Events in Procurement as Risk Factors for Ischemic Cholangiopathy in Liver Transplantation Using Donation After Cardiac Death Donors

Transcription

1 LIVER TRANSPLANTATION 18: , 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 ] and African American recipient race (odds ratio ¼ 5.374, 95% CI ¼ ) 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: , VC 2011 AASLD. Received May 18, 2011; accepted August 1, 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 Telephone: ; FAX: ; taner.burcin@mayo.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2011 American Association for the Study of Liver Diseases.

2 102 TANER ET AL. LIVER TRANSPLANTATION, January 2012 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 End- Stage 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 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. 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

3 LIVER TRANSPLANTATION, Vol. 18, No. 1, 2012 TANER ET AL. 103 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 < 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 The statistical analysis was performed with SPSS 17.0 (SPSS, Chicago, IL) and STATA 10 (StataCorp LP, College Station, TX). 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 In all, 200 LT procedures using DCD liver grafts were performed by February The mean follow-up time for the DCD group was 49.4 months (median ¼ 47 months, range ¼ months). Statistical Analysis Categorical variables were examined with the chisquare test, and continuous variables were analyzed with the Mann-Whitney U test. The graft and patient Graft and Patient Survival 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

4 104 TANER ET AL. LIVER TRANSPLANTATION, January 2012 Figure 1. Graft survival after LT with DBD and DCD grafts. Figure 2. Patient 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 minutes (median ¼ 24 minutes, range ¼ 4-85 minutes), the mean asystoleto-crossclamp time was minutes (median ¼ 9 minutes, range ¼ 3-21 minutes), and incision-tocross clamp time was 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 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 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 years) were alive and had not undergone retransplantation at the time of their last follow-up (median follow-up ¼ 37 months, range ¼ 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

5 LIVER TRANSPLANTATION, Vol. 18, No. 1, 2012 TANER ET AL. 105 TABLE 1. Recipient and Donor Characteristics and Perioperative Data for the DBD and DCD Cohorts DBD Patients (n ¼ 1828) DCD Patients (n ¼ 200) P Value Recipient characteristics Age (years) ( , 55.0) ( , 55.0) Male sex [n (%)] 1203 (65.7) 145 (72.5) Race [n (%)] Caucasian 1484 (81.1) 163 (81.5) African American 84 (4.6) 11 (5.5) Other 262 (14.3) 26 (13.0) MELD score ( , 17.0) ( , 17.0) HCV [n (%)] 722 (39.5) 102 (51.0) HCC [n (%)] 342 (18.7) 46 (23.0) Operating-room time (minutes) ( , 251) ( , 244) Hospital stay (days) ( , 9.0)* ( , 9.0) Donor/graft characteristics DRI ( , 1.62) ( , 1.86) <0.001 Age (years) ( , 48.0) ( , 41.5) <0.001 Male sex [n (%)] 1032 (56.4) 137 (68.5) Height (cm) (94-220, 170) ( , 175) <0.001 Weight (kg) (15-195, 77) (30-233, 80) BMI (kg/m 2 ) ( , 26.0) ( , 26.5) Cause of death [n (%)] <0.001 Trauma 585 (32.1) 95 (47.5) Anoxia 207 (11.3) 51 (25.5) Cerebrovascular accident 995 (54.5) 48 (24.0) Other 38 (2.1) 6 (3.0) Race [n (%)] <0.001 Caucasian 1272 (69.5) 177 (88.5) African American 302 (16.5) 15 (7.5) Other 256 (14.0) 8 (4.0) Location [n (%)] <0.001 Local 404 (22.1) 111 (55.5) Regional 992 (54.3) 72 (36.0) National 432 (23.6) 17 (8.5) Procurement times CIT (hours) ( , 6.7) k ( , 5.75) <0.001 WIT (minutes) ( , 32.0) ( , 32.0) DWIT (minutes) ( , 24.0) Asystole-to-crossclamp duration (minutes) ( , 9.0) Imcision-to-crossclamp duration (minutes) (1.0-12, 4.0) Mandatory waiting time [n (%)] # 2 minutes 61 (32.3) 5 minutes 128 (67.7) Significant P values are presented in bold. NOTE: Continuous variables are presented as means and standard deviations (with ranges and medians in parentheses). *n ¼ n ¼ n ¼ 199. n ¼ 1825 for the DBD patients. k n ¼ # n = 189. retransplantation (mean calculated MELD score ¼ 14, mean time from first transplant ¼ 37 months). Three additional patients were diagnosed with hepatic necrosis during the first month after LT: 1 patient underwent retransplantation, and 2 patients died. Overall, 19 grafts (9.5%) were lost because of IC or hepatic necrosis. Extrahepatic biliary strictures and bile leaks requiring surgical or percutaneous interventions were diagnosed in another 30 recipients (15%): 8 patients (4%) had only a bile leak, 11 patients (5.5%) had only an extrahepatic anastomotic biliary stricture, and 11 patients (5.5%) had a combination of a bile leak and an extrahepatic anastomotic biliary stricture. The predictors of graft loss for the overall LT cohort were examined in a multivariate analysis with Cox regression. In a univariate analysis, CIT, WIT, positive hepatitis C virus (HCV) status, presence of HCC, MELD score, African American recipient race, retransplantation within 1 year, donor age, and DRI

6 106 TANER ET AL. LIVER TRANSPLANTATION, January 2012 Figure 3. Different times during procurement. The time values in the table are means and standard deviations (with ranges and medians in parentheses). The other time values are medians. Figure 4. Major complications after LT with DCD grafts. were significant factors for graft loss; in the final multivariate Cox regression model, MELD score, WIT, positive HCV status, presence of HCC, donor age, and retransplantation within 1 year were significant factors associated with graft loss, whereas DCD status was not a significant factor. CIT was found to be

7 LIVER TRANSPLANTATION, Vol. 18, No. 1, 2012 TANER ET AL. 107 Figure 5. IC and subsequent management of patients with DCD liver grafts. a factor affecting graft survival within the first year after LT (Table 2). African American recipient race approached statistical significance as a factor for graft loss (P ¼ 0.069). Possible predictors of graft loss in the DCD cohort are shown in Table 3. Non-Caucasian recipient race and DCD grafts in retransplantation were significant factors for graft loss, whereas DWIT approached but did not achieve statistical significance. In the DCD cohort, 103 donors were more than 40 years old; the graft survival rates were similar with donors who were donors 40 years or younger and donors who were older than 40 years (P ¼ 0.78). Moreover, the graft survival rate with 25 donors who were 60 years or older was similar to the rate with donors who were less than 60 years old (P ¼ 0.66). Possible predictors of the development of IC or hepatic necrosis were examined with logistic regression. In a multivariate analysis, the asystole-to-cross clamp duration and African American recipient race were significant predictors for IC or hepatic necrosis (Table 4). Each minute increase in the asystole-to-cross clamp duration was associated with a 16.1% increase in the odds for the development of IC or hepatic necrosis, whereas the odds of an African American recipient developing IC or hepatic necrosis was 5.37 times greater than the odds for a Caucasian recipient. DISCUSSION This is the largest reported single-center experience to date concerning the outcomes of DCD liver grafts. Our program began using liver grafts from DCD donors in Since then, we have gained significant experience in using these grafts. Similarly to the national trend, the percentage of DCD liver grafts used at our center peaked in 2007 (19.4% of all LT cases). We previously reported our experience with DCD grafts and demonstrated low rates of IC and graft loss in comparison with other published singleinstitution reports. 9,10 This analysis was performed to identify risk factors associated with graft failure and the development of IC. In the last decade, DCD liver grafts have been identified as one approach to alleviating the donor organ shortage. 1,2 In agreement with the Health Resources and Services Administration goal of increasing the number of DCD donors, the percentage of these donors increased until 2007 when it reached 9.8% of all deceased donors. 4,15 The widespread interest in DCD grafts and their application, however, have been tempered by lower graft survival rates and higher biliary complication rates in comparison with DBD liver grafts. 5-7 Pooled United Network for Organ Sharing data and several single-institution experiences have shown inferior graft survival, which is mostly related to IC. 4-8 Most LT patients receive DBD organs. However, advances in traumatology, neurosurgery, and neuroradiology have improved immediate survival after devastating brain injury. Consequently, patients who are destined to become organ donors are increasingly not meeting brain death criteria. 15 Families wishing to donate in such circumstances can do so only after cardiac death occurs with the discontinuation of intensive care. DCD grafts offer an opportunity to maintain (if not increase) the annual number of LT procedures performed in the United States. To ensure excellent outcomes with these organs, refinements of the techniques for procurement and utilization are warranted.

8 108 TANER ET AL. LIVER TRANSPLANTATION, January 2012 TABLE 2. Univariate and Multivariate Analyses of Risk Factors for Graft Loss in All LT Cases Univariate Analysis Multivariate Analysis HR (95% CI) P Value HR (95% CI) P Value Recipient sex Female Male ( ) 0.191* Recipient age (years) ( ) 0.162* Raw MELD score ( ) <0.001* ( ) HCC No Yes ( ) 0.024* ( ) HCV status Negative Positive ( ) 0.031* ( ) Multiorgan transplant Yes No ( ) Recipient BMI (kg/m 2 ) ( ) 0.182* Recipient race Caucasian African American ( ) 0.048* ( ) Other ( ) Previous LT, <1 year No Yes ( ) <0.001* ( ) <0.001 Previous LT, 1 year No Yes ( ) ( ) CIT (hours) Graft loss, <1 year ( ) 0.000* ( ) <0.001 Graft loss, 1 year ( ) ( ) WIT (minutes) ( ) 0.004* ( ) DRI ( ) 0.004* ( ) <0.001 Donor race Caucasian African American ( ) Other ( ) Donor height (cm) ( ) Donor weight (kg) ( ) Donor BMI (kg/m 2 ) ( ) Organ share Local Regional ( ) National ( ) Donor age (years) ( ) 0.039* ( ) Donor sex Female Male ( ) Graft type DBD DCD ( ) 0.340* ( ) *Included in a preliminary multivariate model. The assumption of proportional hazards was violated; HRs were determined for different time points. IC is the leading cause of DCD graft loss and the complication that has prevented the widespread acceptance of DCD graft use by transplant centers. 2 The exact mechanism or mechanisms leading to IC are unknown. The combination of donor warm ischemia at the time of procurement and reperfusion in the recipient results in compromised blood flow in the peribiliary vasculature. 16 IC is not reversible, and the management options are limited. The identification of the factors playing roles in the development of IC is crucial to encouraging the greater use of these grafts. In the Mayo Clinic Florida experience reported herein, the overall rates of IC and related graft loss for DCD recipients were lower than those from other

9 LIVER TRANSPLANTATION, Vol. 18, No. 1, 2012 TANER ET AL. 109 TABLE 3. Univariate and Multivariate Analyses of Risk Factors for Graft Loss in DCD Graft Recipients Univariate Analysis Multivariate Analysis HR (95% CI) P Value HR (95% CI) P Value Recipient sex Female Male ( ) Recipient age (years) ( ) Raw MELD score ( ) HCC No Yes ( ) ( ) HCV status Negative Positive ( ) Multiorgan transplant Yes No ( ) Recipient BMI (kg/m 2 ) ( ) Recipient race Caucasian African American ( ) ( ) Other ( ) ( ) Previous LT No Yes ( ) ( ) CIT (hours) ( ) WIT (minutes) ( ) DWIT (minutes) ( ) ( ) Asystole/cross-clamp time (minutes) ( ) DRI ( ) Donor race Caucasian African American ( ) Other ( ) Donor height (cm) ( ) Donor weight (kg) ( ) Donor BMI (kg/m 2 ) ( ) Organ share Local Regional ( ) National ( ) Donor age (years) ( ) Donor sex Female Male ( ) centers: 24 recipients (12%) were diagnosed with IC, whereas 3 recipients (1.5%) had overwhelming damage (presenting as graft necrosis) within 2 to 3 weeks of LT. Overall, 19 of the grafts (9.5%) were lost. In most cases, IC was suspected on the basis of a cholangiogram obtained on postoperative day 21, and confirmation was obtained with either ERCP or PTC. Unlike extrahepatic biliary strictures, intrahepatic strictures were less amenable to percutaneous or endoscopic treatments. Diffuse and bilobar intrahepatic disease in the absence of HAT was used as the definition of IC in our study: this type of damage in the liver graft most likely requires retransplantation. Those patients who did not undergo retransplantation may have been on the mild side of the disease spectrum in terms of intrahepatic bile duct injury because they required 2.25 ERCP procedures on average within the first posttransplant year and none after the first year. Patients with a diagnosis of IC enjoy no advantage when they are listed for retransplantation in the current MELD system. However, early recognition and the timely treatment of bacteremia episodes associated with intrahepatic bile duct necrosis may prevent a potentially rapid deterioration of graft function and patient loss. An analysis of donor procurement and recipient variables possibly related to the development of IC revealed that the asystole-to-cross clamp duration was a significant factor. It is well known that hemodynamic events between the withdrawal of cardiopulmonary support

10 110 TANER ET AL. LIVER TRANSPLANTATION, January 2012 TABLE 4. Univariate and Multivariate Analyses of Risk Factors for the Development of IC and Hepatic Necrosis in DCD Liver Grafts Univariate Analysis Multivariate Analysis Odds Ratio (95% CI) P Value Odds Ratio (95% CI) P Value Recipient sex Male Female ( ) Recipient age (years) ( ) Raw MELD score ( ) Raw MELD score* ( ) ( ) Recipient BMI (kg/m 2 ) ( ) Recipient race Caucasian African American ( ) ( ) Other ( ) Steatosis <5% %-30% ( ) >30% ( ) Preservation injury None Mild ( ) Moderate ( ) CIT (hours) ( ) WIT (minutes) ( ) Peak alanine aminotransferase (IU/L) ( ) Trough factor 5 (%) ( ) DRI ( ) Donor age (years) ( ) Donor age* 40 years years ( ) years ( ) Donor sex Male Female Donor weight (kg) ( ) Donor height (cm) ( ) Donor BMI (kg/m 2 ) ( ) Organ share Local Regional ( ) National ( ) DWIT (minutes) ( ) Asystole-to-crossclamp duration (minutes) ( ) ( ) Incision-to-crossclamp duration (minutes) ( ) Mandatory waiting time 2 minutes minutes ( ) *The continuous variable was converted into a categorical variable (for the univariate analysis only). The total amount of microsteatosis and macrosteatosis. and asystole help to predict graft function. 17 Organ damage may be lessened if the donor progresses to cardiac death quickly instead of being exposed to an environment with a prolonged low-perfusion state. To our knowledge, this is the first study demonstrating the relationship of the no-flow state (the asystole-tocrossclamp duration) and the development of IC. Previously, DWIT was thought to be a factor in the development of IC; accordingly, procurement protocols in single institutions limit DWIT to approximately 20 to 30 minutes, and the American Society of Transplant Surgeons recommends minimization of DWIT. 11,18 DWIT

11 LIVER TRANSPLANTATION, Vol. 18, No. 1, 2012 TANER ET AL. 111 includes the asystole-to-crossclamp duration. Our current practice limits DWIT to 30 minutes. In our analysis, DWIT was not a significant factor for the development of IC, and this may be a function of the small overall variation in time. When we examined the individual time points, the asystole-to-crossclamp duration, which includes the mandatory waiting time, was a significant determinant of IC development. It is important to note that the American Society of Transplant Surgeons recommends a mandatory waiting time of 2 minutes, 11 whereas the Institute of Medicine recommends 5 minutes. 12 One of the weaknesses of our study is that the hemodynamic events in the agonal phase until asystole were not examined. Impaired end organ perfusion for an extended period of time can cause damage to the liver parenchyma. Perhaps the combination of an extended poor-perfusion period and a prolonged absence of perfusion can be devastating for the liver graft. Because the development of IC is an intermediate outcome and not all IC cases resulted in graft loss in our DCD experience, factors related to the development of IC were subdued in the analysis of graft loss: only non-caucasian recipient race and the use of a DCD graft for retransplantation were significant factors for graft loss. A firm conclusion about DCD graft use for liver retransplantation should not be extracted from our data because there were only 10 such cases. However, we have not used DCD grafts for retransplantation since There is a need for more reports from other large LT programs and for comparative analyses of liver retransplantation using liver grafts from DCD and DBD donors. Reports from single centers reflect policies and procedures unique to each institution. Since the start of our program, only staff surgeons have performed organ procurement. Even with the start of our transplant surgery training program, our trainees have been accompanied by staff transplant surgeons during organ procurement. For DCD cases, it is especially important for an experienced transplant surgeon to perform the procurement. We believe that part of our success is related to this approach. In our experience, we did not note an obvious learning curve: the incidence of IC remained relatively stable over the years, and the patient and graft survival rates remained comparable to those with DBD grafts. The overall graft and patient survival rates were similar for recipients of DCD and DBD grafts, and this was most likely a reflection of the low rates of IC. In fact, the 3- and 5- year patient survival rates in our DCD group were higher than the rates in the overall US experience. 4 In the multivariate analysis using a Cox regression model, we did not find DCD status to be a significant factor for graft loss. Prolonged CIT was previously reported to be a predictive factor for the development of IC and early graft loss. 16,19,20 Our total CIT was relatively short in comparison with previous reports. In fact, our mean CIT was significantly shorter for DCD grafts versus DBD grafts. A plausible explanation for this is that 55% of the DCD liver grafts were procured in our local OPO, whereas only 23% of our DBD liver grafts were. Another possible factor could be the relatively short median operating times of both groups, which were related in part to the use of the piggyback technique (251 minutes in the DBD group and 244 minutes in the DCD group). In contrast to other studies, donor age in the DCD group was not a significant factor in our study. 6,8,21 The graft survival rate with donors older than 40 years was similar to the rate with donors 40 years or younger; also, the graft survival rate with livers from donors who were 60 years or older was similar to the rate with livers from donors less than 60 years old. Similarly, we did not find any increases in IC or hepatic necrosis when older donors were used. Although the recipient s race was a risk factor for developing IC (Table 3), we are not able to provide an explanation with the current data set (the number of African American recipients of DCD liver grafts was limited); future research is needed to explore the reasons for this finding. Although the use of DCD donors could increase the number of donors, it should not decrease the number of DBD cases with early withdrawal of care. On the other hand, recent advances in the neurosurgical care of patients undoubtedly have resulted in an increasing number of DCD cases. 15,22 As a result of this changing practice, the LT community will have to adapt by identifying strategies for reducing complications related to DCD liver grafts (most commonly IC). The identification of variables associated with poor outcomes and ischemic damage to the graft remains a challenge, especially when pooled data are used. A valid problem with analyses of pooled data from different institutions is that each institution has different protocols for donor and recipient selection and different techniques for DCD procurement. We acknowledge that there is no perfect way of gathering data at the time of DCD organ procurement; however, the observations and analyses in this study have redirected our focus to the procurement process itself. A single-center analysis has the advantages of consistent and homogeneous donor and recipient selection criteria and perioperative and postoperative recipient management. Although this is the largest reported single-center experience, the number of DCD recipients was relatively small for adjustments for all risk factors for IC-related graft loss. Furthermore, we did not perform an analysis addressing the cost differences of DCD and DBD recipients. As the scarcity of liver grafts intensifies, the expansion of donor criteria will be emphasized. The widespread and successful use of DCD grafts could provide more timely access to LT. As suggested previously, the systematic use of extended criteria donors (including DCD donors) maximizes donor use, increases access to LT, and reduces wait-list mortality by providing satisfactory outcomes to select recipients. 23,24 The current analysis illustrates that our recipients had satisfactory outcomes with DCD liver grafts.

12 112 TANER ET AL. LIVER TRANSPLANTATION, January 2012 In conclusion, we have reported the largest singlecenter experience with DCD liver grafts to date and have demonstrated similar graft and patient survival rates with DCD and DBD grafts. Moreover, our analysis has clearly established for the first time a link between the development of IC and the asystole-tocrossclamp duration. Further attempts should be made by regulatory authorities and transplant societies to standardize procurement protocols and techniques with the goal of decreasing the inherent problems related to the use of DCD liver grafts. REFERENCES 1. Klein AS, Messersmith EE, Ratner LE, Kochik R, Baliga PK, Ojo AO. Organ donation and utilization in the United States, Am J Transplant 2010;10(pt 2): Renz JF. Is DCD for liver transplantation DNR? Am J Transplant 2008;8: Merion RM, Pelletier SJ, Goodrich N, Englesbe MJ, Delmonico FL. Donation after cardiac death as a strategy to increase deceased donor liver availability. 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