at the discretion of the on-site coordinator for reasons of poor cardiac function (left ventricular ejection fraction, <50%) or persistent high vasopressor requirements (vasoactive-inotropic score [VIS], >10 and poor tolerance of continued weaning). In addition to collection of donor baseline demographic variables, serial hemodynamic measurements and vasopressor doses were recorded just before initiation of randomized HRT (t0), 4 h later (t4), and just before procurement (tOR).

The primary endpoint of the study was the difference in vasopressor requirement to maintain goal hemodynamics among the 4 treatment groups. Vasopressor requirement was determined by the VIS (Wernovsky et al,14 modified by Nguyen et al15). This score combines weight-based dosing of all commonly used vasopressor and inotropic agents, weighted according to potency, calculated as follows: VIS = dose of dopamine + dobutamine + 100× epinephrine + 100× norepinephrine + 10× phenylephrine + 10× milrinone (all as µg/kg/min) + 10 000× vasopressin (U/kg/min). VIS allows standardization and thus easy comparison of various combinations of vasopressor and inotropic agents and has been validated as a predictor of outcomes in sepsis and following cardiac surgery in adult and pediatric populations.16

Secondary mechanistic endpoints included the determination of baseline TH levels and evaluation of change in levels with and without administration of T4, determination of baseline cortisol levels and change in levels over time without corticosteroid administration, and determination of baseline markers of inflammation (C-reactive protein [CRP] and multiple cytokines) and their changes with and without corticosteroid treatment.

Secondary clinical endpoints included the number, types, and proportion of organs procured versus consented, transplant rates of procured organs, and graft/patient outcomes of organ recipients exposed to the various treatments. Within 120 d after procurement, recipient data were obtained from the recipient’s transplant program using a case report form faxed to the program’s transplant coordinator with an accompanying letter of explanation and institutional review board (IRB) documentation. In addition to vital status at 30 and 90 d, organ-specific data regarding allograft function were requested.

The study was approved by the IRB of the Medical University of South Carolina. Donor authorization specifically for the study was waived by the IRB. Justification for this included as follows: (1) the treatments involved in this study were already being administered, though inconsistently, as part of standard donor management and (2) the donors in this study had been declared dead before authorization for organ donation and thus were not human subjects. Consent for collection of protected health information from the recipients of these organs was also waived by the IRB as impractical, given the wide geographic distribution of the transplanted organs.

Hormone and Cytokine Analyses

Venous blood was collected in serum separator tubes at (t0, t4, and tOR;, centrifuged at room temperature; decanted; and refrigerated for later analysis.

TH, cortisol, and CRP levels were determined by commercial immunoassay (ADVIA Centaur System, Siemens, Tarrytown, NY [TH and cortisol]; Beckman DXC 800, Beckman Coulter, Indianapolis, IN [CRP]). Levels above and below the limits of detection were assigned values of their respective upper and lower limits.

Plasma samples from a subset of randomized donors were obtained at t0 and tOR for determination of proinflammatory cytokine levels. Venous blood was collected in ethylenediaminetetraacetic acid tubes, placed on ice, and centrifuged at 1300 g for 10 min within 1 h of collection. Plasma was separated into 1.5-mL polypropylene tubes, immediately placed on ice for transport, and then stored at –80 °C for later analysis. Plasma samples were analyzed using a 15-cytokine multiplex laser bead panel (Eve Technologies, Calgary, AB, Canada). Samples were analyzed in duplicate and results averaged.

Statistical Analysis

Based on previously published retrospective data from our group17 assuming a 10% crossover rate and 5% dropout rate, we calculated that a group size of 39 donors would provide a power of 0.80 to determine a treatment effect on the VIS.

All donor and recipient data were compiled by We Are Sharing Hope SC and stored on a secure server. Encrypted data were transferred to an analytical database at the Data Coordinating Center in the Department of Public Health Sciences at the Medical University of South Carolina. Clinical data were analyzed using SAS 9.4 (SAS Institute, Cary, NC). Hormone and cytokine levels were analyzed using SPSS Version 25 (IBM, Armonk, NY). Because a large number of subjects crossed over between treatment groups, clinical analyses were performed for both intention-to-treat (ITT) and per-protocol (PP) assignments and are presented separately. Bivariate analyses to compare treatment groups for various demographic and treatment variables, number of organs recovered and transplanted, and hormone and cytokine levels were performed using chi-square or Fisher exact tests (for small samples) for categorical variables, and analysis of variance or Kruskal-Wallis tests (for nonnormal data) for continuous measures. Statistical significance for these analyses was based on 2-sided alternatives at alpha = 0.05. Missing data were not imputed.

For VIS and CI, data were analyzed using the linear mixed-model approach for repeated measures to account for within-subject correlation. Assumptions of normality were assessed using residual diagnostics. Baseline VIS and CI values were included in their respective models as covariates. Statistical significance for the between-group comparisons in these analyses was adjusted for multiple comparisons using the Bonferroni method. Comparisons were made between each treatment assignment and control with significance based on a 2-sided alpha = 0.017. Because the VIS was being evaluated for reduction over time, an additional sensitivity analysis was performed by removing those with a baseline VIS of 0 because further reduction was not possible for these subjects.

RESULTS

Consecutive donors (N = 200) were randomized from September 2010 to August 2012. One pediatric donor was mistakenly randomized and withdrawn, leaving 199 randomized adult donors. A Consolidated Standards of Reporting Trials diagram illustrating recruitment and treatment allocation is presented in Figure 1. Following initial treatment assignment, organ procurement was aborted in 14 patients. While on assigned treatment, 33 donors crossed over from other arms to the Combo arm. The mean VIS for donors who crossed over for hemodynamic instability was 31.5 ± 11.4 compared with 11.5 ± 11.4 in those who remained on assigned treatment. The mean ejection fraction of donors who crossed over for poor left ventricular function was 40% (range, 20%–45%), with subsequent echocardiogram showing improvement to 52% (range, 20%–75%). After crossover, 3 donors were subsequently aborted, all because of persistent hemodynamic instability. At least 1 organ was procured from 182 donors.

F1
FIGURE 1.:
Consolidated Standards of Reporting Trials diagram: randomized treatment allocation in top row constitutes the ITT population. Treatment allocation in the bottom row constitutes the PP population. ITT, intention-to-treat; PP, per-protocol.

Tables 1 and 2 contain donor demographic and baseline clinical information. The ITT analysis disclosed no significant differences in donor demographic or clinical variables between the 4 treatment groups. The PP analysis, however, found a significantly shorter time from brain death to organ procurement in Control versus Combo and from randomization to procurement in Combo versus Levo and Control. Additionally, a trend toward higher incidence of stroke as a cause of death in the MP group was observed; however, this did not contribute to increased baseline VIS compared with other causes of death (13.2 ± 15.2 versus 17.9 ± 18.5).

TABLE 1. - Donor demographics—intention to treat
Variable N (%) or mean ± SD P
All Levothyroxine Methylprednisolone Combination Control
N 199 49 50 51 49
Age 42.3 ± 13 43.3 ± 13.6 43.5 ± 11.8 43.5 ± 12.7 38.7 ± 13.4 0.172
Female 73 (37) 20 (41) 17 (34) 22 (43) 14 (29) 0.421
Race 0.535
 White/Caucasian 115 (58) 24 (49) 31 (62) 31 (61) 29 (59)
 Black/AA 70 (35) 23 (47) 16 (32) 16 (31) 15 (31)
 Hispanic/Latino 12 (6) 2 (4) 3 (6) 4 (8) 3 (6)
 Other 2 (1) 0 (0) 0 (0) 0 (0) 2 (4)
Blood group 0.339
 O 89 (45) 21 (43) 21 (42) 27 (53) 20 (41)
 A/A1 70 (35) 18 (37) 13 (26) 18 (35) 21 (43)
 B 32 (16) 8 (16) 14 (28) 4 (8) 6 (12)
 AB 8 (4) 2 (4) 2 (4) 2 (4) 2 (4)
BMI 27.2 ± 6.5 28.6 ± 7.2 26.7 ± 7.5 26.8 ± 5.5 26.7 ± 5.8 0.422
Cause of death 0.213
 CVA/stroke 94 (47) 21 (43) 30 (60) 24 (47) 19 (39)
 Head trauma 73 (37) 17 (35) 15 (30) 17 (33) 24 (49)
 Anoxia 28 (14) 9 (18) 4 (8) 9 (18) 6 (12)
 CNS tumor 2 (1) 2 (4) 0 (0) 0 (0) 0 (0)
 Other 2 (1) 0 (0) 1 (2) 1 (2) 0 (0)
ECD 52 (26) 13 (27) 16 (32) 16 (31) 7 (14) 0.159
Admission to brain death (h) 72.2 ± 106.9 82.0 ± 136.2 76.2 ± 109.5 72.9 ± 105.7 58.0 ± 68.3 0.724
Time in ICU before brain death (h) 60.9 ± 100.1 74.8 ± 139.3 59.8 ± 94.7 61.6 ± 96.7 48.8 ± 60.1 0.669
Brain death to organ procurement (h) 31.1 ± 11.2 29.4 ± 11.2 32.5 ± 12.0 30.3 ± 11.7 32.2 ± 9.9 0.476
Randomization to procurement (h) 23.7 ± 8.1 21.6 ± 7.5 24.5 ± 8.7 24.5 ± 7.2 24.3 ± 8.9 0.277
Initiation of hormonal Rx to procurement (h) 16.1 ± 6.3 14.9 ± 5.9 16.8 ± 6.7 16.5 ± 6.5 16.2 ± 6.0 0.509
Use of PA catheter 188 (95) 46 (96) 46 (94) 49 (96) 47 (96) 0.97
Vasopressin at any time 140 (71) 33 (69) 33 (67) 36 (71) 38 (79) 0.574
Vasopressin at time of any VIS determination 112 (56) 28 (57) 25 (50) 29 (57) 30 (61) 0.727
AA, African American; BMI, body mass index; CNS, central nervous system; CVA, cerebrovascular accident; ECD, extended criteria donor; ICU, intensive care unit; PA, pulmonary artery; Rx, prescription; VIS, vasoactive inotrope score.

TABLE 2. - Donor demographics—per protocol
Variable N (%) or mean ± SD P
All Levothyroxine Methylprednisolone Combination Control
N 182 41 37 76 28
Age 42.3 ± 13 42.9 ± 13.8 44.1 ± 12.5 41.3 ± 12.7 41.6 ± 13.8 0.726
Female 68 (37) 17 (41) 14 (38) 29 (38) 8 (29) 0.743
Race 0.666
 White/Caucasian 109 (60) 21 (51) 22 (59) 48 (63) 18 (64)
 Black/AA 61 (34) 19 (46) 12 (32) 21 (28) 9 (32)
 Hispanic/Latino 10 (5) 1 (2) 3 (8) 5 (7) 1 (4)
 Other 2 (1) 0 (0) 0 (0) 2 (3) 0 (0)
Blood group 0.489
 O 82 (45) 16 (39) 15 (41) 40 (53) 11 (39)
 A/A1 63 (35) 16 (39) 11 (30) 23 (30) 13 (46)
 B 29 (16) 7 (17) 9 (24) 11 (14) 2 (7)
 AB 8 (4) 2 (5) 2 (5) 2 (3) 2 (7)
BMI 27.3 ± 6.6 29.0 ± 7.2 27.2 ± 7.6 26.3 ± 5.8 27.6 ± 5.7 0.198
Cause of death 0.083
 CVA/stroke 87 (48) 18 (44) 25 (68) 30 (39) 14 (50)
 Head trauma 68 (37) 14 (34) 11 (30) 34 (45) 9 (32)
 Anoxia 23 (13) 7 (17) 1 (3) 10 (13) 5 (18)
 CNS tumor 2 (1) 2 (5) 0 (0) 0 (0) 0 (0)
 Other 2 (1) 0 (0) 0 (0) 2 (3) 0 (0)
ECD 46 (25) 11 (27) 11 (30) 19 (25) 5 (18) 0.739
Admission to Brain death (h) 68.7 ± 103.6 82.1 ± 145.1 62.1 ± 81.8 68.8 ± 99.3 57.7 ± 65.7 0.771
Time in ICU before brain death (h) 56.7 ± 95.7 74.4 ± 149.4 44.7 ± 53.5 57.7 ± 89.4 46.2 ± 57.2 0.54
Brain death to organ procurement (h) 33 ± 8.4 31.8 ± 8.1 34.0 ± 8.6 34.6 ± 8.6 a 29.2 ± 6.7 a 0.019
Randomization to procurement (h) 23.7 ± 8.1 21.9 ± 7.6 b 23.5 ± 8.6 25.5 ± 8.1 b,c 20.9 ± 7.1 c 0.04
Initiation of hormonal Rx to procurement (h) 16.1 ± 6.3 15.2 ± 5.9 17.2 ± 6.8 16.1 ± 6.6 15.9 ± 5.2 0.564
Use of PA catheter 174 (96) 39 (95) 35 (95) 73 (96) 27 (96) 0.957
Vasopressin at any time 134 (74) 29 (71) 26 (70) 59 (78) 20 (74) 0.797
Vasopressin at time of any VIS determination 107 (59) 24(59) 19 (51) 19 (51) 18 (64) 0.732
aP < 0.05.
bP < 0.05.
cP < 0.05.
AA, African American; BMI, body mass index; CNS, central nervous system; CVA, cerebrovascular accident; ECD, extended criteria donor; ICU, intensive care unit; PA, pulmonary artery; Rx, prescription; VIS, vasoactive inotrope score.

Confirming adequate intravascular volume resuscitation and appropriate weaning of vasopressors based on MAP, invasive hemodynamic measurements and VIS are numerically displayed in Tables S1 (ITT) and S2 (PP) (SDC, https://links.lww.com/TP/C414).

The VIS at 3 time points in each group (t0, t4, and tOR) is displayed in Figure 2A (ITT) and Figure 2B (PP). The VIS declined modestly from t0 to t4 in all but the Levo group. In the ITT analysis, the mean (±SD) reduction in VIS from t0 to tOR was 1.6 ± 2.6, 14.9 ± 2.6, 10.9 ± 2.6, and 7.1 ± 2.6 for the Levo, MP, Combo, and Control groups, respectively. When controlling for baseline score, the VIS at tOR was significantly higher in the Levo group and significantly lower in donors randomized to the MP and Combo groups compared with controls. Results were similar when donors requiring no baseline vasopressor support (VIS = 0 at t0) were removed from the analyses. Relative reductions in VIS were similar in the PP analysis, although the Levo group was no longer significantly different from Control group (P = 0.455). Additionally, because of a reduction in baseline (t0) VIS, the MP group trended toward significance (P = 0.022) in this analysis. We also analyzed the change in donor CI from t0 to tOR and found no significant difference between groups in similarly adjusted analyses (Figures 3A and B).

F2
FIGURE 2.:
A and B, Donor VIS by treatment group measured at baseline (t0), 4 h after initiation of hormonal therapy (t4), and just before procurement (tOR). Results are expressed as mean ± SEM. P values for least squares mean differences between groups at tOR are adjusted for baseline values and for multiple comparisons using the Bonferroni method with 2-sided alpha = 0.017 for significance. ITT, intention-to-treat; PP, per-protocol; VIS, vasoactive inotrope score.
F3
FIGURE 3.:
A and B, Donor CI by treatment group measured at baseline (t0), 4 h after initiation of hormonal therapy (t4), and just before procurement (tOR). Results are expressed as mean ± SEM. P values for least squares means differences between groups at tOR are adjusted for baseline values and for multiple comparisons using the Bonferroni method with 2-sided alpha = 0.017 for significance. CI, cardiac index; ITT, intention-to-treat; PP, per-protocol.

TH levels are displayed in Table 3 and represent the PP population. Mean baseline levels of thyroid-stimulating hormone were in the normal range and remained so regardless of treatment. Baseline levels of total T4, free T4, and total triiodothyronine (T3) were at the lower end of their respective normal ranges, with 52.3% of total T3 values below the lower limit of normal (LLN). Mean baseline free T3 levels were slightly below the LLN with 67.8% being below the LLN, whereas reverse T3 levels were all above the upper limit of normal.

TABLE 3. - Thyroid hormone levels—per protocol
Variable Mean ± SD (% <LLN:WNL:>ULN) P
Levothyroxine Methylprednisolone Combination Control
N 38 36 73 25
Total T4 (4.5–10.9 µg/dL) t0 5.93 ± 2.64 5.72 ± 2.31 5.39 ± 2.22 5.86 ± 1.75 0.625
(33.3:63.9:2.8) (36.1:63.9:0.0) (35.6:61.6:2.7) (25.0:75.0:0.0)
t4 11.78 ± 5.41 6.13 ± 2.56 9.22 ± 4.19 5.69 ± 1.68 <0.001
(10.8:40.5:48.6) (33.3:63.9:2.8) (12.3:60.3:27.4) (21.7:78.3:0.0)
tOR 23.99 ± 6.65 5.80 ± 2.27 23.32 ± 8.07 6.34 ± 1.55 <0.001
(0.0:2.9:97.1) (40.0:60.0:0.0) (0.0:4.5:95.5) (16.0:84.0:0.0)
Free T4(0.89–1.76 ng/dL) t0 0.94 ± 0.35 0.92 ± 0.32 0.88 ± 0.24 0.99 ± 0.25 0.318
(44.4:52.8:2.8) (50.0:47.2:2.8) (50.7:49.3:0.0) (29.2:70.8:0.0)
t4 2.29 ± 1.43 1.02 ± 0.43 1.77 ± 1.31 0.98 ± 0.23 < 0.001
(10.8:29.7:59.5) (38.9:58.3:2.8) (13.7:50.7:35.6) (29.2:70.8:0.0)
tOR 6.75 ± 2.61 1.01 ± 0.33 6.48 ± 2.78 1.11 ± 0.25 <0.001
(0.0:0.0:100) (37.1:60.0:2.9) (0.0:7.6:92.4) (20.0:80.0:0.0)
Total T3 (60–181 ng/dL) t0 78.39 ± 56.54 65.25 ± 30.98 61.32 ± 31.36 68.83 ± 37.76 0.184
(47.2:47.2:5.6) (50.0:50.0:0.0) (58.9:39.7:1.4) (45.8:54.2:0.0)
t4 87.54 ± 48.45 64.78 ± 32.23 65.92 ± 29.53 67.25 ± 32.70 0.014
(24.3:70.3:5.4) (54.1:45.9:0.0) (49.3:50.7:0.0) (37.5:62.5:0.0)
tOR 148.76 ± 65.63 63.37 ± 29.49 118.30 ± 57.11 74.60 ± 34.87 <0.001
(8.8:58.8:32.4) (51.4:48.6:0.0) (6.1:86.4:7.6) (40.0:60.0:0.0)
Free T3 (2.3–4.2 pg/mL) t0 2.27 ± 1.06 1.98 ± 0.71 1.93 ± 0.77 2.10 ± 0.92 0.224
(61.1:33.3:5.6) (69.4:27.8:2.8) (72.6:26.0:1.4) (73.9:21.7:4.3)
t4 2.69 ± 1.12 1.98 ± 0.75 2.10 ± 0.79 2.11 ± 0.82 0.002
(35.1:56.8:8.1) (75.7:21.6:2.7) (64.4:34.2:1.4) (66.7:29.2:4.2)
tOR 4.96 ± 2.16 1.99 ± 0.71 3.83 ± 1.70 2.49 ± 1.21 <0.001
(5.9:32.4:61.8) (60.0:37.1:2.9) (10.6:59.1:30.3) (64.0:28.0:8.0)
Reverse T3(90–350 pg/mL) t0 386.58 ± 298.80 408.80 ± 298.04 405.19 ± 285.04 400.45 ± 252.67 0.987
(0:0:100) (0:0:100) (0:0:100) (0:0:100)
tOR 1445.59 ± 1239.26 612.38 ± 404.41 2334.68 ± 2310.03 497.50 ± 260.87 <0.001
(0:0:100) (0:0:100) (0:0:100) (0:0:100)
TSH (0.35–5.5 mIU/L) t0 2.44 ± 2.70 1.77 ± 2.85 1.42 ± 2.04 1.39 ± 1.46 0.155
(17.1:74.3:8.6) (27.8:66.7:5.6) (21.9:75.3:2.8) (20.8:75.0:4.2)
t4 2.92 ± 2.60 1.80 ± 1.92 1.67 ± 2.15 1.57 ± 1.36 0.022
(16.2:70.3:13.5) (18.9:70.3:8.1) (12.5:83.3:4.2) (20.0:76.0:4.0)
tOR 2.86 ± 2.47 1.91 ± 1.49 1.85 ± 2.40 2.69 ± 1.73 0.081
(14.7:73.5:11.8) (8.6:88.6:2.8) (10.6:86.4:3.0) (12.0:80.0:8.0)
LLN, lower limit of normal; t0, time 0 (baseline); t4, time 4 h; tOR, time of procurement; T3, triiodothyronine; T4, levothyroxine; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; WNL, within normal limits.

TH levels did not change significantly from baseline to procurement in the MP and Control groups. T4 was infused to a mean cumulative dose of 3238 ± 1412 µg (range, 600–5720 µg) in the Levo group and 3098 ± 1661 µg (range, 250–6670 µg) in the Combo group. Excepting thyroid-stimulating hormone, the infusion of T4 significantly increased all TH levels. The proportion of donors with free T3 levels below the LLN decreased from 61.1% to 5.9% and from 72.6% to 10.6% in the Levo and Combo groups, respectively. Reverse T3 levels increased in all groups, but the increase was significant only in the Levo and Combo groups. In keeping with the known effect of corticosteroids on T4 deiodination patterns, we observed a strong trend (P = 0.061) toward greater increase of reverse T3 in the Combo group compared with the Levo group.

TH ratios (Table 4) remained unchanged in the MP and Control groups. With T4 infusion, as expected, the total T3/total T4 and free T3/free T4 ratios significantly decreased. At the doses delivered, the free T4/total T4 ratio significantly increased, suggesting saturation of T4 binding sites, whereas the free T3/total T3 ratio remained unchanged.

TABLE 4. - Thyroid hormone ratios—per protocol
Variable Mean ± SD P
Levothyroxine Methylprednisolone Combination Control
N 38 36 73 25
Total T3/total T4 t0 13.36 ± 5.91 12.64 ± 6.46 12.08 ± 5.08 11.79 ± 5.10 0.639
t4 8.31 ± 4.39 11.71 ± 5.12 7.96 ± 3.67 11.91 ± 5.10 <0.001
tOR 6.11 ± 1.94 11.37 ± 4.13 5.24 ± 2.08 11.61 ± 4.07 <0.001
Free T4/total T4 t0 0.174 ± 0.056 0.175 ± 0.054 0.182 ± 0.064 0.178 ± 0.039 0.909
t4 0.193 ± 0.053 0.178 ± 0.049 0.189 ± 0.066 0.181 ± 0.039 0.651
tOR 0.276 ± 0.067 0.186 ± 0.049 0.278 ± 0.103 0.180 ± 0.033 <0.001
Free T3/free T4 t0 2.41 ± 0.65 2.23 ± 0.61 2.19 ± 0.55 2.12 ± 0.71 0.241
t4 1.14 ± 0.66 2.01 ± 0.55 1.54 ± 0.88 2.15 ± 0.61 <0.001
tOR 0.77 ± 0.25 2.01 ± 0.44 0.71 ± 0.46 2.23 ± 0.85 <0.001
Free T3/total T3 t0 0.033 ± 0.011 0.033 ± 0.008 0.033 ± 0.007 0.031 ± 0.009 0.846
t4 0.033 ± 0.008 0.033 ± 0.009 0.034 ± 0.008 0.033 ± 0.007 0.956
tOR 0.034 ± 0.007 0.034 ± 0.008 0.033 ± 0.005 0.035 ± 0.007 0.609
t0, time 0 (baseline); t4, time 4 h; tOR, time of procurement; T3, triiodothyronine; T4, levothyroxine.

Cortisol levels are displayed in Table 5. Mean baseline cortisol levels are in the middle of the normal range; however, 21.8% were below the LLN, 48.3% <10 µg/dL, and 75.3% <20 µg/dL. In the Levo and Control groups, these levels did not significantly change from baseline to procurement; however, the proportion of these donors with levels below the LLN decreased to 13.8%, whereas levels in 68.8% remained <20 µg/dL. Treatment with supraphysiologic doses of MP substantially interfered with the cortisol assay used and these values are not reported.

TABLE 5. - Cortisol, CRP, and inflammatory cytokine levels—per protocol
Variable Mean ± SD(% <LLN:<10 µg/dL:<20 µg/dL) P
Levothyroxine Methylprednisolone Combination Control
N 38 36 73 25
Cortisol (3.4–22.5 µg/dL) t0 12.1 ± 12.1 11.7 ± 9.4 13.5 ± 11.2 13.0 ± 10.6 0.850
(25.0:58.3:80.6) (25.0:50.0:72.2) (20.5:50.0:72.2) (20.8:41.7:83.3)
t4 14.2 ± 18.3 12.1 ± 10.6
(18.9:56.8:75.0) (12.5:54.2:87.5)
tOR 15.1 ± 14.2 14.7 ± 11.4
(17.6:41.7:72.2) (8.0:44.0:64.0)
Mean ± SD (% WNL:>ULN)
CRP(<1 mg/dL) t0 15.5 ± 9.8 13.6 ± 9.4 15.9 ± 9.7 17.4 ± 9.4 0.497
(2.8:97.2) (0:100) (1.4:98.6) (0:100)
t4 16.4 ± 9.1 16.4 ± 9.9 18.0 ± 10.1 18.6 ± 8.6 0.685
(2.7:97.3) (0:100) (2.7:97.3) (0:100)
tOR 20.9 ± 9.3 20.6 ± 9.5 24.0 ± 11.1 23.7 ± 9.9 0.285
(0:100) (0:100) (0:100) (0:100)
Mean ± SD
Methylprednisolone + combination Levothyroxine + control P
Inflammatory cytokines
 N 16 15
 INF-γ (0–40 pg/mL) t0 4.5 ± 4.0 4.7 ± 3.4 0.118
tOR 2.1 ± 1.8 4.3 ± 3.9
 IL-1β(0–14.8 pg/mL) t0 9.3 ± 11.2 5.8 ± 4.7 0.117
tOR 7.1 ± 8.2 5.5 ± 6.7
 IL-1Ra(0–166 pg/mL) t0 286.23 ± 563.9 72.3 ± 119.8 0.063
tOR 41.5 ± 81.8 122.8 ± 213.8
 IL-5 (0–1.1 pg/mL) t0 3.6 ± 5.5 4.8 ± 4.2 0.055
tOR 1.5 ± 1.6 6.3 ± 5.9
 IL-6 (0–39.6 pg/mL) t0 652.6 ± 1007.7 403.8 ± 432.5 0.042
tOR 61.9 ± 59.219 418.4 ± 418.1
 IL-8(0–25.3 pg/mL) t0 47.8 ± 108.9 6.5 ± 6.0 0.127
tOR 12.0 ± 31.9 4.4 ± 6.4
 IL-10 (0–45.6 pg/mL) t0 31.7 ± 52.3 17.3 ± 19.9 0.944
tOR 25.9 ± 26.8 12.1 ± 9.4
 IL-12p40 (0–130 pg/mL) t0 40.0 ± 32.2 43.6 ± 41.6 0.009
tOR 22.9 ± 21.4 48.7 ± 52.0
 MCP-1 (70.7–675.0 pg/mL) t0 316.0 ± 172.3 330.3 ± 227.3 0.481
tOR 239.4 ± 180.8 317.7 ± 244.4
 TNF-α(4.4–58.7 pg/mL) t0 46.4 ± 43.4 46.3 ± 20.4 0.030
tOR 19.7 ± 11.9 45.6 ± 26.8
CRP, C-reactive protein; IFN, interferon; IL, interleukin; LLN, lower limit of normal; MCP-1, monocyte chemoattractant protein-1; t0, time 0 (baseline); t4, time 4 h; tOR, time of procurement; T3, triiodothyronine; T4, levothyroxine; TNF-α, tumor necrosis factor alpha; ULN, upper limit of normal; WNL, within normal limits.

Levels of multiple inflammatory markers are displayed in Table 5. CRP levels were high at baseline and increased slightly over time in all groups. We found no significant treatment effect of steroid administration. Plasma levels of 15 proinflammatory cytokines were measured in a small subset of donors. Because of small numbers, treatment groups were combined to reflect MP versus no MP dosing. In this limited data set, levels of interleukin (IL)-2, IL-4, IL-12p70, IL-13, and granulocyte-macrophage colony-stimulating factor were below the range of detection in at least 30% of samples and are not reported. Mean levels of IL-5 and IL-6 were elevated above their reported upper limits of normal. From t0 to tOR, MP administration significantly reduced the levels of IL-6, IL-12p40, and tumor necrosis factor alpha (TNFα), whereas levels of IL-5 showed a strong trend toward reduction (P = 0.055).

We found no inverse correlation between free T3 levels or cortisol levels and VIS at baseline. Additionally, there was no correlation between free T3 levels and VIS at tOR. We noted significant positive correlation between baseline IL-6 levels and VIS (r = 0.403, P = 0.022); we found no correlation between any other cytokine and VIS at baseline or procurement.

Organ-specific yield and transplant rates are shown in Tables 6 and 7. Of 1272 organs consented for procurement, a total of 725 (57%) were recovered for transplantation, yielding 3.64 organs/donor. The only significant difference among groups was the proportion of lungs recovered in the Control group compared with the Levo group in the ITT analysis. This finding was not present in the PP analysis.

TABLE 6. - Organ yield and transplantation rate—intention to treat
Variable N (%) or mean ± SD P
All Levothyroxine Methylprednisolone Combination Control
Organ yield  (% of consented organs) 725 (57) 162 (53) 172 (55) 190 (59) 201 (61) 0.158
Organ yield/donor 3.6±1.8 3.3±1.8 3.4±1.8 3.7±1.8 4.1±1.9 0.141
Organ-specific yield
 Heart 65 (41) 11 (28) 15 (38) 18 (47) 21 (51) 0.155
 Lung 115 (32) 20 (24) a 26 (29) 29 (32) 40 (43) a 0.045
 Liver 169 (86) 42 (86) 40 (82) 43 (84) 44 (94) 0.362
 Kidney 344 (88) 82 (84) 83 (88) 92 (90) 87 (91) 0.413
 Pancreas 32 (27) 7 (26) 8 (32) 8 (27) 9 (26) 0.950
 Intestine 0 (0)
Transplant rate  (% of recovered organs) 616 (85) 128 (79) 148 (86) 158 (83) 182 (91) 0.933
Organ-specific transplant rate
 Heart 65 (100) 11 (100) 15 (100) 18 (100) 21 (100) 1.000
 Lung 108 (94) 19 (95) 24 (92) 26 (90) 39 (98) 0.557
 Liver 145 (86) 35 (83) 34 (85) 37 (79) 42 (95) 0.158
 Kidney 277 (81) 58 (71) 69 (83) 75 (82) 75 (86) 0.065
 Pancreas 21 (66) 5 (71) 6 (75) 5 (63) 5 (56) 0.836
aP < 0.05.

TABLE 7. - Organ yield and transplantation rate—per protocol
Variable N (%) or mean ± SD P
All Levothyroxine Methylprednisolone Combination Control
Organ yield  (% of consented organs) 725 (61) 156 (60) 141 (57) 323 (65) 105 (57) 0.210
Organ yield/donor 4.0 ± 1.5 3.8 ± 1.4 3.8 ± 1.6 4.3 ± 1.5 3.8 ± 1.6 0.257
Organ-specific yield
 Heart 65 (41) 11 (34) 14 (47) 33 (52) 7 (33) 0.291
 Lung 115 (32) 20 (29) 20 (29) 57 (41) 18 (35) 0.238
 Liver 169 (86) 40 (98) 33 (89) 69 (93) 27 (96) 0.475
 Kidney 344 (88) 78 (95) 67 (93) 149 (98) 50 (93) 0.153
 Pancreas 32 (27) 7 (30) 7 (35) 15 (31) 3 (17) 0.615
 Intestine 0 (0)
Transplant rate  (% of recovered organs) 616 (85) 125 (80) 120 (85) 277 (86) 94 (89) 0.819
Organ-specific transplant rate
 Heart 65 (100) 11 (100) 14 (100) 33 (100) 7 (100) 1.000
 Lung 108 (94) 19 (95) 18 (90) 53 (93) 18 (100) 0.608
 Liver 145 (86) 34 (85) 28 (85) 57 (83) 26 (96) 0.382
 Kidney 277 (81) 56 (72) 55 (82) 124 (83) 42 (84) 0.174
 Pancreas 21 (66) 5 (71) 5 (71) 10 (67) 1 (33) 0.659

A total of 616 organs were transplanted (85% of organs recovered). Ultimately, 544 patients received 571 organs from the 199 donors in this study, including 473 single organ, 44 double lung, 15 kidney-pancreas, 10 liver-kidneys, 1 heart-kidney, and 1 heart–double lung transplants.

We received recipient outcomes information for 521 of 571 transplanted organs (90.3% response rate). Organ-specific outcomes are shown in supplemental Table S3 (SDC, https://links.lww.com/TP/C414). As donor treatment crossovers occurred early in donor management, these data are presented as a PP safety analysis. We found no differences in patient or graft survival among the treatment groups.

DISCUSSION

HRT has been recommended to improve hemodynamic stability by allowing reduction or elimination of potentially detrimental catecholamine vasopressors, improve marginal heart function resulting from myocardial stunning, and increase the number of suitable organs for transplantation. Recent meta-analyses of TH use18-20 and corticosteroid use18,19,21 have not consistently demonstrated efficacy, mainly because of small numbers in the few randomized trials and lack of suitable controls in the many observational studies. In addition, varied treatment regimens, dosing, timing of administration, and endpoints have led to substantial disparity of results.

Hypotension after brain death is nearly universal. Between 2010 and 2020, data from the Scientific Registry of Transplant Recipients showed no organs were recovered from 1892 donors (1.8%) because of hemodynamic instability, resulting in the potential loss of up to 1085 hearts, 1585 double lungs and 728 livers (Scientific Registry of Transplant Recipients; email communication, October 5, 2021). Additionally, highlighting the need for more granular data, the US Organ Procurement and Transplantation Network has recently updated organ refusal codes to include donor instability/high vasopressor usage.

Though some donors respond to volume loading, many require vasopressor support to maintain adequate perfusion pressure to target organs. Intense vasoconstriction from high-dose catecholamines, especially norepinephrine, seems to be detrimental to potentially transplantable hearts, whereas lower-dose support with dopamine may improve kidney and heart function.22-25 Although a recent retrospective study showed no difference in 1-y mortality between heart recipients from donors supported with no versus low- versus high-dose norepinephrine, the authors concluded that their results apply to selected favorable donor–recipient sex combinations with anticipated short ischemic times.26 Thus, the preponderance of evidence suggests that maintenance of hemodynamic stability, while weaning catecholamine vasopressors remains a priority in deceased organ donor management.

The current study was designed to determine whether early administration of T4, MP, or their combination would improve hemodynamic stability measured by reduction in vasopressor requirements. In both ITT and PP analyses, we found a significant reduction in vasopressor use (VIS) in donors treated with high-dose MP (alone or in combination with high-dose T4) compared with T4 alone or controls.

In a blinded, randomized trial, Venkateswaran et al13 reported no improvement in CI with T3, MP, or both over control. This trial differed from our study in several important ways. The dose of MP used in their study was approximately half that used in ours, which, combined with the relatively short duration of treatment (6.9 ± 1.3 versus 16.1 ± 6.3 h), may have subverted any benefit. Vasopressor agents and doses were not quantified. This confounds any putative treatment effect on CI. Our study takes this into consideration and includes vasopressin in the calculation of the VIS. Although comparatively large, their sample size may have been inadequate for their primary endpoint. Confirming their findings, we found no significant change in CI attributable to any hormonal treatment.

Brain death-associated perturbations of pituitary-derived hormones undoubtedly contribute to hemodynamic derangement and the need for vasopressor support. The extent of hormone depletion has been most severe in animal models that used a sudden increase in intracranial pressure to produce brain death.27,28 Novitzky et al29 later demonstrated reversal of anaerobic metabolism and resolution of lactic acidosis with administration of TH in a baboon model. Subsequent publications have attributed most of the hemodynamic benefit of donor HRT to TH replacement.

The extent of TH depletion in human brain-dead organ donors is highly variable.3,11,30 Despite the lack of demonstrated benefit, many US organ procurement organizations administer TH to the majority of their donors.31 Our study noted 67.8% of donors with free T3 below the LLN at baseline and 61.6% at procurement in those not receiving T4. The administration of exogenous T4 provided adequate substrate for conversion to T3, increasing free T3 levels to or above the normal range in the vast majority of donors. Despite this, we found no significant improvement in VIS compared with controls and no correlation between free T3 levels and VIS either at baseline or procurement.

Free T3 has known vascular effects that increase cardiac preload and decrease afterload. Myocardial effects that manifest within hours of TH administration include downregulation of genes regulating phospholamban and upregulation of ryanodine channel, sarcoplasmic endoplasmic reticular calcium adenosine triphosphatase 2, and beta-adrenergic receptor genes.32 These changes contribute to increased chronotropy, inotropy, and lusitropy, resulting in increased cardiac output that may be useful in resuscitating marginal donor hearts8,12 and may have contributed to the more robust reduction of VIS in the Combo group compared with the MP group. However, these positive cardiac effects come at the cost of increased ATP utilization.32 Two recent publications by Peled et al33,34 provide a cautionary note, reporting higher rates of primary graft dysfunction in hearts from donors given TH, postulating a TH withdrawal effect in the setting of beta receptor upregulation. Another possibility is that with significantly increased ATP turnover, along with continued, albeit reduced, consumption in static cold storage, TH may contribute to severely reduced mitochondrial energy stores in treated hearts.

Corticosteroids are important regulators of vascular tone during homeostasis and in the setting of inflammation, and have been shown to enhance responsiveness to catecholamine vasopressors and angiotensin II.35,36 Additionally, activation of certain glucocorticoid response elements in the nucleus of multiple cell types downregulates the transcription of many cytokines and other inflammatory mediators.36

Treatment of donors with corticosteroids has had mixed results related to the endpoint studied. Some studies have shown improvement in donor hemodynamics when corticosteroids were used as part of a 2- or 3-component HRT regimen, always in conjunction with TH.37,38 In agreement with our findings, 2 recent nonrandomized trials of low-dose hydrocortisone after brain death resulted in a lower mean dose of vasopressors, shorter duration of vasopressor support, and a higher probability of norepinephrine weaning in the steroid treatment groups.39,40

Severe brain injury/death constitutes a highly stressed state in which cortisol levels would be expected to be above the normal range. Critical illness-related corticosteroid insufficiency (CIRCI) has been defined as failure to increase cortisol by ≥9 µg/dL following cosyntropin (250 µg) or as random plasma cortisol <10 µg/dL.41 In our study, random cortisol levels in 21.8% were below the LLN, whereas 48.3% met criteria for CIRCI at baseline and, absent steroid dosing, 42.6% at procurement. Although the doses of MP used were supraphysiologic, our study does not address other potential contributors to CIRCI.

Linked to CIRCI, and a profound contributor to systemic vasoplegia, is the severe inflammatory state mediated by increases of multiple systemic proinflammatory cytokines including IL-1, IL-6, TNFα, CRP, and procalcitonin,5,6,42,43 In a randomized trial by Venkateswaran et al,6 MP was administered as a single 1000-mg dose. Although this should have corrected any cortisol deficiency, they reported no effect on multiple proinflammatory markers. Two other studies demonstrated significant reduction in multiple cytokines using a lower-dose MP bolus followed by infusion42 or repeated dosing.44 These findings mimic the clinical response to lower dose/prolonged infusion of corticosteroids in septic shock. Although sample size was limited, we demonstrated significant declines in levels of several cytokines with high-dose MP. This could be related to the high initial dose used or to repeat dosing.

Several studies have shown combination HRT to be useful in maximizing the number of total organs and number of thoracic organs recovered.7-10 Although we found no difference in organ yield, transplantation rates, or recipient outcomes, the present study had insufficient power to determine treatment effects on these endpoints. However, given the higher-than-standard dosing of HRT, we report these as safety endpoints.

Limitations

Although ours is the largest randomized trial of combination HRT to date, it has several important limitations. Despite its size, it is underpowered for organ yield and recipient outcomes, important secondary endpoints. Although pulmonary artery catheter use to guide donor management is less frequent today, it allowed more certainty in achieving target hemodynamic goals and confirmed adequate volume resuscitation, thus eliminating these as confounders. Donors were managed by organ procurement organization personnel rather than by intensivist physicians.

In this study, vasopressin was used specifically to treat diabetes insipidus rather than as a vasopressor. Although this may be a confounder, we feel any effect would be minimal as the proportion of donors treated with vasopressin was not different between groups in either analysis and its use was accounted for in the calculation of the VIS.

The lack of blinding and donor coordinator bias in favor of T4 replacement may have contributed to the substantial crossover to the Combo group and fewer appropriate crossovers from the Levo group. Despite this, the effect of MP alone and combined with T4 on reducing VIS was significant in the ITT analysis. In the PP analysis, the effect of combination treatment on reducing VIS remained significant, whereas MP alone demonstrated a strong trend compared with controls.

Finally, data accumulation for this study started 10 y ago. Unfortunately, administrative issues precluded earlier reporting of the results found in this article. Despite the lengthy delay, with the exception of newer guidelines recommending vasopressin as a first-line pressor agent,45-47 donor management strategies continue to emphasize vasopressor weaning. Thus, our findings remain relevant today.

CONCLUSIONS

HRT using high-dose MP alone or in combination with T4 allowed for significant reduction in catecholamine-based vasopressors during management of brain-dead organ donors. Despite achievement of normal or supraphysiologic levels of free T3 in most donors, T4 infusion alone had no effect on vasopressor requirements. These findings suggest that treatment of CIRCI and the systemic inflammatory state with corticosteroids has a greater impact on donor hemodynamic stability than TH replacement.

Though underpowered for several other endpoints, we found no adverse effect of high-dose HRT on organ yield, transplantation rates, or recipient outcomes. Our data strongly argue against the routine use of TH in donor management and lend substantial support to the same recommendation made in a recent Canadian clinical practice guideline.47 Future studies are needed to elucidate the role of TH in the setting of marginal cardiac function and to identify the most appropriate specific corticosteroid, as well as the dose and timing needed to reverse CIRCI and reduce inflammatory cytokine levels.

ACKNOWLEDGMENTS

The authors are grateful to Anna Alishauskas at We Are Sharing Hope SC for her assistance in database construction and management and to Viswanathan Ramakrishanan, PhD, for his guidance and assistance in statistical analysis for this article.

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