Abstract
This study compares graft and patient survival rates after transplantation of livers donated after euthanasia vs after circulatory death or brain death at a hospital in Belgium, where euthanasia is legalized.
Transplantation of organs donated after euthanasia may help alleviate the critical organ shortage.1 However, aside from preliminary data on lung transplantation,2 data on graft and patient survival following transplantation of organs donated after euthanasia are unavailable. Because donation after euthanasia entails a period of detrimental warm ischemia that hampers graft survival, similar to donation after circulatory death,3 results after transplantation of this type of graft need to be carefully evaluated.
The 2002 Belgian Euthanasia Act legalized euthanasia in Belgium for patients who experience unbearable physical or mental suffering because of an irremediable illness and who are able to deliberately, voluntarily, and repeatedly express their euthanasia request.4 In 2009, the liver transplant unit at the University Hospitals Leuven started including donor livers from individuals who had voluntarily requested to donate their organs after euthanasia. We report on the clinical outcome of the initial series of liver transplants donated after euthanasia.
Methods
We retrospectively reviewed data for all adult solitary livers transplanted at the University Hospitals Leuven between January 1, 2009, and December 31, 2015, and compared donor and recipient characteristics, ischemia time, and 3-year graft and patient survival after transplantation of livers obtained after donor euthanasia, circulatory death, or brain death. Graft loss was defined as retransplantation or graft failure leading to a recipient’s death. The final date of follow-up was April 25, 2019.
Continuous variables were analyzed using Kruskal-Wallis 1-way analysis of variance or Mann-Whitney U test, categorical variables were analyzed using χ2 or Fisher exact test, and graft and patient survival were analyzed using Kaplan-Meier curves and log-rank test. A 2-sided P < .05 was considered statistically significant. Analyses were performed using SPSS version 20 (IBM) and Prism version 8 (GraphPad Software). All transplant recipients provided written informed consent for data collection, and the study was approved by the University Hospitals Leuven’s ethical committee.
Results
Among 409 transplantations performed, 320 livers (78%) were donated after brain death, 78 (19%) after circulatory death, and 11 (2.7%) after euthanasia (Table), with donor median ages of 56 years (interquartile range [IQR], 46-68 years), 53 years (IQR, 44-61 years), and 44 years (IQR, 33-58 years), respectively (P = .09). All donor-related characteristics except for peak aspartate aminotransferase were similar among groups. Compared with livers donated after euthanasia, livers donated after circulatory death had longer median total donor warm ischemia time (20 minutes [IQR, 15-25 minutes] vs 13 minutes [IQR, 12-15 minutes]; P = .001) and longer median agonal warm ischemia time (10 minutes [IQR, 7-16 minutes] vs 3 minutes [IQR, 1-9 minutes]; P = .001), while median asystolic warm ischemia time was comparable. The median cold ischemia time during liver transplantation from euthanasia donors (4.84 hours [IQR, 4.10-6.20 hours]) was similar to that of circulatory death donors (5.30 hours [IQR, 4.58-6.25 hours]; P = .99) but was shorter than that of brain death donors (7.75 hours [IQR, 6.05-9.08 hours]; P = .002).
Table. Baseline Recipient and Donor Characteristics.
| Characteristics | Donor Type | ||
|---|---|---|---|
| Brain Death (n = 320) | Circulatory Death (n = 78) | Euthanasia (n = 11) | |
| Recipient Characteristics | |||
| Age, median (IQR), y | 58 (48-65) | 61 (52-66) | 64 (51-68) |
| Model for End-stage Liver Disease score, median (IQR)a | 15 (10-26) | 16 (12-21) | 17 (12-26) |
| Sex, No. (%)b | |||
| Male | 187 (58.4) | 62 (79.5) | 6 (54.5) |
| Female | 133 (41.6) | 16 (20.5) | 5 (45.5) |
| Indication for transplantation, No. (%)c | |||
| Hepatocellular carcinoma | 6 (21.6) | 6 (7.7) | 1 (9.1) |
| Cirrhosis | |||
| Postalcoholic | 47 (14.7) | 32 (41) | 2 (18.2) |
| Post–hepatitis C | 11 (3.4) | 5 (6.4) | 0 |
| Post–hepatitis B | 5 (1.6) | 0 | 1 (0.09) |
| Nonalcoholic steatohepatitis | 17 (5.3) | 8 (10.3) | 2 (18.2) |
| Acute liver failure | 24 (7.5) | 1 (1.3) | 1 (9.1) |
| Metabolic diseases | 8 (2.5) | 5 (6.4) | 0 |
| Primary nonfunction | 1 (0.3) | 0 | 0 |
| Cold ischemia time, median (IQR), hd | 7.75 (6.05-9.08) | 5.30 (4.58-6.25) | 4.84 (4.1-6.2) |
| Donor Characteristics | |||
| Age, median (IQR), y | 56 (46-68) | 53 (44-61) | 44 (33-58) |
| Sex, No. (%) | |||
| Male | 161 (50.3) | 54 (69.2) | 6 (54.5) |
| Female | 159 (49.7) | 24 (30.8) | 5 (45.5) |
| Warm ischemia time, median (IQR), min | |||
| Totale | 20 (15-25) | 13 (12-15) | |
| Agonalf | 10 (7-16) | 3 (1-9) | |
| Asystolicg | 8 (8-10) | 8 (5-11) | |
| Highest concentrations observed before organ donation, median (IQR) | |||
| AST, U/L | 47 (30-92) | 62 (36-148) | 26 (21-29) |
| ALT, U/L | 30 (19-67) | 59 (29-116) | 23 (18-31) |
| Creatinine, mg/dL | 0.93 (0.72-1.20) | 0.99 (0.73-1.3) | 0.74 (0.68-0.93) |
| Intensive care unit hospitalization, median (IQR), d | 2 (1-4) | 6 (3-14) | 1 (0-2) |
| No. of organs per donor, median (IQR) | 3 (3-5) | 3 (1-4) | 5 (3-5) |
| Arterial hypertension, No. (%) | 98 (37.3) | 19 (24.7) | 0 |
| Diabetes, No. (%) | 23 (8.8) | 7 (9.2) | 0 |
| Histidine-tryptophan-ketoglutarate preservation solution, No. (%) | |||
| No | 191 (59.7) | 72 (92.3) | 8 (72.7) |
| Yes | 129 (40.3) | 6 (7.7) | 3 (27.3) |
Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IQR, interquartile range.
SI conversion: To convert creatinine to μmol/L, multiply by 88.4.
Severity of underlying hepatic disease was defined according to the Model for End-stage Liver Disease score at the time of transplantation, without exception points. This continuous score ranges from 6 to 40 points and is calculated as 10 × ([0.957 × lncreatinine] + [0.378 × lnbilirubin] + [1.12 × lninternational normalized ratio]) + 6.43.
Percentages may not sum to 100% because of rounding.
Indications for liver transplantation are not mutually exclusive.
Cold ischemia time was defined as the time between initiation of cold flush with preservation solution in the donor and the graft being taken out of ice and placed in the recipient’s abdomen.
Total warm ischemia time was defined as the time between withdrawal of life-sustaining therapy (for circulatory death) or administration of the euthanasia mix (for euthanasia) and start of cold flush with preservation solution in the donor.
Agonal warm ischemia time was defined as the time between decrease of mean arterial blood pressure to below 60 mm Hg after withdrawal of life-sustaining therapy and start of cold flush with preservation solution in the donor.
Asystolic warm ischemia time was defined as the time between occurrence of circulatory arrest and start of cold flush with preservation solution in the donor.
The median ages of recipients undergoing transplantation with livers donated after brain death, circulatory death, and euthanasia were 58 years (IQR, 48-65 years), 61 years (IQR, 52-66 years), and 64 years (IQR, 51-68 years), respectively (P = .33). The Model for End-stage Liver Disease score was similar between groups.
Liver transplantation after donor brain death, circulatory death, or euthanasia resulted in 3-year graft survival of 80.2% (95% CI, 75.4%-84.2%), 82% (95% CI, 71.6%-89%), and 90.9% (95% CI, 50.8%-98.7%) (P = .67) and 3-year patient survival of 86.1% (95% CI, 81.9%-89.5%), 84.6% (95% CI, 74.5%-91%), and 90.9% (95% CI, 50.8%-98.7%) (P = .84), respectively (Figure).
Figure. Graft Survival and Patient Survival 3 Years After Liver Transplantation From Donors With Brain Death, Circulatory Death, or Euthanasia.
Graft survival and patient survival were similar 3 years after transplantation of livers procured from donors after brain death, circulatory death, or euthanasia. Vertical lines on the curves indicate censored events.
Discussion
This retrospective analysis showed that medium-term graft and patient survival following transplantation of livers donated after euthanasia was similar to the survival observed following donation after circulatory death and after brain death. Although time to circulatory arrest is generally longer for donation following circulatory death, livers donated after euthanasia are still exposed to a period of warm ischemia, which increases the risk of posttransplantation complications and graft loss. As such, livers donated after euthanasia should still be considered high-risk livers, and, similar to donation after circulatory death, precautions such as minimization of cold ischemia time should be continued.5 These data support the notion that within a very strict ethicolegal and logistic framework, donation after euthanasia may represent a valuable source of donor organs. The small sample size, limited follow-up, and monocentric nature of the study preclude definitive conclusions but provide a rationale for larger, longer-term studies on efficacy and safety of donation after euthanasia.
Section Editor: Jody W. Zylke, MD, Deputy Editor.
References
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