LIVER TRANSPLANTATION 18:101-112, 2012
ORIGINAL ARTICLE
Events in Procurement as Risk Factors for Ischemic Cholangiopathy in Liver Transplantation Using Donation After Cardiac Death Donors C. Burcin Taner, Ilynn G. Bulatao, Darrin L. Willingham, Dana K. Perry, Lena Sibulesky, Surakit Pungpapong, Jaime Aranda-Michel, Andrew P. Keaveny, David J. Kramer, and Justin H. Nguyen Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL
The use of donation after cardiac death (DCD) liver grafts is controversial because of the overall increased rates of graft loss and morbidity, which are mostly related to the consequences of ischemic cholangiopathy (IC). In this study, we sought to determine the factors leading to graft loss and the development of IC and to compare patient and graft survival rates for recipients of DCD liver grafts and recipients of donation after brain death (DBD) liver grafts in a large series at a single transplant center. Two hundred liver transplants with DCD donors were performed between 1998 and 2010 at Mayo Clinic Florida. Logistic regression models were used in the univariate and multivariate analyses of predictors for the development of IC. Additional analyses using Cox regression models were performed to identify predictors of graft survival and to compare outcomes for DCD and DBD graft recipients. In our series, the patient survival rates for the DCD and DBD groups at 1, 3, and 5 years was 92.6%, 85%, and 80.9% and 89.8%, 83.0%, and 76.6%, respectively (P ¼ not significant). The graft survival rates for the DCD and DBD groups at 1, 3, and 5 years were 80.9%, 72.7%, and 68.9% and 83.3%, 75.1%, and 68.6%, respectively (P ¼ not significant). In the DCD group, 5 patients (2.5%) had primary nonfunction, 7 patients (3.5%) had hepatic artery thrombosis, and 3 patients (1.5%) experienced hepatic necrosis. IC was diagnosed in 24 patients (12%), and 11 of these patients (5.5%) required retransplantation. In the multivariate analysis, the asystole-to-cross clamp duration [odds ratio ¼ 1.161, 95% confidence interval (CI) ¼ 1.021-1.321] and African American recipient race (odds ratio ¼ 5.374, 95% CI ¼ 1.368-21.103) were identified as significant factors for predicting the development of IC (P < 0.05). This study has established a link between the development of IC and the asystole-to-cross clamp duration. Procurement techniques that prolong the nonperfusion period increase the risk for the development of IC in DCD liver grafts. Liver Transpl 18:101-112, 2012. V 2011 AASLD. C
Received May 18, 2011; accepted August 1, 2011.
See Editorial on Page 5 The large imbalance between the number of available donor liver grafts and the number of patients waiting for liver transplantation (LT) has been the catalyst for
identifying new donor sources. Donation after cardiac death (DCD) donors are a significant source that could be used to expand the donor pool. For this type of donor, the declaration of death is based on cardiopulmonary criteria rather than the cessation of brain and brainstem function. The use of liver grafts from DCD
Abbreviations: BMI, body mass index; CI, confidence interval; CIT, cold ischemia time; DBD, donation after brain death; DCD, donation after cardiac death; DRI, donor risk index; DWIT, donor warm ischemia time; ERCP, endoscopic retrograde cholangiopancreatography; HAT, hepatic artery thrombosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; IC, ischemic cholangiopathy; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; OPO, organ procurement organization; PNF, primary nonfunction; PTC, percutaneous transhepatic cholangiography; WIT, warm ischemia time. 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.22404 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 2011 American Association for the Study of Liver Diseases. V
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donors increased in the first half of the last decade but has reached a plateau in recent years.1 The reported outcomes with this type of liver graft have been inferior to the outcomes with donation after brain death (DBD) liver grafts.2,3 DCD procurement subjects the liver graft to warm ischemia, which may result in increased rates of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and ischemic cholangiopathy (IC). IC can lead to intrahepatic bile duct strictures, hepatic abscesses, and hepatic necrosis, which can result in graft loss. An analysis of pooled national data has identified DCD liver grafts as high-risk grafts because of the overall increased rates of graft loss and morbidity, which are mostly related to the consequences of IC.4 The reported experiences of individual transplant programs also have recognized DCD grafts as high-risk grafts.5,6 Even though the transplant community has recognized the need to increase the number of organs to reduce the number of deaths while patients are on the waiting list, there is an overall reluctance to use DCD liver grafts. Previous publications have sought to identify risk factors for the development of complications in DCD grafts as well as ways to delineate the care for patients experiencing these complications. The United Network for Organ Sharing registry provides data for a large number of transplants, which can be used to analyze a variety of factors for different outcomes. However, because of data heterogeneity and a lack of registry data for events at the time of procurement, our understanding of the differences in the outcomes of DCD and DBD grafts is incomplete.4,7 Reports from individual transplant centers with relatively limited experience have also fallen short of identifying risk factors.5,6,8 This retrospective analysis, which represents the largest single-center experience to date, was undertaken to compare the outcomes of DCD and DBD LT during the same time period. In addition, we specifically examined the events during DCD procurement as potential risk factors. We present new data and analyses related to the procurement timeline for the DCD group that build on our previous reports assessing risk factors for the development of IC and graft loss.9,10
PATIENTS AND METHODS This is a retrospective review of LT cases using grafts from DCD donors between December 1998 and February 2010 at Mayo Clinic Florida (Jacksonville, FL). Approval for the study was obtained from the Mayo Clinic institutional review board. The study was performed via chart reviews of all LT cases with DCD or DBD organs during the same time period. The recipient data included the age, sex, liver disease etiology, presence of hepatocellular carcinoma (HCC), body mass index (BMI), calculated Model for EndStage Liver Disease (MELD) score at the time of transplant, and follow-up time. Detailed information regarding the DCD and DBD donors was obtained from the Mayo Clinic Florida procurement database. The donor information included the age, sex, share status (geographic loca-
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tion), cause of death, donor warm ischemia time (DWIT), cold ischemia time (CIT), warm ischemia time (WIT), donor risk index (DRI), and individual DRI components. All DCD donors were classified as Maastricht type 3 (controlled and awaiting cardiac death).11 For DCD donors, DWIT was defined as the time from the withdrawal of both ventilator and cardiac support to the start of cold perfusion of the organ (which was immediately followed by aortic cross-clamping). CIT was defined as the time from the infusion of the cold preservation solution to the portal reperfusion of the liver in the recipient. WIT was defined as the warming period for the liver graft during implantation (ie, the period between the removal of the cold preservation solution and reperfusion through portal flow). For DCD donors, detailed information for different time points during procurement (withdrawal of support to asystole period; mandatory wait period; asystole to aortic cross clamp period; incision to aortic cross clamp period) were collected. The outcomes included the patient and graft survival rates for recipients of liver grafts from DCD or DBD donors, the retransplantation rates, and the incidence of PNF, HAT, and IC in recipients of DCD grafts. After 2008, informed consent for the use of DCD grafts was obtained from LT candidates at the time of their transplant evaluation.
Surgical Techniques For the DCD donors, the withdrawal of support, the institution of comfort measures, and the declaration of death were in strict compliance with local organ procurement organization (OPO) and donor hospital policies. At no time was the transplant team involved in the withdrawal process or in determining the way in which withdrawal should occur. After consent was obtained, each patient was either taken to a preoperative holding area or brought to the operating room with full cardiopulmonary support in place. An independent physician from the donor hospital who was separate from the OPO and the transplant center was assigned to withdraw artificial life support and provide end-of-life care to the patient. The blood pressure, oxygen saturation, and respiratory rate were recorded at 1-minute intervals. After the declaration of death by the independent physician, mandatory observation for another 2 or 5 minutes was performed as described in the 1997 Institute of Medicine guidelines.12 During the mandatory waiting period, the patient was transported to the operating room (if he was not already there) and was prepared for organ recovery. Heparin was administered to the patient according to the donor hospital policy. After the mandatory waiting time, a rapid retrieval technique was used; that is, the abdomen was opened with a cruciate incision.9,10,13 The small bowel was reflected superiorly, and the aorta and portal systems were cannulated for an in situ flush. A cold preservation fluid, which consisted of University of Wisconsin solution, heparin, and glutathione, was flushed through the abdominal aorta and portal system (via the
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inferior mesenteric vein). The intrathoracic descending aorta was cross-clamped either by 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 infusion of the preservation solution, 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 was packaged in cold University of Wisconsin solution and transported back to the hospital for implantation. Thrombolytic agents were not used in either the donor or the recipient. The retrieval of organs from DBD donors was performed according to a standard technique with an aortic and portal system flush using University of Wisconsin solution. All transplants were performed with the piggyback technique without portocaval shunts, caval clamping, or venovenous bypass. All liver grafts were reperfused with portal flow, which was followed by arterial flow. Duct-to-duct biliary reconstruction with transcystic biliary tube was used except in recipients with primary sclerosing cholangitis or when deemed unfeasable by the recipient surgeon. In a duct-to-duct biliary reconstruction, a 5-Fr ureteral stent (a polyurethane ureteral catheter, C. R. Bard, Inc, Covington, GA) was placed via a cystic duct and was secured to a cystic duct stump with 5-0 Vicryl sutures and a hemorrhoidal rubber band. The biliary tube was then externalized through the abdominal wall, secured to skin, and left to gravity drainage. After a posttransplant cholangiogram on day 3, the biliary tube was capped until a cholangiogram on day 21. If this cholangiogram revealed a normal biliary tree, the biliary tube was then removed.14 The standard immunosuppression protocol consisted of tacrolimus, mycophenolate mofetil, and prednisone. Pretransplant liver graft biopsy is not routine in our practice; it is performed only when we suspect steatosis or a poor-quality liver graft. Preservation injury was determined by our liver pathologists on the basis of postreperfusion liver biopsy samples obtained 1 hour after liver graft reperfusion. The pathologists were blinded to the type of liver graft. Parenchymal damage was reported subjectively as mild, moderate, or severe preservation injury. Rejection episodes were treated with intravenous steroid boluses and with increases in the target range for tacrolimus. Steroid-resistant rejection was treated with thymoglobulin. IC was defined as diffuse intrahepatic bile duct strictures in the absence of HAT and was diagnosed either with cholangiography via an intraoperatively placed transcystic duct biliary tube or with endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC).
survival rates of the groups were compared with Kaplan-Meier plots and log-rank tests. Graft 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). Cox regression was used in the univariate and multivariate analyses of predictors for graft survival. The assumption of proportional hazards was assessed with log-log plots, with an examination of the correlation of Schoenfeld residuals with time, and with extended Cox models with time-dependent variables. When the assumption of proportional hazards was violated, we ran extended Cox models that included interaction terms involving the variable and a Heaviside function to obtain constant hazard ratios (HRs) for different time intervals. Logistic regression was used in the univariate and multivariate analyses of predictors for the development of IC and hepatic necrosis. For both Cox regression and logistic regression analyses, variables that were significant at P < 0.20 in the univariate analysis and variables that might have confounding effects or are clinically important were entered into the initial multivariate model. After the fitting of the preliminary multivariate model, variables that were not significant at P < 0.05 and whose removal would not produce significant (>20%) changes in the coefficients of the remaining variables were excluded from the final model. Clinically important variables were retained in the final multivariate model. Multicollinearity among covariates was determined by an examination of the correlation of regression coefficients. None of the variables that were entered into the multivariate model were collinear. Significance was defined as P < 0.05. Given our sample size of 2030 subjects (a 1:9 DCD/ DBD ratio), we estimated the power to detect a 10% difference in DCD and DBD graft survival rates and patient survival rates at 5 years: our sample had >85% power to detect graft survival differences at a ¼ 0.05 and >90% power to detect patient survival differences at a ¼ 0.05. The statistical analysis was performed with SPSS 17.0 (SPSS, Chicago, IL) and STATA 10 (StataCorp LP, College Station, TX).
Statistical Analysis
Graft and Patient Survival
Categorical variables were examined with the chisquare test, and continuous variables were analyzed with the Mann-Whitney U test. The graft and patient
There were no significant differences in the graft and patient survival rates of DCD and DBD graft recipients (Figs. 1 and 2). The graft survival rates for the
RESULTS Between February 1998 and February 2010, 2030 LT procedures were performed at the Mayo Clinic Florida transplant program. We first performed LT with a graft from a DCD donor in December 1998. In all, 200 LT procedures using DCD liver grafts were performed by February 2010. The mean follow-up time for the DCD group was 49.4 months (median ¼ 47 months, range ¼ 0-139 months).
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Figure 1.
Graft survival after LT with DBD and DCD grafts.
DCD and DBD groups at 1, 3, and 5 years were 80.9%, 72.7%, and 68.9% and 83.3%, 75.1%, and 68.6%, respectively. The patient survival rates for the DCD and DBD groups at 1, 3, and 5 years were 92.6%, 85.0%, and 80.9% and 89.8%, 83.0%, and 76.6%, respectively.
Donor and Recipient Characteristics The recipient and donor characteristics and the perioperative data are summarized in Table 1. The DCD and DBD groups were similar with respect to the recipient age, sex, race, and calculated MELD score at the time of LT as well as WIT. The groups were significantly different with respect to the donor age, sex, race, cause of death, and geographic distribution (with respect to our program) as well as CIT and DRI. The DCD donors were younger, more likely to be male, and Caucasian; trauma was more common as the cause of death in the DCD group; and more than half of the DCD grafts came from our local OPO service area. Specific time points of DCD liver graft procurement are illustrated in Fig. 3. For the whole DCD group, the mean DWIT was 25.3 6 10.8 minutes (median ¼ 24 minutes, range ¼ 4-85 minutes), the mean asystoleto-crossclamp time was 9.4 6 3.2 minutes (median ¼ 9 minutes, range ¼ 3-21 minutes), and incision-tocross clamp time was 4.2 6 2.2 minutes (median ¼ 4 minutes, range ¼ 1-12 minutes). The mandatory waiting time after asystole was available in 189 cases: there was a 2-minute waiting time in 61 cases and a 5-minute waiting time in 128 cases. There was no available information about the location of the patients at the time of life-support withdrawal.
Complications in DCD Recipients Major complications in the DCD group are shown in Fig. 4. One patient died intraoperatively because of a
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Figure 2.
Patient survival after LT with DBD and DCD grafts.
cardiac event. Five patients (2.5%) had PNF: all underwent retransplantation and demonstrated longterm survival after the second graft. Seven patients (3.5%) had HAT: early HAT was diagnosed within the first week after LT for 5 patients, and delayed HAT was diagnosed beyond the first 7 days after LT for 2 patients. Four of these patients had successful second transplants. Three patients (1.5%) had hepatic necrosis, and IC was diagnosed in 24 patients (12%). In comparison, 26 recipients of DBD liver grafts had PNF (1.4%), 37 had early HAT (2%), and 35 had IC (1.9%).
Biliary Complications and IC Eleven of 24 recipients who were diagnosed with IC underwent retransplantation (5.5%; Fig. 5). Eight of these recipients were alive as of December 2010, whereas 3 patients died from congestive heart failure, metastatic HCC, or sepsis. Five of the recipients who were diagnosed with IC (median age ¼ 56 years, range ¼ 49-66 years) died before they received a second transplant (all from complications of IC; median survival ¼ 7 months, range ¼ 3-36 months). Eight of the recipients (median age ¼ 57.5 years, range ¼ 39-72 years) were alive and had not undergone retransplantation at the time of their last follow-up (median follow-up ¼ 37 months, range ¼ 19-55 months). These patients had a complicated postoperative course: 1 patient required reoperation for postoperative hemorrhaging, 4 patients experienced postoperative bacteremia, all 8 patients underwent 1 to 3 ERCP procedures (mean number ¼ 2.25) within the first postoperative year, and none of these patients required any additional surgical or endoscopic/percutaneous treatments beyond the first posttransplant year. None of the 8 patients were on chronic suppressive antibiotics or had indwelling PTC tubes at the time of this writing. Three of the 8 patients were listed for
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TABLE 1. Recipient and Donor Characteristics and Perioperative Data for the DBD and DCD Cohorts
Recipient characteristics Age (years) Male sex [n (%)] Race [n (%)] Caucasian African American Other MELD score HCV [n (%)] HCC [n (%)] Operating-room time (minutes) Hospital stay (days) Donor/graft characteristics DRI Age (years) Male sex [n (%)] Height (cm) Weight (kg) BMI (kg/m2) Cause of death [n (%)]§ Trauma Anoxia Cerebrovascular accident Other Race [n (%)] Caucasian African American Other Location [n (%)] Local Regional National Procurement times CIT (hours) WIT (minutes) DWIT (minutes) Asystole-to-crossclamp duration (minutes) Imcision-to-crossclamp duration (minutes) Mandatory waiting time [n (%)]# 2 minutes 5 minutes
DBD Patients (n ¼ 1828)
DCD Patients (n ¼ 200)
P Value
54.1 6 10.4 (15.0-80.0, 55.0) 1203 (65.7)
55.1 6 9.4 (15.0-75.0, 55.0) 145 (72.5)
0.154 0.055 0.762
1484 (81.1) 84 (4.6) 262 (14.3) 18.5 6 8.6 (6.0-63.0, 17.0) 722 (39.5) 342 (18.7) 271.8 6 103.6 (107-860, 251) 19.2 6 33.3 (1.0-394.0, 9.0)*
163 (81.5) 11 (5.5) 26 (13.0) 17.9 6 7.9 (6.0-51.0, 17.0) 102 (51.0) 46 (23.0) 259.9 6 85.3 (100-547, 244) 19.2 6 34.4 (5.0-338.0, 9.0)
1.66 6 0.46 (0.83-4.35, 1.62)† 46.6 6 19.7 (2.0-90.0, 48.0) 1032 (56.4) 169.3 6 12.9 (94-220, 170) 79.5 6 23.6 (15-195, 77) 27.6 6 7.7 (11.5-77.5, 26.0)
1.98 6 0.51 (1.29-4.15, 1.86)‡ 40.3 6 16.4 (7.0-81.0, 41.5) 137 (68.5) 173.0 6 11.2 (122-193, 175) 82.4 6 21.6 (30-233, 80) 27.6 6 6.9 (13.4-71.9, 26.5)
585 (32.1) 207 (11.3) 995 (54.5) 38 (2.1)
95 (47.5) 51 (25.5) 48 (24.0) 6 (3.0)
1272 (69.5) 302 (16.5) 256 (14.0)
177 (88.5) 15 (7.5) 8 (4.0)
404 (22.1) 992 (54.3) 432 (23.6)
111 (55.5) 72 (36.0) 17 (8.5)
7.0 6 1.9 (1.97-15.25, 6.7)k 34.2 6 12.7 (8.0-72.0, 32.0)†
6.0 6 1.5 (3.02-10.52, 5.75)‡ 33.9 6 12.3 (17.0-66.0, 32.0)‡ 25.3 6 10.8 (4.0-85.0, 24.0) 9.4 6 3.2 (3.0-21.0, 9.0) 4.2 6 2.2 (1.0-12, 4.0)
0.405 0.002 0.141 0.117 0.997
