LIVER TRANSPLANTATION 20:1447–1453, 2014
ORIGINAL ARTICLE
Early Allograft Dysfunction in Liver Transplantation With Donation After Cardiac Death Donors Results in Inferior Survival David D. Lee, Amandeep Singh, Justin M. Burns, Dana K. Perry, Justin H. Nguyen, and C. Burcin Taner Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL
Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P 5 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P 5 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) 5 1.26, 95% confidence interval (CI) 5 1.01-1.56, P 5 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR 5 2.26, 95% CI 5 1.11-4.58, P 5 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future C 2014 AASLD. investigations. Liver Transpl 20:1447-1453, 2014. V Received March 28, 2014; accepted August 7, 2014. The success of liver transplantation (LT) has expanded its therapeutic utility and necessitated the increased use of marginal donors to meet the growing demand. To understand the impact of these marginal organs, a clinical tool for identifying early allograft dysfunction (EAD) has been previously described by multiple groups.1-4 A simple definition (characterized by high early aminotransferase levels, persistent cholestasis, and prolonged coagulopathy in the first week after LT) has previously been validated in a multicenter retrospective review of 297 LT recipients of liver allografts from both donation after brain death (DBD) and dona-
tion after cardiac death (DCD) donors.5 This clinical tool has served as a marker for an increased risk of mortality, morbidity, allograft failure, and cost.6 EAD has also become a target for therapeutic intervention to reduce morbidity and mortality in LT.7-9 To date, there has been no published study delineating the incidence of and risk factors for EAD specifically in the recipients of liver allografts from DCD donors. Liver allografts from DCD donors are considered inferior because of an overall increased rate of allograft failure.10-12 For this type of donor, the declaration of death is based on cardiopulmonary criteria
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CI, confidence interval; CIT, cold ischemia time; CVA, cerebrovascular accident; DBD, donation after brain death; DCD, donation after cardiac death; DRI, donor risk index; DWIT, donor warm ischemia time; EAD, early allograft dysfunction; HAT, hepatic artery thrombosis; HCC, hepatocellular cancer; HCV, hepatitis C virus; IC, ischemic cholangiopathy; INR, international normalized ratio; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OPO, organ procurement organization; OR, odds ratio; PNF, primary nonfunction; PRBC, packed red blood cell; UNOS, United Network for Organ Sharing; UW, University of Wisconsin; WIT, warm ischemia time. Potential conflict of interest: Nothing to report. Address reprint requests to C. Burcin Taner, M.D., Department of Transplantation, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224. Telephone: 904-956-3261; FAX: 904-956-3359; E-mail: [email protected] DOI 10.1002/lt.23985 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
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rather than the cessation of brain and brainstem function. Procurement in this setting subjects the liver allograft to warm ischemia, which may result in increased rates of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and ischemic cholangiopathy (IC). The recipients of allografts from DCD donors are potentially at increased risk for EAD because of hemodynamic changes after withdrawal of life support and warm ischemia incurred during the mandatory hands-off period.13 In the last decade, DCD liver allografts were identified as one approach to alleviating the donor organ shortage. Recent publications point to a trend toward increased numbers of DCD donors.14-16 Advances in the last decade in trauma care and neurosurgical and neuroradiological interventions immediately after brain injury may result in improved initial survival of patients. As a result, patients who are to become organ donors are increasingly not meeting brain death criteria. Although the widespread and successful utilization of DCD allografts could provide more timely access to LT, this has been tempered by lower allograft survival and higher biliary complication rates in comparison with DBD liver allografts. DCD allografts offer an opportunity to maintain if not increase the annual number of LT procedures performed in the United States, and it is imperative that transplant programs learn to decrease complications related to liver allografts from DCD donors. Since the inception of the LT program at Mayo Clinic Florida (Jacksonville, FL) in 1998, DCD donors have been used aggressively to meet the demand for organs. Our program represents the largest singlecenter experience with this type of donor, so we sought to investigate the incidence of and reasons for EAD and its role in predicting morbidity and mortality in recipients of liver allografts from DCD donors.
PATIENTS AND METHODS A retrospective review of LT cases with DCD allografts between December 1998 and December 2011 at Mayo Clinic Florida was performed. The exclusion criteria for this study were recipients of multiorgan transplants (simultaneous liver-kidney transplants), recipients of liver retransplants, and recipients whose follow-up was inadequate for assessing EAD. Approval for this study was obtained from the Mayo Clinic institutional review board. As previously described, data regarding EAD were defined by the presence of 1 or more of the following variables: (1) bilirubin 10 mg/dL on postoperative day 7, (2) INR 1.6 on postoperative day 7, and (3) an aminotransferase level [alanine aminotransferase (ALT) or aspartate aminotransferase (AST)] 2000 IU/ mL within the first 7 postoperative days.5 Detailed information regarding the DCD donors and the recipients were obtained from the Mayo Clinic Florida transplant database. Recipient data included the following: age, sex, body mass index (BMI), liver disease etiology, presence of hepatocellular carcinoma (HCC)
LIVER TRANSPLANTATION, December 2014
as a secondary diagnosis, biological Model for EndStage Liver Disease (MELD) score at the time of LT, operative time, intraoperative packed red blood cell (PRBC) transfusions, length of hospital stay, and follow-up time. The donor information included the following: age, sex, BMI, share status (geographic location), cause of death, donor warm ischemia time (DWIT), cold ischemia time (CIT), warm ischemia time (WIT), donor risk index (DRI), and individual DRI components. DWIT was defined as the time from the withdrawal of both ventilator and cardiac support to the start of cold perfusion of the organ. CIT was defined as the time from the infusion of the cold preservation solution to portal reperfusion of the liver in the recipient. WIT was the warming period of the liver allograft during implantation (out of the cold preservation solution to reperfusion through portal flow). Surgical techniques for both the DCD procurement and the recipient operation have been previously described.17,18 For the DCD organ procurement, a rapid retrieval technique was used in which the abdomen was opened with a cruciate incision. The small bowel was reflected superiorly, and the aorta and portal systems were cannulated for an in situ flush. The cold preservation fluid, consisting of University of Wisconsin solution (UW), heparin, and glutathione, was flushed through the abdominal aorta and portal system (via the inferior mesenteric vein). The intrathoracic descending aorta was cross-clamped either through a median sternotomy or through the left hemidiaphragm immediately after the start of cold perfusion through the aorta. Finally, the suprahepatic inferior vena cava was opened to allow venting. After the completion of the preservation solution infusion, the liver (in most cases together with the head of the pancreas) was then removed from the abdomen, and the biliary system was flushed on the back table. Finally, the liver allograft was packaged in cold UW solution and transported back to the hospital for implantation. All LT procedures were performed via the piggyback technique without a portocaval shunt, caval clamping, or venovenous bypass. All liver allografts were reperfused with portal flow, which was followed by arterial flow. Duct-to-duct biliary reconstruction with a transcystic biliary tube was used except in recipients with primary sclerosing cholangitis or when it was deemed necessary by the recipient surgeon. Thrombolytic agents were not used in either the donor or the recipient.
Statistical Analysis Allograft survival was timed from the transplant date until the date of retransplantation or death (whichever came first) and was censored for the date of the end of the study period or for the date of the last correspondence (for losses to follow-up). The allograft and patient survival rates were compared with KaplanMeier plots and log-rank tests. A univariate analysis of clinical risk factor associations with EAD was
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Figure 1.
LEE ET AL. 1449
Kaplan-Meier survival estimates for (A) patient survival and (B) allograft survival in DCD liver allograft recipients.
conducted with the chi-square test for categorical variables and with the Mann-Whitney t test for continuous variables after an assessment for normality. Risk factor variables with P < 0.20 in the univariate analysis were included in an explanatory analysis, as previously described,19 using a multivariate logistic regression model to adjust for potential confounding. A P value of 0.05 after adjustments for confounding was considered statistically significant. All statistical analysis was performed with Stata 13 (StataCorp LP, College Station, TX).
RESULTS Between December 1998 and December 2011, 228 LT procedures with liver allografts from DCD donors were performed at the Mayo Clinic Florida Transplant Program. Twenty-three LT cases were excluded. Among these, 12 cases were excluded because they received multiorgan transplants (simultaneous liverkidney transplants), 8 received liver retransplants, and 3 died within the first week of LT (this did not allow for a complete analysis). Two hundred and five patients were identified as primary recipients of DCD liver allografts. One hundred fifty-three recipients (75%) were male, and 104 (51%) had hepatitis C virus as a primary diagnosis. The mean recipient age was 55.1 years (median 5 55, range 5 15-75 years); the mean donor age was 40.5 years (median 5 42, range 5 7-81 years). The mean DRI was 1.97 (median 5 1.87, range 5 1.29-4.15). The mean followup time was 68.2 months (median 5 66 months, range 5 10 days to 14 years). Ischemic cholangiopathy was diagnosed in 29 of the 205 patients, as has been previously described for this patient subset.15,20 Eighty-one recipients (39.5%) were found to have had EAD. The patient survival rates for those who did not meet EAD criteria and for those who did at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and
61% and 54%, respectively (P 5 0.009). Allograft survival rates in the no-EAD group and the EAD group at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P 5 0.003; Fig. 1). When patients who developed IC were excluded from the survival analysis, the difference in graft survival was similar and remained statistically significant (P 5 0.002). Although the patient survival did show a difference as well, this was not statistically significant (P 5 0.064). The association of clinical risk factors with EAD is presented in Table 1. In the univariate analysis, CIT correlated with EAD. Despite an increase in CIT in patients who developed EAD, the share type for these 2 groups was almost equivalent, with local donors representing 59% of the no-EAD group and 57% of the EAD group. In the EAD group, the WIT, operative time, and proportion of recipients with HCC as a secondary diagnosis were higher. These variables were then analyzed with a logistic regression model, which demonstrated a significant association between the development of EAD and CIT [odds ratio (OR) 5 1.26, 95% confidence interval (CI) 5 1.01-1.56, P 5 0.037] and HCC as a secondary diagnosis (OR 5 2.26, 95% CI 5 1.11-4.58, P 5 0.025; Table 2). There was no correlation between EAD and IC diagnosis (Table 3). In the subset of 50 recipients in the DCD cohort who had HCC as a secondary diagnosis, 26 recipients experienced EAD; there was no association between those patients with HCC who had EAD and IC development. The majority of the patients (85%) who met the criteria for EAD met the criteria by satisfying only 1 of the individual components of the definition (Table 4). Most commonly elevated transaminases were found in 58 patients (72%), and these patients had only modestly decreased survival and allograft survival at 6 months and 1 year. Patients who met the criteria for elevated INR and total bilirubin on day 7, however, had significantly worse graft and overall survival, as demonstrated in a previous publication.13
1450 LEE ET AL.
LIVER TRANSPLANTATION, December 2014
TABLE 1. Recipient, Donor, and Operative Characteristics for EAD and No-EAD Cohorts
Recipient characteristics Age (years) MELD score Male sex [n (%)] Race: white/black/other [n (%)] HCV [n (%)] HCC as a secondary diagnosis [n (%)] Hospital stay (days) Development of IC [n (%)] BMI (kg/m2) Donor characteristics Age (years) DRI BMI (kg/m2) DWIT (minutes) CIT (hours) Race: white/black/other [n (%)] Cause of death: anoxia/CVA/ trauma/other [n (%)] Share type: local/regional/ national [n (%)] Operative characteristics WIT (minutes) Operative time (minutes) Volume of red blood cell transfusion (mL)
No EAD (n 5 124)
EAD (n 5 81)
P Value
54.7 6 10.1 (15-56, 55) 17.0 6 6.8 (6-40, 16) 94 (76) 111 (90)/8 (6)/5 (4) 61 (49) 24 (19) 13.4 6 12.2 (5-245, 8) 16 (13) 28.5 6 6.6 (17-39.5, 27.5)
55.8 6 8.69 (33-75, 55) 16.8 6 7.8 (6-51, 16) 59 (73) 72 (89)/6 (7)/3 (4) 43 (53) 26 (32) 22.3 6 40.4 (6-338, 10) 13 (16) 30.3 6 6.6 (20-53.3, 29.4)
0.3948 0.8450 0.6330 0.3710 0.5879 0.0379 0.0478 0.5270 0.0579
40.2 6 16.2 (7-81, 16.15) 1.96 6 0.47 (1.29-3.68, 1.84) 26.9 6 5.9 (16-55.8, 25.9) 24.7 6 8.4 (4-57, 24) 5.7 6 1.5 (3.0-10.5, 5.5) 111 (90)/8 (6)/5 (4) 39 (31)/27 (22)/55 (44)/3 (2)
41.0 6 15.7 (8-67, 43) 1.99 6 0.52 (1.29-4.15, 1.89) 28.7 6 8.0 (16-71.9, 27.2) 24.5 6 9.6 (5-59, 23.5) 6.4 6 1.4 (3.6-10.3, 6.4) 72 (89)/6 (7)/3 (4) 16 (20)/20 (25)/41 (51)/4 (5)
0.7044 0.7000 0.0683 0.8258 0.0013 0.8870 0.3800
73 (59)/39 (31)/12 (10)
46 (57)/29 (36)/6 (7)
0.9839
31.7 6 11.4 (17-88, 30) 236.7 6 79.4 (79.4-547, 221) 3051.9 6 2740.6 (0-21,700, 2450)
37.4 6 13.2 (21-106, 35) 278.2 6 82.5 (141-444, 277) 3665.2 6 2281.5 (0-9800, 2800)
0.0014 0.0004 0.0963
NOTE. Significant P values are in boldface. Continuous variables are presented as means and standard deviations (with ranges and medians in parentheses).
TABLE 2. Multivariate Analysis of Risk Factors for
TABLE 3. Patients Who Experienced IC and EAD
EAD OR Donor BMI (kg/m2) Recipient BMI (kg/m2) CIT (hours) WIT (minutes) Operative time (minutes) Volume of PRBC transfusion (mL) HCC as secondary diagnosis
1.03 1.03 1.26 1.02 1.00
95% CI P Value 0.982-1.076 0.980-1.080 1.014-1.563 0.987-1.053 0.998-1.008
0.237 0.252 0.037 0.230 0.234
1.00 0.9999-1.000
0.347
2.26
0.025
1.110-4.58
DISCUSSION This report represents the first and largest series to validate the current definition of EAD in LT using allografts from DCD donors. In this report of 205 consecutive recipients of liver allografts from DCD donors, we identified a high incidence of EAD. More importantly, those recipients with EAD had a significant patient and allograft survival disadvantage in comparison with those without an EAD diagnosis. EAD defines allografts with marginal function early after LT and provides a marker for potential morbidity
IC No IC
No EAD
EAD
16 108
13 68
NOTE. Pearson chi square test: P 5 0.527.
from early allograft loss and mortality. This definition has been validated as a predictor of poor allograft and patient outcomes in a multicenter study of 297 deceased donor LT cases.5 However, only 10% of the patients in the cited study were recipients of DCD liver allografts. The incidence of EAD in this specific subset of LT recipients and their outcomes have previously not been studied. In our series, 39.5% of the patients who had undergone transplantation with livers from DCD donors met the criteria for EAD. This rate is higher than that in other reported series, such as the National Institute of Diabetes and Digestive and Kidney Diseases cohort and the multicenter cohort study, which demonstrated an overall 23% incidence.1 A previous publication from a single institution reported an incidence of 39.8%, but the breakdown of DCD and DBD allografts was not reported.21 The University of Western Ontario reported a series of
NOTE. Patient survival and graft survival are listed as percentages for patients who did not have the components of EAD versus those who did.
90 versus 100 90 versus 60 90 versus 86 90 versus 100 90 versus 43 90 versus 0 90 versus 0 96 versus 100 96 versus 60 96 versus 94 96 versus 100 96 versus 85 96 versus 100 96 versus 50 100 versus 100 100 versus 80 100 versus 96 100 versus 100 100 versus 86 100 versus 100 100 versus 50 1 2 2 1 2 1 1
2 1 2 1 1 2 1
2 2 1 2 1 1 1
1 10 58 1 7 2 2
95 versus 100 95 versus 70 95 versus 87 95 versus 100 95 versus 57 95 versus 0 95 versus 0
at 1 Year (%) at 1 Year (%)
Survival Graft Survival
at 6 Months (%) 6 Months (%) Patients (n)
Survival at 2000
ALT or AST
IU/mL 10 mg/dL
TABLE 4. Individual Components of EAD Day 7
Bilirubin Day 7
INR 1.6
Graft Survival
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38 recipients of DCD allografts, among whom 26 (68%) met the criteria for EAD.13 In its comparative cohort of DBD recipients, only 19 of 89 (21%) met the criteria for EAD. It is clear from previously published reports and the current report that DCD liver allograft recipients are at higher risk for developing EAD, and this supports the belief that these are higher risk organs. In this report, we also sought to identify risk factors for EAD. Insight into the development of EAD may help to identify areas for intervention to improve outcomes after LT. The univariate analysis suggests that events in the operating room may be most important in driving the development of EAD. Variables such as recipient BMI, CIT, WIT, and operative time were significantly higher in the EAD group. Although the volume of intraoperative PRBC transfusions was not statistically different, there appeared to be a skewing toward higher transfusion requirements for those recipients who developed EAD. An elevated BMI is a known confounder of LT and contributes to prolonged operative times and postoperative morbidity.22 In this study, the mean BMI for our DCD recipients straddled the distinction between overweight and obese. Those patients who did not experience EAD had a mean BMI of 28.5 kg/m2, and those who did have EAD had a mean BMI of 30.3 kg/ m2. This subtle difference was almost statistically significant and may serve as a proxy for the difficult operative candidate. Other proxies for the difficult operation are represented by CIT, WIT, and operative times. CIT was on the whole within a very tight range: 6.4 hours in recipients with EAD and 5.7 hours in recipients without EAD. This small difference proved also to be statistically significant in the logistic regression model as an independent risk factor for developing EAD. The impact of CIT on early graft function has been known since the early experience of LT. Shortening the distance to be traveled for organ procurement and the geographic area of organ sharing have an impact on overall outcomes and perhaps are more important for DCD liver allografts.23 In our experience, CIT was independent of the geographic distance from the donor hospital to our transplant center. This difference in travel time may be different for other transplant programs, however. In theory, those patients who require a more complex hepatectomy as a result of body habitus, prior upper abdominal surgery, or their degree of portal hypertension are more likely to have prolonged CIT. This operative complexity is also confirmed by the statistically significant longer average WIT and operative time for those patients who developed EAD. Certainly, the variables in the operating room are more difficult to assess, and the detail of data needed to address this question exceeds the capacity of our current database. For now, the proxies for a difficult LT operation—an increased BMI; longer operating times, CIT, and WIT; and increased transfusion requirements—all support the notion that events in the operating room play a critical role in the development of EAD in the recipients of DCD liver allografts.
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An important finding in the current analysis is the increased risk for developing EAD in recipients with HCC as a secondary diagnosis. It is unclear to us at this time why this diagnosis would provide an increased risk. One previous study suggests an interaction between HCC and receiving a DCD allograft that leads to inferior survival.24 However, the study is plagued by the limitations of registry-based data and absence of HCC recurrence data. Even though the authors provide an important observation, they are left to speculate on the reasons for the poorer outcomes for recipients with an HCC diagnosis when DCD allografts are used. Drawing from animal models, the authors speculate that there is an interplay between ischemia/reperfusion injury and HCC recurrence. However, the HCC recurrence data are not available in the registry data set. In the same study, parallel to our findings, prolonged CIT and WIT were found to contribute to poorer patient survival in the HCC recipients of DCD allografts. The interaction of DCD allografts in recipients with HCC as it specifically relates to tumor recurrence is beyond the scope of this study and deserves a future detailed analysis with properly matched DBD controls. This interaction is an important finding because the proportion of recipients with HCC as a secondary diagnosis has been increasing. The mechanism underlying the development of EAD presents a challenge to LT practice using DCD donors independent of the development of IC. Previous studies have sought to define DWIT to identify its impact on LT outcomes with DCD grafts. In this study, DWIT, defined as the time from extubation to crossclamping, did not have any impact on the risk for EAD, just as in our previous analyses, in which DWIT did not have an impact on the development of either IC or overall biliary complications. As demonstrated by our data, EAD suggests a process of primary liver dysfunction that cannot predict patients who will develop IC. With an IC diagnosis for 29 (14%) of our DCD recipients, our study may be too small to clarify the interaction between EAD and IC. This study fills a void in the current understanding of EAD in LT using DCD liver allografts. Although this is the largest DCD experience addressing the incidence of, reasons for, and outcomes of EAD in this subset of LT patients, it is limited by the single-center nature of the data set. One advantage of single-center data is the granular and homogeneous nature of the data without center-specific variation. We acknowledge that the experience with liver allografts from DCD donors is not universal. High rates of IC, PNF, and HAT are thought to be reasons for poor outcomes in LT with DCD allografts. However, in the recipients who do not experience these well-known complications, the initial injury sustained by the allograft is here shown to result in inferior outcomes in the long term. Further analysis with DBD controls may provide a deeper understanding of differences between LT with DCD donors and LT with DBD donors; however, this is beyond the scope of this study. Although the
LIVER TRANSPLANTATION, December 2014
length of the hospital stay was prolonged in recipients who had EAD and serves as a proxy for resource utilization, a lack of detailed resource utilization data remains a weakness of the current study. In conclusion, this study in a single large transplant center demonstrates that EAD in LT using DCD liver grafts results in inferior graft and patient outcomes. The high incidence of EAD in the DCD recipient cohort supports the notion that livers from DCD donors are marginal grafts. Also, EAD is not predictive of patients who will develop IC. In addition to HCC as a secondary diagnosis, events in the perioperative period predispose the recipients of DCD allografts to EAD. As the liver graft scarcity intensifies, an emphasis on expanding donor criteria occurs. Systematic utilization of extended criteria donors, such as DCD donors, increases access to LT and reduces wait-list mortality.25 As a result of increasing numbers of extended criteria donors, the LT community will have to adapt by identifying strategies to decrease complications related to liver allografts coming from these donors. Understanding the events that cause EAD and developing preventative and early therapeutic approaches should be the focus of future investigations to increase allograft and patient survival and to decrease resource utilization in the posttransplant period.
REFERENCES 1. Desch^ enes M, Belle SH, Krom RA, Zetterman RK, Lake JR. Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Transplantation 1998;66: 302-310. 2. Ploeg RJ, D’Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, et al. Risk factors for primary dysfunction after liver transplantation—a multivariate analysis. Transplantation 1993;55:807-813. 3. Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation. Hepatology 1994;20(4 Pt 1): 829-838. 4. Gonz alez FX, Rimola A, Grande L, Antolin M, GarciaValdecasas JC, Fuster J, et al. Predictive factors of early postoperative graft function in human liver transplantation. Hepatology 1994;20:565-573. 5. Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010;16:943949. 6. Croome KP, Hernandez-Alejandro R, Chandok N. Early allograft dysfunction is associated with excess resource utilization after liver transplantation. Transplant Proc 2013;45:259-264. 7. Camci C, Akdogan M, Gurakar A, Gilcher R, Rose J, Monlux R, et al. The impact of total plasma exchange on early allograft dysfunction. Transplant Proc 2004;36: 2567-2569. 8. Deschenes M. Early allograft dysfunction: causes, recognition, and management. Liver Transpl 2013;19(suppl 2): S6-S8. 9. Friedman BH, Wolf JH, Wang L, Putt ME, Shaked A, Christie JD, et al. Serum cytokine profiles associated
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with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl 2012;18:166-176. 10. Renz JF. Is DCD for liver transplantation DNR? Am J Transplant 2008;8:485-488. 11. Mathur AK, Heimbach J, Steffick DE, Sonnenday CJ, Goodrich NP, Merion RM. Donation after cardiac death liver transplantation: predictors of outcome. Am J Transplant 2010;10:2512-2519. 12. Merion RM, Pelletier SJ, Goodrich N, Englesbe MJ, Delmonico FL. Donation after cardiac death as a strategy to increase deceased donor liver availability. Ann Surg 2006;244:555-562. 13. Croome KP, Wall W, Quan D, Vangala S, McAlister V, Marotta P, Hernandez-Alejandro R. Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts. Hepatobiliary Pancreat Dis Int 2012;11: 372-376. 14. Saidi RF, Bradley J, Greer D, Luskin R, O’Connor K, Delmonico F, et al. Changing pattern of organ donation at a single center: are potential brain dead donors being lost to donation after cardiac death? Am J Transplant 2010;10:2536-2540. 15. Kramer AH, Zygun DA, Doig CJ, Zuege DJ. Incidence of neurologic death among patients with brain injury: a cohort study in a Canadian health region. CMAJ 2013; 185:E838-E845. 16. Bendorf A, Kelly PJ, Kerridge IH, McCaughan GW, Myerson B, Stewart C, Pussell BA. An international comparison of the effect of policy shifts to organ donation following cardiocirculatory death (DCD) on donation rates after brain death (DBD) and transplantation rates. PLoS One 2013;8:e62010. 17. Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783-790.
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18. Taner CB, Bulatao IG, Willingham DL, Perry DK, Sibulesky L, Pungpapong S, et al. Events in procurement as risk factors for ischemic cholangiopathy in liver transplantation using donation after cardiac death donors. Liver Transpl 2012;18:100-111. 19. Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol 1993; 138:923-936. 20. Taner CB, Bulatao IG, Perry DK, Sibulesky L, Willingham DL, Kramer DJ, Nguyen JH. Asystole to cross-clamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors. Transpl Int 2012;25:838846. 21. Wagener G, Raffel B, Young AT, Minhaz M, Emond J. Predicting early allograft failure and mortality after liver transplantation: the role of the postoperative Model for End-Stage Liver disease score. Liver Transpl 2013;19: 534-542. 22. LaMattina JC, Foley DP, Fernandez LA, Pirsch JD, Musat AI, D’Alessandro AM, Mezrich JD. Complications associated with liver transplantation in the obese recipient. Clin Transplant 2012;26:910-918. 23. Furukawa H, Todo S, Imventarza O, Casavilla A, Wu YM, Scotti-Foglieni C, et al. Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution. Transplantation 1991;51:1000-1004. 24. Croome KP, Wall W, Chandok N, Beck G, Marotta P, Hernandez-Alejandro R. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl 2013;19:1214-1223. 25. Renz JF, Kin C, Kinkhabwala M, Jan D, Varadarajan R, Goldstein M, et al. Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg 2005;242:556-563.
ORIGINAL ARTICLE
Early Allograft Dysfunction in Liver Transplantation With Donation After Cardiac Death Donors Results in Inferior Survival David D. Lee, Amandeep Singh, Justin M. Burns, Dana K. Perry, Justin H. Nguyen, and C. Burcin Taner Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL
Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P 5 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P 5 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) 5 1.26, 95% confidence interval (CI) 5 1.01-1.56, P 5 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR 5 2.26, 95% CI 5 1.11-4.58, P 5 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future C 2014 AASLD. investigations. Liver Transpl 20:1447-1453, 2014. V Received March 28, 2014; accepted August 7, 2014. The success of liver transplantation (LT) has expanded its therapeutic utility and necessitated the increased use of marginal donors to meet the growing demand. To understand the impact of these marginal organs, a clinical tool for identifying early allograft dysfunction (EAD) has been previously described by multiple groups.1-4 A simple definition (characterized by high early aminotransferase levels, persistent cholestasis, and prolonged coagulopathy in the first week after LT) has previously been validated in a multicenter retrospective review of 297 LT recipients of liver allografts from both donation after brain death (DBD) and dona-
tion after cardiac death (DCD) donors.5 This clinical tool has served as a marker for an increased risk of mortality, morbidity, allograft failure, and cost.6 EAD has also become a target for therapeutic intervention to reduce morbidity and mortality in LT.7-9 To date, there has been no published study delineating the incidence of and risk factors for EAD specifically in the recipients of liver allografts from DCD donors. Liver allografts from DCD donors are considered inferior because of an overall increased rate of allograft failure.10-12 For this type of donor, the declaration of death is based on cardiopulmonary criteria
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CI, confidence interval; CIT, cold ischemia time; CVA, cerebrovascular accident; DBD, donation after brain death; DCD, donation after cardiac death; DRI, donor risk index; DWIT, donor warm ischemia time; EAD, early allograft dysfunction; HAT, hepatic artery thrombosis; HCC, hepatocellular cancer; HCV, hepatitis C virus; IC, ischemic cholangiopathy; INR, international normalized ratio; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OPO, organ procurement organization; OR, odds ratio; PNF, primary nonfunction; PRBC, packed red blood cell; UNOS, United Network for Organ Sharing; UW, University of Wisconsin; WIT, warm ischemia time. Potential conflict of interest: Nothing to report. Address reprint requests to C. Burcin Taner, M.D., Department of Transplantation, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224. Telephone: 904-956-3261; FAX: 904-956-3359; E-mail: [email protected] DOI 10.1002/lt.23985 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
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rather than the cessation of brain and brainstem function. Procurement in this setting subjects the liver allograft to warm ischemia, which may result in increased rates of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and ischemic cholangiopathy (IC). The recipients of allografts from DCD donors are potentially at increased risk for EAD because of hemodynamic changes after withdrawal of life support and warm ischemia incurred during the mandatory hands-off period.13 In the last decade, DCD liver allografts were identified as one approach to alleviating the donor organ shortage. Recent publications point to a trend toward increased numbers of DCD donors.14-16 Advances in the last decade in trauma care and neurosurgical and neuroradiological interventions immediately after brain injury may result in improved initial survival of patients. As a result, patients who are to become organ donors are increasingly not meeting brain death criteria. Although the widespread and successful utilization of DCD allografts could provide more timely access to LT, this has been tempered by lower allograft survival and higher biliary complication rates in comparison with DBD liver allografts. DCD allografts offer an opportunity to maintain if not increase the annual number of LT procedures performed in the United States, and it is imperative that transplant programs learn to decrease complications related to liver allografts from DCD donors. Since the inception of the LT program at Mayo Clinic Florida (Jacksonville, FL) in 1998, DCD donors have been used aggressively to meet the demand for organs. Our program represents the largest singlecenter experience with this type of donor, so we sought to investigate the incidence of and reasons for EAD and its role in predicting morbidity and mortality in recipients of liver allografts from DCD donors.
PATIENTS AND METHODS A retrospective review of LT cases with DCD allografts between December 1998 and December 2011 at Mayo Clinic Florida was performed. The exclusion criteria for this study were recipients of multiorgan transplants (simultaneous liver-kidney transplants), recipients of liver retransplants, and recipients whose follow-up was inadequate for assessing EAD. Approval for this study was obtained from the Mayo Clinic institutional review board. As previously described, data regarding EAD were defined by the presence of 1 or more of the following variables: (1) bilirubin 10 mg/dL on postoperative day 7, (2) INR 1.6 on postoperative day 7, and (3) an aminotransferase level [alanine aminotransferase (ALT) or aspartate aminotransferase (AST)] 2000 IU/ mL within the first 7 postoperative days.5 Detailed information regarding the DCD donors and the recipients were obtained from the Mayo Clinic Florida transplant database. Recipient data included the following: age, sex, body mass index (BMI), liver disease etiology, presence of hepatocellular carcinoma (HCC)
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as a secondary diagnosis, biological Model for EndStage Liver Disease (MELD) score at the time of LT, operative time, intraoperative packed red blood cell (PRBC) transfusions, length of hospital stay, and follow-up time. The donor information included the following: age, sex, BMI, share status (geographic location), cause of death, donor warm ischemia time (DWIT), cold ischemia time (CIT), warm ischemia time (WIT), donor risk index (DRI), and individual DRI components. DWIT was defined as the time from the withdrawal of both ventilator and cardiac support to the start of cold perfusion of the organ. CIT was defined as the time from the infusion of the cold preservation solution to portal reperfusion of the liver in the recipient. WIT was the warming period of the liver allograft during implantation (out of the cold preservation solution to reperfusion through portal flow). Surgical techniques for both the DCD procurement and the recipient operation have been previously described.17,18 For the DCD organ procurement, a rapid retrieval technique was used in which the abdomen was opened with a cruciate incision. The small bowel was reflected superiorly, and the aorta and portal systems were cannulated for an in situ flush. The cold preservation fluid, consisting of University of Wisconsin solution (UW), heparin, and glutathione, was flushed through the abdominal aorta and portal system (via the inferior mesenteric vein). The intrathoracic descending aorta was cross-clamped either through a median sternotomy or through the left hemidiaphragm immediately after the start of cold perfusion through the aorta. Finally, the suprahepatic inferior vena cava was opened to allow venting. After the completion of the preservation solution infusion, the liver (in most cases together with the head of the pancreas) was then removed from the abdomen, and the biliary system was flushed on the back table. Finally, the liver allograft was packaged in cold UW solution and transported back to the hospital for implantation. All LT procedures were performed via the piggyback technique without a portocaval shunt, caval clamping, or venovenous bypass. All liver allografts were reperfused with portal flow, which was followed by arterial flow. Duct-to-duct biliary reconstruction with a transcystic biliary tube was used except in recipients with primary sclerosing cholangitis or when it was deemed necessary by the recipient surgeon. Thrombolytic agents were not used in either the donor or the recipient.
Statistical Analysis Allograft survival was timed from the transplant date until the date of retransplantation or death (whichever came first) and was censored for the date of the end of the study period or for the date of the last correspondence (for losses to follow-up). The allograft and patient survival rates were compared with KaplanMeier plots and log-rank tests. A univariate analysis of clinical risk factor associations with EAD was
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Figure 1.
LEE ET AL. 1449
Kaplan-Meier survival estimates for (A) patient survival and (B) allograft survival in DCD liver allograft recipients.
conducted with the chi-square test for categorical variables and with the Mann-Whitney t test for continuous variables after an assessment for normality. Risk factor variables with P < 0.20 in the univariate analysis were included in an explanatory analysis, as previously described,19 using a multivariate logistic regression model to adjust for potential confounding. A P value of 0.05 after adjustments for confounding was considered statistically significant. All statistical analysis was performed with Stata 13 (StataCorp LP, College Station, TX).
RESULTS Between December 1998 and December 2011, 228 LT procedures with liver allografts from DCD donors were performed at the Mayo Clinic Florida Transplant Program. Twenty-three LT cases were excluded. Among these, 12 cases were excluded because they received multiorgan transplants (simultaneous liverkidney transplants), 8 received liver retransplants, and 3 died within the first week of LT (this did not allow for a complete analysis). Two hundred and five patients were identified as primary recipients of DCD liver allografts. One hundred fifty-three recipients (75%) were male, and 104 (51%) had hepatitis C virus as a primary diagnosis. The mean recipient age was 55.1 years (median 5 55, range 5 15-75 years); the mean donor age was 40.5 years (median 5 42, range 5 7-81 years). The mean DRI was 1.97 (median 5 1.87, range 5 1.29-4.15). The mean followup time was 68.2 months (median 5 66 months, range 5 10 days to 14 years). Ischemic cholangiopathy was diagnosed in 29 of the 205 patients, as has been previously described for this patient subset.15,20 Eighty-one recipients (39.5%) were found to have had EAD. The patient survival rates for those who did not meet EAD criteria and for those who did at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and
61% and 54%, respectively (P 5 0.009). Allograft survival rates in the no-EAD group and the EAD group at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P 5 0.003; Fig. 1). When patients who developed IC were excluded from the survival analysis, the difference in graft survival was similar and remained statistically significant (P 5 0.002). Although the patient survival did show a difference as well, this was not statistically significant (P 5 0.064). The association of clinical risk factors with EAD is presented in Table 1. In the univariate analysis, CIT correlated with EAD. Despite an increase in CIT in patients who developed EAD, the share type for these 2 groups was almost equivalent, with local donors representing 59% of the no-EAD group and 57% of the EAD group. In the EAD group, the WIT, operative time, and proportion of recipients with HCC as a secondary diagnosis were higher. These variables were then analyzed with a logistic regression model, which demonstrated a significant association between the development of EAD and CIT [odds ratio (OR) 5 1.26, 95% confidence interval (CI) 5 1.01-1.56, P 5 0.037] and HCC as a secondary diagnosis (OR 5 2.26, 95% CI 5 1.11-4.58, P 5 0.025; Table 2). There was no correlation between EAD and IC diagnosis (Table 3). In the subset of 50 recipients in the DCD cohort who had HCC as a secondary diagnosis, 26 recipients experienced EAD; there was no association between those patients with HCC who had EAD and IC development. The majority of the patients (85%) who met the criteria for EAD met the criteria by satisfying only 1 of the individual components of the definition (Table 4). Most commonly elevated transaminases were found in 58 patients (72%), and these patients had only modestly decreased survival and allograft survival at 6 months and 1 year. Patients who met the criteria for elevated INR and total bilirubin on day 7, however, had significantly worse graft and overall survival, as demonstrated in a previous publication.13
1450 LEE ET AL.
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TABLE 1. Recipient, Donor, and Operative Characteristics for EAD and No-EAD Cohorts
Recipient characteristics Age (years) MELD score Male sex [n (%)] Race: white/black/other [n (%)] HCV [n (%)] HCC as a secondary diagnosis [n (%)] Hospital stay (days) Development of IC [n (%)] BMI (kg/m2) Donor characteristics Age (years) DRI BMI (kg/m2) DWIT (minutes) CIT (hours) Race: white/black/other [n (%)] Cause of death: anoxia/CVA/ trauma/other [n (%)] Share type: local/regional/ national [n (%)] Operative characteristics WIT (minutes) Operative time (minutes) Volume of red blood cell transfusion (mL)
No EAD (n 5 124)
EAD (n 5 81)
P Value
54.7 6 10.1 (15-56, 55) 17.0 6 6.8 (6-40, 16) 94 (76) 111 (90)/8 (6)/5 (4) 61 (49) 24 (19) 13.4 6 12.2 (5-245, 8) 16 (13) 28.5 6 6.6 (17-39.5, 27.5)
55.8 6 8.69 (33-75, 55) 16.8 6 7.8 (6-51, 16) 59 (73) 72 (89)/6 (7)/3 (4) 43 (53) 26 (32) 22.3 6 40.4 (6-338, 10) 13 (16) 30.3 6 6.6 (20-53.3, 29.4)
0.3948 0.8450 0.6330 0.3710 0.5879 0.0379 0.0478 0.5270 0.0579
40.2 6 16.2 (7-81, 16.15) 1.96 6 0.47 (1.29-3.68, 1.84) 26.9 6 5.9 (16-55.8, 25.9) 24.7 6 8.4 (4-57, 24) 5.7 6 1.5 (3.0-10.5, 5.5) 111 (90)/8 (6)/5 (4) 39 (31)/27 (22)/55 (44)/3 (2)
41.0 6 15.7 (8-67, 43) 1.99 6 0.52 (1.29-4.15, 1.89) 28.7 6 8.0 (16-71.9, 27.2) 24.5 6 9.6 (5-59, 23.5) 6.4 6 1.4 (3.6-10.3, 6.4) 72 (89)/6 (7)/3 (4) 16 (20)/20 (25)/41 (51)/4 (5)
0.7044 0.7000 0.0683 0.8258 0.0013 0.8870 0.3800
73 (59)/39 (31)/12 (10)
46 (57)/29 (36)/6 (7)
0.9839
31.7 6 11.4 (17-88, 30) 236.7 6 79.4 (79.4-547, 221) 3051.9 6 2740.6 (0-21,700, 2450)
37.4 6 13.2 (21-106, 35) 278.2 6 82.5 (141-444, 277) 3665.2 6 2281.5 (0-9800, 2800)
0.0014 0.0004 0.0963
NOTE. Significant P values are in boldface. Continuous variables are presented as means and standard deviations (with ranges and medians in parentheses).
TABLE 2. Multivariate Analysis of Risk Factors for
TABLE 3. Patients Who Experienced IC and EAD
EAD OR Donor BMI (kg/m2) Recipient BMI (kg/m2) CIT (hours) WIT (minutes) Operative time (minutes) Volume of PRBC transfusion (mL) HCC as secondary diagnosis
1.03 1.03 1.26 1.02 1.00
95% CI P Value 0.982-1.076 0.980-1.080 1.014-1.563 0.987-1.053 0.998-1.008
0.237 0.252 0.037 0.230 0.234
1.00 0.9999-1.000
0.347
2.26
0.025
1.110-4.58
DISCUSSION This report represents the first and largest series to validate the current definition of EAD in LT using allografts from DCD donors. In this report of 205 consecutive recipients of liver allografts from DCD donors, we identified a high incidence of EAD. More importantly, those recipients with EAD had a significant patient and allograft survival disadvantage in comparison with those without an EAD diagnosis. EAD defines allografts with marginal function early after LT and provides a marker for potential morbidity
IC No IC
No EAD
EAD
16 108
13 68
NOTE. Pearson chi square test: P 5 0.527.
from early allograft loss and mortality. This definition has been validated as a predictor of poor allograft and patient outcomes in a multicenter study of 297 deceased donor LT cases.5 However, only 10% of the patients in the cited study were recipients of DCD liver allografts. The incidence of EAD in this specific subset of LT recipients and their outcomes have previously not been studied. In our series, 39.5% of the patients who had undergone transplantation with livers from DCD donors met the criteria for EAD. This rate is higher than that in other reported series, such as the National Institute of Diabetes and Digestive and Kidney Diseases cohort and the multicenter cohort study, which demonstrated an overall 23% incidence.1 A previous publication from a single institution reported an incidence of 39.8%, but the breakdown of DCD and DBD allografts was not reported.21 The University of Western Ontario reported a series of
NOTE. Patient survival and graft survival are listed as percentages for patients who did not have the components of EAD versus those who did.
90 versus 100 90 versus 60 90 versus 86 90 versus 100 90 versus 43 90 versus 0 90 versus 0 96 versus 100 96 versus 60 96 versus 94 96 versus 100 96 versus 85 96 versus 100 96 versus 50 100 versus 100 100 versus 80 100 versus 96 100 versus 100 100 versus 86 100 versus 100 100 versus 50 1 2 2 1 2 1 1
2 1 2 1 1 2 1
2 2 1 2 1 1 1
1 10 58 1 7 2 2
95 versus 100 95 versus 70 95 versus 87 95 versus 100 95 versus 57 95 versus 0 95 versus 0
at 1 Year (%) at 1 Year (%)
Survival Graft Survival
at 6 Months (%) 6 Months (%) Patients (n)
Survival at 2000
ALT or AST
IU/mL 10 mg/dL
TABLE 4. Individual Components of EAD Day 7
Bilirubin Day 7
INR 1.6
Graft Survival
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LEE ET AL. 1451
38 recipients of DCD allografts, among whom 26 (68%) met the criteria for EAD.13 In its comparative cohort of DBD recipients, only 19 of 89 (21%) met the criteria for EAD. It is clear from previously published reports and the current report that DCD liver allograft recipients are at higher risk for developing EAD, and this supports the belief that these are higher risk organs. In this report, we also sought to identify risk factors for EAD. Insight into the development of EAD may help to identify areas for intervention to improve outcomes after LT. The univariate analysis suggests that events in the operating room may be most important in driving the development of EAD. Variables such as recipient BMI, CIT, WIT, and operative time were significantly higher in the EAD group. Although the volume of intraoperative PRBC transfusions was not statistically different, there appeared to be a skewing toward higher transfusion requirements for those recipients who developed EAD. An elevated BMI is a known confounder of LT and contributes to prolonged operative times and postoperative morbidity.22 In this study, the mean BMI for our DCD recipients straddled the distinction between overweight and obese. Those patients who did not experience EAD had a mean BMI of 28.5 kg/m2, and those who did have EAD had a mean BMI of 30.3 kg/ m2. This subtle difference was almost statistically significant and may serve as a proxy for the difficult operative candidate. Other proxies for the difficult operation are represented by CIT, WIT, and operative times. CIT was on the whole within a very tight range: 6.4 hours in recipients with EAD and 5.7 hours in recipients without EAD. This small difference proved also to be statistically significant in the logistic regression model as an independent risk factor for developing EAD. The impact of CIT on early graft function has been known since the early experience of LT. Shortening the distance to be traveled for organ procurement and the geographic area of organ sharing have an impact on overall outcomes and perhaps are more important for DCD liver allografts.23 In our experience, CIT was independent of the geographic distance from the donor hospital to our transplant center. This difference in travel time may be different for other transplant programs, however. In theory, those patients who require a more complex hepatectomy as a result of body habitus, prior upper abdominal surgery, or their degree of portal hypertension are more likely to have prolonged CIT. This operative complexity is also confirmed by the statistically significant longer average WIT and operative time for those patients who developed EAD. Certainly, the variables in the operating room are more difficult to assess, and the detail of data needed to address this question exceeds the capacity of our current database. For now, the proxies for a difficult LT operation—an increased BMI; longer operating times, CIT, and WIT; and increased transfusion requirements—all support the notion that events in the operating room play a critical role in the development of EAD in the recipients of DCD liver allografts.
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An important finding in the current analysis is the increased risk for developing EAD in recipients with HCC as a secondary diagnosis. It is unclear to us at this time why this diagnosis would provide an increased risk. One previous study suggests an interaction between HCC and receiving a DCD allograft that leads to inferior survival.24 However, the study is plagued by the limitations of registry-based data and absence of HCC recurrence data. Even though the authors provide an important observation, they are left to speculate on the reasons for the poorer outcomes for recipients with an HCC diagnosis when DCD allografts are used. Drawing from animal models, the authors speculate that there is an interplay between ischemia/reperfusion injury and HCC recurrence. However, the HCC recurrence data are not available in the registry data set. In the same study, parallel to our findings, prolonged CIT and WIT were found to contribute to poorer patient survival in the HCC recipients of DCD allografts. The interaction of DCD allografts in recipients with HCC as it specifically relates to tumor recurrence is beyond the scope of this study and deserves a future detailed analysis with properly matched DBD controls. This interaction is an important finding because the proportion of recipients with HCC as a secondary diagnosis has been increasing. The mechanism underlying the development of EAD presents a challenge to LT practice using DCD donors independent of the development of IC. Previous studies have sought to define DWIT to identify its impact on LT outcomes with DCD grafts. In this study, DWIT, defined as the time from extubation to crossclamping, did not have any impact on the risk for EAD, just as in our previous analyses, in which DWIT did not have an impact on the development of either IC or overall biliary complications. As demonstrated by our data, EAD suggests a process of primary liver dysfunction that cannot predict patients who will develop IC. With an IC diagnosis for 29 (14%) of our DCD recipients, our study may be too small to clarify the interaction between EAD and IC. This study fills a void in the current understanding of EAD in LT using DCD liver allografts. Although this is the largest DCD experience addressing the incidence of, reasons for, and outcomes of EAD in this subset of LT patients, it is limited by the single-center nature of the data set. One advantage of single-center data is the granular and homogeneous nature of the data without center-specific variation. We acknowledge that the experience with liver allografts from DCD donors is not universal. High rates of IC, PNF, and HAT are thought to be reasons for poor outcomes in LT with DCD allografts. However, in the recipients who do not experience these well-known complications, the initial injury sustained by the allograft is here shown to result in inferior outcomes in the long term. Further analysis with DBD controls may provide a deeper understanding of differences between LT with DCD donors and LT with DBD donors; however, this is beyond the scope of this study. Although the
LIVER TRANSPLANTATION, December 2014
length of the hospital stay was prolonged in recipients who had EAD and serves as a proxy for resource utilization, a lack of detailed resource utilization data remains a weakness of the current study. In conclusion, this study in a single large transplant center demonstrates that EAD in LT using DCD liver grafts results in inferior graft and patient outcomes. The high incidence of EAD in the DCD recipient cohort supports the notion that livers from DCD donors are marginal grafts. Also, EAD is not predictive of patients who will develop IC. In addition to HCC as a secondary diagnosis, events in the perioperative period predispose the recipients of DCD allografts to EAD. As the liver graft scarcity intensifies, an emphasis on expanding donor criteria occurs. Systematic utilization of extended criteria donors, such as DCD donors, increases access to LT and reduces wait-list mortality.25 As a result of increasing numbers of extended criteria donors, the LT community will have to adapt by identifying strategies to decrease complications related to liver allografts coming from these donors. Understanding the events that cause EAD and developing preventative and early therapeutic approaches should be the focus of future investigations to increase allograft and patient survival and to decrease resource utilization in the posttransplant period.
REFERENCES 1. Desch^ enes M, Belle SH, Krom RA, Zetterman RK, Lake JR. Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Transplantation 1998;66: 302-310. 2. Ploeg RJ, D’Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, et al. Risk factors for primary dysfunction after liver transplantation—a multivariate analysis. Transplantation 1993;55:807-813. 3. Strasberg SM, Howard TK, Molmenti EP, Hertl M. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation. Hepatology 1994;20(4 Pt 1): 829-838. 4. Gonz alez FX, Rimola A, Grande L, Antolin M, GarciaValdecasas JC, Fuster J, et al. Predictive factors of early postoperative graft function in human liver transplantation. Hepatology 1994;20:565-573. 5. Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010;16:943949. 6. Croome KP, Hernandez-Alejandro R, Chandok N. Early allograft dysfunction is associated with excess resource utilization after liver transplantation. Transplant Proc 2013;45:259-264. 7. Camci C, Akdogan M, Gurakar A, Gilcher R, Rose J, Monlux R, et al. The impact of total plasma exchange on early allograft dysfunction. Transplant Proc 2004;36: 2567-2569. 8. Deschenes M. Early allograft dysfunction: causes, recognition, and management. Liver Transpl 2013;19(suppl 2): S6-S8. 9. Friedman BH, Wolf JH, Wang L, Putt ME, Shaked A, Christie JD, et al. Serum cytokine profiles associated
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with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl 2012;18:166-176. 10. Renz JF. Is DCD for liver transplantation DNR? Am J Transplant 2008;8:485-488. 11. Mathur AK, Heimbach J, Steffick DE, Sonnenday CJ, Goodrich NP, Merion RM. Donation after cardiac death liver transplantation: predictors of outcome. Am J Transplant 2010;10:2512-2519. 12. Merion RM, Pelletier SJ, Goodrich N, Englesbe MJ, Delmonico FL. Donation after cardiac death as a strategy to increase deceased donor liver availability. Ann Surg 2006;244:555-562. 13. Croome KP, Wall W, Quan D, Vangala S, McAlister V, Marotta P, Hernandez-Alejandro R. Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts. Hepatobiliary Pancreat Dis Int 2012;11: 372-376. 14. Saidi RF, Bradley J, Greer D, Luskin R, O’Connor K, Delmonico F, et al. Changing pattern of organ donation at a single center: are potential brain dead donors being lost to donation after cardiac death? Am J Transplant 2010;10:2536-2540. 15. Kramer AH, Zygun DA, Doig CJ, Zuege DJ. Incidence of neurologic death among patients with brain injury: a cohort study in a Canadian health region. CMAJ 2013; 185:E838-E845. 16. Bendorf A, Kelly PJ, Kerridge IH, McCaughan GW, Myerson B, Stewart C, Pussell BA. An international comparison of the effect of policy shifts to organ donation following cardiocirculatory death (DCD) on donation rates after brain death (DBD) and transplantation rates. PLoS One 2013;8:e62010. 17. Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783-790.
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18. Taner CB, Bulatao IG, Willingham DL, Perry DK, Sibulesky L, Pungpapong S, et al. Events in procurement as risk factors for ischemic cholangiopathy in liver transplantation using donation after cardiac death donors. Liver Transpl 2012;18:100-111. 19. Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol 1993; 138:923-936. 20. Taner CB, Bulatao IG, Perry DK, Sibulesky L, Willingham DL, Kramer DJ, Nguyen JH. Asystole to cross-clamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors. Transpl Int 2012;25:838846. 21. Wagener G, Raffel B, Young AT, Minhaz M, Emond J. Predicting early allograft failure and mortality after liver transplantation: the role of the postoperative Model for End-Stage Liver disease score. Liver Transpl 2013;19: 534-542. 22. LaMattina JC, Foley DP, Fernandez LA, Pirsch JD, Musat AI, D’Alessandro AM, Mezrich JD. Complications associated with liver transplantation in the obese recipient. Clin Transplant 2012;26:910-918. 23. Furukawa H, Todo S, Imventarza O, Casavilla A, Wu YM, Scotti-Foglieni C, et al. Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution. Transplantation 1991;51:1000-1004. 24. Croome KP, Wall W, Chandok N, Beck G, Marotta P, Hernandez-Alejandro R. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl 2013;19:1214-1223. 25. Renz JF, Kin C, Kinkhabwala M, Jan D, Varadarajan R, Goldstein M, et al. Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg 2005;242:556-563.
