Experimental studies at the University of Cape Town in the 1980s confirmed that, after the induction of brain death in a baboon, an “autonomic storm” occurred, which was associated with rapid declines in plasma levels of thyroid hormones (free triiodothyronine [T3], free levothyroxine [T4]), cortisol, insulin, and antidiuretic hormone [ADH] (1) reviewed by Cooper et al. (2)). Brain-dead animals became unable to aerobically metabolize radiolabeled metabolites administered intravenously (2, 3) (Supplementary Introduction, SDC,https://links.lww.com/TP/A984). These metabolic changes were associated with a decline in myocardial function. Replacement of certain hormones improved the metabolic and hemodynamic status of the brain-dead animal. Hormonal therapy that included T3 was first administered to a series of brain-dead potential organ donors in 1984 with excellent outcome (2, 4, 5) (Supplementary Introduction, SDC,https://links.lww.com/TP/A984).
After these initial reports, multiple small studies of hormonal therapy were reported with varying outcome (2, 6) possibly because, in clinical practice, the rates of depletion of T3/T4 and other hormones vary greatly. For several years, relatively few transplant groups administered T3/T4.
In 2001, the United Network for Organ Sharing (UNOS) performed a retrospective analysis of all brain-dead potential donors from January 2000 to September 2001, inclusive (7, 8). Multivariate studies revealed significant increases in the number of transplantable organs when hormonal treatment was given (9–11) and an improvement in the 1-year survival of kidneys and hearts after transplantation when T3/T4 had been administered to the donor (10–12). Guidelines were developed for maximizing the number of organs recovered and transplanted from deceased donors (7, 8, 13). Hormonal resuscitation therapy gradually became more widely accepted as being beneficial (2, 6, 12), but at the level of the individual Organ Procurement Organization, there remained considerable variability in its use (14). Indeed, two recent meta-analyses (15, 16) concluded that there were insufficient data to “support a role for routine administration of thyroid hormone in the brain-dead potential organ donor” (15) or that the study suggested “limited efficacy of interventions focusing on the management of brain-dead donors” (16).
Although it is difficult to determine the exact numbers, a significant number of brain-dead potential donors are lost from the donor pool owing to progressive acidosis and hemodynamic instability, which becomes refractory to high-dose inotropic support (17, 18). There is a constant organ shortage for purposes of transplantation, and any intervention that increases the donor organ pool should surely be welcome.
Currently, hormonal therapy can include the administration of four hormones as follows: thyroid (T3 or T4), a corticosteroid, ADH (e.g., desmopressin [1-deamino-8-d-arginine vasopressin, DDAVP), and insulin (Table S1, SDC,https://links.lww.com/TP/A984). We have now reviewed data provided by UNOS on hormonal resuscitation therapy in the management of 66,629 brain-dead potential organ donors in the 10-year period, 2000 to 2009. To our knowledge, this retrospective analysis is the largest to date.
In the 10-year period, 71,571 donors were registered with UNOS, but 4,942 were excluded as non–heart beating (or heart-beating status uncertain), and 3,036 were excluded because T3/T4 treatment information was not recorded (Figure S1, SDC,https://links.lww.com/TP/A984). The remaining 63,593 potential donors (mean age, 39.79±19.12 years) included 37,263 males (58.6%; mean age, 37.50±18.74 years) and 26,330 females (41.4%; mean age, 43.04±19.19 years).
Of the 63,593 donors, 30,962 (48.69%) received T3/T4 therapy (with or without other undetermined hormonal therapy) and 32,631 (51.31%) received no T3/T4 (but may have received other hormonal therapy). Of those who received T3/T4, a mean of 3.35±1.76 organs was procured, whereas of those who did not receive T3/T4, the mean was 2.97±1.72 organs, a 12.8% increase when T3/T4 was administered (P<0.0001).
Of the total 40,124 potential donors, group A consisted of 23,022 (57.38%) and group B of 17,102 (42.62%) (Table 1).
Percentage of Organs Procured or Transplanted
In group A, 76,183 organs were procured from 23,022 donors (a mean of 3.31±1.78 organs per donor) (Table 1). In group B, 49,101 organs were procured from 17,102 donors (a mean of 2.87±1.74 organs per donor) (Table 1), an increase in organs procured in group A of 15.3% (P<0.0001).
A greater number of organs was procured from every subgroup of group A compared with group B (all P<0.0001) (Table 2), the highest procurement rate being in the subgroup receiving a combination of T3/T4, corticosteroid, ADH, and insulin (subgroup A1: 3.52±1.74 organs per donor).
The effect of ADH, corticosteroids, or insulin on organ procurement or transplantation is indicated in Table 3. Antidiuretic hormone was always beneficial and corticosteroids were beneficial in some subgroups, particularly when T3/T4 had not been administered (group B). However, when insulin was administered, in one subgroup of group A (A5 vs. A6), the yield of organs was significantly reduced when compared with the subgroup treated identically but without insulin.
Procurement and Transplantation Rates of Individual Organs
The rate of procurement of the various organs was considered individually.
Treatment with T3/T4 (group A) demonstrated a significant impact in increasing the number of procured hearts (Table 4), irrespective of the other hormones administered (group B). The percentages of hearts procured from groups A and B were 34.99% and 25.76%, respectively, an increase of 9.23% in group A (P<0.0001). All subgroups of group A showed a beneficial effect of T3/T4 compared with the corresponding subgroup of group B.
Antidiuretic hormone was always and corticosteroids were sometimes (but only in group B) beneficial (Table 5), but in one subgroup of group A (A5 vs. A6), the administration of insulin was associated with a significant reduction in the number of hearts procured compared with the corresponding subgroup in which insulin was not administered.
When both lungs could be procured from a single donor (and transplanted into the same recipient or into two different recipients), an overall beneficial effect of T3/T4 was observed (Table 4). Both lungs were procured from 17.53% of the group A donors and from 12.51% of the group B donors, an increase of 5.02% in group A (P<0.0001). T3/T4 was significantly beneficial in every subgroup except between A5 and B5 (P=0.0624, after Bonferroni-Holm adjustment).
Antidiuretic hormone and corticosteroids were beneficial in several subgroups, with corticosteroids again being beneficial particularly when T3/T4 was not administered (Table 5). In one subgroup of group B (B5 vs. B6), insulin therapy was associated with a significantly increased number of lungs being procured, and in no case was insulin therapy associated with a reduction in lungs procured.
When it was possible to procure only a single lung, for example, because of trauma to the second lung, aspiration into one bronchial tree, T3/T4 therapy again increased the rate of procurement (Table 1). The procurement rate in group A was 798 from 23,022 donors (3.47%) and that in group B was 442 from 17,102 donors (2.58%), an increase of 0.89% in group A (P<0.0001). Because the numbers in each subgroup were very small, we did not determine whether there were any significant differences in procurement rate.
When the numbers of donors from which only one lung was procured were added to those from which two lungs were procured (group A, n=4,833; group B, n=2,581), the percentage of lungs procured remained significantly greater in group A (20.99%) than in group B (15.09%), an increase of 5.90% in group A (P<0.0001).
When both kidneys could be procured from a single donor (whether these were transplanted into one or two recipients) the beneficial effect of T3/T4 therapy on the procurement/transplantation rate was marked (Table 4). Both kidneys were procured from 73.24% of the group A donors, whereas this was possible in only 64.37% of the group B donors, an increase of 8.87% in group A (P<0.0001). Significantly more kidneys were procured in each subgroup of group A, except one (A2 vs. B2).
Antidiuretic hormone was uniformly beneficial, but corticosteroids were only beneficial in two subgroups in group B (Table 5). There was a trend in both groups A and B for insulin administration to be associated with a reduced procurement of kidneys, but in no case was this statistically significant.
When it was possible to procure only a single kidney, for example, because of trauma to the other kidney, T3/T4 therapy had no beneficial effect on procurement (Table 1). The procurement rate in group A was 1,566 from 23,022 donors (6.80%) and that in group B was 1,234 from 17,102 donors (7.22%) (P=0.1595). The numbers in each subgroup did not show any significant differences (not shown).
When the numbers of donors from which only one kidney was procured were added to those from which two kidneys were procured (group A, n=18,427; group B, n=12,243), the percentage of kidneys procured was still significantly greater in group A (80.04%) than in group B (71.59%), an increase of 8.45% in group A (P<0.0001).
In the absence of information on final disposition (i.e., whether the liver was transplanted), data on 481 donors (group A, n=303; group B, n=178) were excluded from the analysis.
There was no overall beneficial effect of T3/T4 therapy on procurement of the liver (Table 4). In only one subgroup (A1 vs. B1) was there a significant increase in procurement associated with T3/T4 therapy (P<0.05).
In contrast to T3/T4, ADH had a beneficial effect in all subgroups (Table 5). Corticosteroids proved beneficial in four subgroups (group A, n=2; group B, n=2). There was again a trend for insulin therapy to be associated with no or minimal benefit, particularly in group B, but this was significantly detrimental in only one instance (B1 vs. B2).
In the absence of information on final disposition, data on three donors (group A, n=2; group B, n=1) were excluded from the analysis.
T3/T4 had a marked overall beneficial effect on procurement of the pancreas (Table 4). In group A, the pancreas was procured from 21.35% of the donors, whereas in group B, it was procured from only 15.68%, an increase of 5.67% in group A (P<0.0001). In every subgroup except one (A8 vs. B8), T3/T4 therapy had a significantly beneficial effect on the number of pancreases procured.
Antidiuretic hormone was uniformly beneficial, but corticosteroids were beneficial in only one subgroup of each of groups A and B (Table 5). Insulin was uniformly associated with a reduced number of pancreases procured, but this was statistically significant in only two subgroups in group A and two in group B.
In the absence of information on final disposition, data on four donors (group A, n=3; group B, n=1) were excluded from the analysis.
There was a small overall beneficial effect of T3/T4 therapy on procurement of the intestine (P<0.05) (Table 4). In two of the eight subgroups (A6 vs. B6, A7 vs. B7), there were significant increases in the number of intestines procured from the group A donors (P<0.05 and P<0.025, respectively). The small numbers may have influenced the statistical analysis.
Antidiuretic hormone proved beneficial in three subgroups (group A, n=1; group B, n=2), but corticosteroids had no benefit (Table 5). Insulin was associated with a significantly reduced number of procurements in two comparisons in group A and in one in group B.
Multivariate analyses indicated a beneficial effect of T3/T4 therapy on organ procurement independent of the other factors studied (odds ratio, 1.23; P<0.0001) (Table S2, SDC,https://links.lww.com/TP/A984). Furthermore, T3/T4 therapy was beneficial for the procurement of the heart, lungs, kidneys, and pancreas, with odds ratios of 1.28, 1.21, 1.26, and 1.31, respectively. However, T3/T4 therapy had no (beneficial or detrimental) effect on the procurement of livers or intestines.
Impact of T3/T4 Therapy to the Donor on Posttransplantation Graft and Recipient Survival
In study 1, there was a statistically comparable or improved graft and recipient survival at 1 or 12 months of the patients who had received heart, lung, kidney, and liver grafts from T3/T4–treated donors (Table 6). Because the number of intestinal transplants was small, survival data were not analyzed.
In study 2, there was no difference in graft or recipient survival at 1 or 12 months in relation to any organ except (i) increased kidney graft (P<0.002) and recipient (P<0.01) survival at 12 months when the donor had received T3/T4, and (ii) decreased pancreas recipient (but not graft) survival at 12 months (P<0.01) (Table 6).
Although a prospective randomized study of hormonal replacement therapy would carry greater scientific value, the current retrospective analysis has sufficient statistical power to provide clear results. In study 1, there was a clear benefit in the number of organs that could be procured from donors who received T3/T4, representing an increase in organs procured by 12.8% (P<0.0001). In study 2, there was an increased procurement rate of the heart, lung, kidney, pancreas, and intestine when T3/T4 had been administered (group A), but no overall benefit of T3/T4 on liver procurement, although one subgroup showed a significantly higher procurement rate. The reason why T3/T4 did not have a beneficial effect on the procurement of the liver remains uncertain, but this therapy was not significantly detrimental. This observation has been made previously (20), but data from one group indicate that T3/T4 therapy can be beneficial (21).
Importantly, multivariate analysis indicated that the increased procurement rates were independent of the other covariates examined.
The reasons why some donors received T3/T4 and others did not and why any combination of replacement therapy was selected were not available to us. As some transplant groups administer T3/T4 only to donors who are hemodynamically unstable or progressively acidotic, it might be anticipated that some of the group A donors began at a disadvantage to those in group B. The mechanism of action of the thyroid hormones has been discussed previously (6, 22, 23) and is summarized in the Supplementary Discussion, SDC (https://links.lww.com/TP/A984).
We also separately and individually analyzed the effect on organ procurement of ADH, corticosteroids, and insulin. Although the beneficial effect of ADH was clear (and superior to T3/T4 with regard to the liver), corticosteroids were less consistently beneficial (most frequently when T3/T4 had not been administered), although never detrimental. When insulin was administered, the yield of organs was sometimes reduced, particularly of the pancreas and intestine, an observation that does not seem to have been reported previously. However, this potentially adverse effect was not uniform; indeed, insulin seemed to be beneficial to lung procurement. The cause of the reduction associated with insulin remains uncertain (briefly discussed in the Supplementary Discussion, SDC,https://links.lww.com/TP/A984).
With regard to the outcome after transplantation of the organs, a previous study indicated that there was a significant survival benefit associated with heart and kidney transplantation from donors treated with T3/T4 (11). The present study 1 confirms this benefit and also indicates that survival of lungs is improved by T3/T4 treatment of the donor. Perhaps surprisingly (in view of the lack of benefit of therapy on the number of livers procured), liver graft and recipient survival was also significantly increased when the donor had received T3/T4.
Study 2, however, suggested some detrimental effect on pancreas recipient survival, although this was only seen at 12 months, which perhaps casts some doubt on its relevance.
Although not investigated in the present study, we have previously reported a significant benefit in early graft function after heart transplantation if the recipient is also treated with T3/T4 (2, 6, 24, 25).
In conclusion, our data strongly suggest that T3/T4 therapy should be considered in all brain-dead potential organ donors, particularly if combined with ADH and corticosteroids. The number of organs procured is significantly increased, and there is improvement or no detrimental effect on outcome after transplantation. The administration of insulin may not always provide further advantage or may even be detrimental.
MATERIALS AND METHODS
Data were provided from January 1, 2000, to December 31, 2009 (Supplementary Methods, SDC,https://links.lww.com/TP/A984). A total of 71,571 donors were registered with UNOS, of whom 4,942 were excluded on the basis of being non–heart-beating donors or donors without heartbeat information (Figure S1, SDC,https://links.lww.com/TP/A984). Of the 66,629 heart-beating donors, 3,036 were without T3/T4 treatment information. Therefore, the initial study analysis (study 1, T3/T4 vs. no T3/T4) was performed on 63,593 donors. (mechanisms, circumstances, and causes of death are indicated in Table S3, SDC,https://links.lww.com/TP/A984.) Of these, all had documentation on whether T3/T4 was administered. However, only 40,124 had documentation of all hormonal management (with 23,469 having incomplete documentation, except for T3/T4), and these formed the basis of study 2 (in which data on all four hormones were analyzed).
Hormonal Treatment Modalities
Currently, hormonal therapy can include the administration of four hormones as follows: thyroid (T3 or T4), a corticosteroid, ADH (e.g., desmopressin [1-deamino-8-d-arginine vasopressin, DDAVP), and insulin (Table 2 and 3 and Table S1, SDC,https://links.lww.com/TP/A984).
In both studies 1 and 2, the analysis was focused on the number of organs procured and transplanted. In study 1, the effect of T3/T4 on the mean number of organs procured/transplanted from a donor was determined and compared with the mean number procured from donors who did not receive T3/T4 (irrespective of any other therapy).
In study 2, group A (n=23,022) consisted of donors who received T3/T4 alone or in combination with one or more other hormones (corticosteroid, ADH, insulin) (Table 2). Group B (n=17,102) did not receive T3/T4 but may have received one or more of the other hormones. Comparison of groups was therefore based on the eight comparable pairs (subgroups) of hormonal treatment modalities with or without T3/T4 (Table 2 and 3 and Table S1, SDC,https://links.lww.com/TP/A984).
In study 2, two metrics were calculated as follows: (i) the average number of organs procured from a donor and (ii) the percentage of donors from which a specific individual organ, for example, heart, was procured and transplanted (Supplementary Methods, SDC,https://links.lww.com/TP/A984). When the final disposition of the organs was not indicated, that is, it was not confirmed that a specific organ had been transplanted, the donor was excluded from the analysis. This information affected only the liver, pancreas, and intestine and is recorded in the tables. The total numbers of donors for those specific organs are therefore different (see Results section).
The outcome of the transplantation was determined by documenting both graft and patient survival at 1 and 12 months after transplantation.
Data analyses were performed using SAS version 9.2.1 (SAS Inc., Cary, NC). A univariate analysis was performed to compare the effect of T3/T4 on organ procurement, and a multivariate analysis was performed to determine whether age, sex, ethnicity, cause of death, body mass index, Organ Procurement Organization region, or other hormonal therapy (non–T3/T4) influenced procurement. Posttransplantation graft and recipient survivals were compared by the Kaplan-Meier method and log-rank test (Supplementary Methods, SDC,https://links.lww.com/TP/A984).
The authors thank Rakesh Sindhi, M.D., of the Department of Surgery of the Children’s Hospital of Pittsburgh for generously providing statistical support. The authors acknowledge with gratitude the data provided by UNOS. This report is based on OPTN data as of January 14, 2011.
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