Split liver transplantation and risk to the adult recipient: analysis using matched pairs

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1 Volume 195, Issue 5, Pages (November 2002) Split liver transplantation and risk to the adult recipient: analysis using matched pairs Dieter C. Broering, Stefan Topp, Ulrich Schaefer, Lutz Fischer, Matthias Gundlach, Martina Sterneck, Volker Schoder, Werner Pothmann and Xavier Rogiers Orthotopic liver transplantation, established as a successful treatment for end-stage liver disease, is hampered by a persistent lack of cadaveric organs. In 2000, 853 patients awaiting liver transplantation in United States died before a suitable donor could be found [1]. Historically, the situation has been worse in children because of the difficulty of finding sizematched donors [2], but development of a reduced-size liver transplant technique has provided a first step in alleviating this problem [3-5]. Although this technique does not increase the number of grafts available, it shifts available organs from adults to pediatric recipients. Split liver transplantation (SLT) is another development in which the donor liver is divided in such a way that two grafts can be used for transplantation [6,7]. Initial results of SLT were poor, primarily because of a high incidence of primary nonfunction of the graft and technical problems [8-11]. Because of the general organ shortage, the high (up to 50%) mortality rates of pediatric patients on the waiting list [9,12], and the increasing need for size reduction to serve pediatric recipients, the method of liver splitting became ethically accepted. But the potential risk to the adult patient receiving the right extended graft (segment I, IV to VIII) was questionable. Over the years, better recipient selection and technical improvements led to better results [13-18]. Despite many publications of favorable results from transplantation of right extended split-liver grafts, a residual skepticism persists that these might be the result of favorable recipient and donor selection. Lingering concern that extended right liver grafts increase recipient risk has prohibited the implementation of mandatory liver splitting. A prospective randomized trial, comparing transplantation of a whole organ to an extended right lobe, is currently unavailable and is ethically questionable. We chose to perform a retrospective analysis using matched pairs to compare these two liver transplantation techniques. Methods An SLT program has been operational at the University of Hamburg since 1993, from which time liver splitting has been considered in all suitable donors. The decision whether the liver is suitable for splitting is made by an experienced transplant surgeon according to the following criteria: 1) cause of death, 2) length of stay in the ICU, 3) amount of catecholamines, 4) anatomic considerations, 5) quality of the graft, and 6) age of the donor. The splitting procedure is performed either in situ or ex situ, the in-situ technique preferred in the absence of hemodynamic instability or logistical problems. During the study period, the center allocation system was still implemented in Europe, and in our center every patient listed for liver transplantation was considered a potential

2 candidate for receiving a right extended split-liver graft. Urgency and cause of underlying liver disease did not influence allocation of split liver grafts. Between January 1993 and October 1999, 613 liver transplants (360 adults, 223 children) were performed in our institution. Three hundred sixty-two recipients received full size organs, 31 received reduced size organs, 74 got grafts from living donors, and 146 got split liver grafts. Informed consent for a split graft was obtained from all patients. Of the 146 SLTs, 122 were primary cases and 24 were retransplants using split liver grafts. Among the 122 primary SLTs, 62 were right grafts (59 adults and 3 children), with a median weight of 1,200 g (680 g to 1,700 g), and 60 were left grafts (5 adults and 55 children), with a median weight of 319 g (200 g to 667 g). The 59 adult recipients of SLT were the subjects of this study and were matched to recipients who received a whole liver transplantation (WLT) in the same period. Matching Matching was performed for the following prognostic factors: 1) indication for transplantation, 2) United Network for Organ Sharing (UNOS) status (1 to 5), 3) donor age (<50; >50 years), 4) recipient age (<50; >50 years), 5) cold ischemic time (<12 hours; >12 hours), 6) Child-Pugh classification, and 7) year of transplantation. By using these 7 matching criteria, 40 matched pairs of adult recipients of right extended grafts (27 from in-situ and 13 from ex situ split) and whole organs were identified. The matching was done blinded to patient outcomes. Postoperative courses of these 80 patients were retrospectively analyzed. All splits in this study resulted in a left-lateral graft (segments II and III) for implantation in a pediatric recipient and an extended-right graft (segments I and IV to VIII) for implantation in an adult recipient. Immunosuppression Standard immunosuppression consisted of induction with antilymphocyte globulin, cyclosporine, azathioprine, and corticosteroids. Two patients in the SLT group and three patients in the WLT group received tacrolimus instead of cyclosporin as primary immunosuppression therapy. Definition of complications Primary nonfunction was defined as retransplantation within 10 days of implantation or death from a nonfunctioning graft. Primary poor function was identified if one of the transaminases (alanine transaminase, aspartate transaminase, and glutamate dehydrogenase) was higher than 2,000 U/L; or fresh frozen plasma had to be substituted for more than 5 days postoperatively. Fresh frozen plasma was substituted if the prothrombin time or factor 5 levels were below 35%. Rejection was defined as increasing serum transaminase levels accompanied by signs of rejection on biopsy. Biliary complications were defined as bile duct necrosis or stenosis or bile leakage requiring surgical intervention within 3 months of transplantation. Bile leakage was defined as total bilirubin in drainage fluid that doubled serum total bilirubin. In general, a policy of early surgical reintervention in case of potential complications was practiced, and every proved bile leakage underwent surgical intervention.

3 Statistics Survival rates were calculated according to the Kaplan-Meier method [19]. Differences in survival curves were compared using log-rank statistics. In the analysis of patient characteristics, Fishers exact test was used for categoric variables and the Mann-Whitney U- test was used for continuous variables. A p value less than 0.05 was considered statistically significant. The statistical power to detect a different 1-year survival rate of 25% (90 versus 65) was 73% (hazard ratio: 4). Results Recipients Of the 59 adult recipients of SLT grafts, only 40 recipients of right extended grafts could be matched with recipients of WLT. Both groups were similar with respect to recipient age, gender, urgency, and laboratory findings (Table 1). The main indications for transplantation were alcoholic liver cirrhosis (18 of 80, 22%), hepatitis-b (16 of 80, 20%), hepatitis-c (14 of 80, 17.5%), and fulminant hepatic failure (10 of 80, 12.5%) (Table 2). Fifty percent of the patients were in Child-Pugh class C.

4 Donors Characteristics and laboratory findings in the donors were similar (Table 3). Cold ischemic time was 620 minutes (range 295 to 1,455 minutes) in WLT and 540 minutes (range 285 1,490 minutes) in the SLT group (p = 0.21). ICU length of stay before graft harvesting was 3 days (range 0 to 11 days) in the SLT group compared with 2 days in the WLT group. Intraoperative and postoperative courses Median operation time was 7.3 hours (range 3.7 to 11.6 hours) in the SLT group and 7.8 hours (range 5 to 13.9 hours) in the WLT group (p = 0.49). The need for transfusion of packed red cells, fresh frozen plasma, and platelets during the transplant procedure was not different: 14.5 (range 0 to 60), 24.5 (range 0 to 112), and 7 (range 0 to 50), respectively, for the SLT group and 15.5 (range 0 to 38), 27 (range 0 to 64), and 8 (range 0 to 53), respectively, for the WLT group (p = 0.46, 0.31, and 0.8, respectively). There was no difference between the two groups in the need to transfuse packed red cells (WLT, 0 [range 0 to 17] versus SLT, 0.5 [range 0 to 16] P = 0.64), fresh frozen plasma (WLT, 0 [range 0 to 22] versus SLT, 1 [range 0 to 52] P = 0.69), and platelets (WLT, 4.5 [range 0 to 44] versus SLT, 0 [range 0 to 46] P = 0.51) during the postoperative period. The transaminase peak was higher in the SLT group. The aspartate aminotransaminase in the SLT group was 390 IU/L (range 26 to 4,384 IU/L), and in the WLT group was 260 IU/L (range 29 to 3,696 IU/L) (p = 0.45). Alanine aminotransaminase in the SLT group was 495 IU/L (range 106 to 2,838 IU/L) and in the WLT group was 318 IU/L (range 31 to 3,168 IU/L) (p = 0.49). The glutamate dehydrogenase peak was higher after SLT (Fig. 1). The incidence of reoperation in the first 3 postoperative months was 45% for the WLT group versus 32.5% in the SLT group (Table 4). The median postoperative ventilation time was 1 day in both groups.

5 Figure 1. Peak of ALT (alanine aminotransferase), AST (aspartate aminotransferase), and GLDH (glutamate dehydrogenase) after whole liver transplantation (WLT) and split liver transplantation (SLT). *Mann-Whitney U- test. The 3- and 12-month patient survival rates in the WLT group were 92.5% and 87.5%, respectively; they were 82.5% and 77.1%, respectively, in the SLT group (p = 0.358, log-rank test) (Fig. 2). The main causes of death are listed in Table 5. None of the deaths in the SLT group were related to the splitting procedure itself. The 3- and 12-month graft survival rates were 87.5% and 77.4%, respectively, in the WLT group and 80% and 74.5%, respectively, in the SLT group (p = 0.887, log- rank test) (Fig. 3). Patient and graft survival rates of the six UNOS 1 status patients receiving WLT was 100% after 3 and 12 months. The 3- and 12- month patient survival rate of the six emergency patients in the SLT group was 66.7% (p = 0.198); the graft survival rate was 50% (p = 0.139). Three- and 12-month patient survival rates in the elective patients (UNOS 3 and 4) were 91% and 82.4%, respectively, in the WLT group and 85.3% and 78.9%, respectively, in the SLT group (p = 0.944). Three- and 12- month graft survival rates in the elective patients were 85.3% and 73.5%, respectively, after WLT and 85.3% and 78.7%, respectively, after SLT (p = 0.682). Figure 2. Patient survival 24 months after transplantation of a whole organ (WLT, N = 40) or a split liver graft (SLT, N = 40). SLT, split liver transplantation; WLT, whole liver transplantation

6 Figure 3. Graft survival 24 months after transplantation of a whole organ (WLT, N = 40) or a split liver graft (SLT, N = 40). SLT, split liver transplantation; WLT, whole liver transplantation The rate of primary nonfunction was similar in both groups (1.5%). In both groups, neither hepatic artery thrombosis nor portal vein thrombosis led to primary nonfunction. Primary poor function was diagnosed in three patients (7.5%) after SLT and in six patients (15%) after WLT (p = 0.29) (Fig. 4). Biopsy-proved rejection was observed in 32.5% (13 of 40) of the WLT group and in 27.5% (11 of 40) of the SLT group (p = 0.63). Retransplantation was required in 7.5% of the patients (3 of 40) in both groups within 3 months. Figure 4. Incidence of postoperative complications within 3 months after whole liver transplantation (n = 40) and split liver transplantation (n = 40). LTX, liver transplantation; PNF, primary nonfunction; PPF, primary poor function; WLT, whole liver transplantation. Within 3 months of transplantation, four patients in the WLT group and five patients in the SLT group underwent reoperation for biliary complications (p = 0.5). Two patients (5%) in each group developed bile duct stenosis, and two patients in each group had bile duct necrosis. The rate of bile leakage was 5% in the SLT group and 2.5% in the WLT group (p = 0.17) (Fig. 4). Postoperative synthetic function (prothrombin time) did not differ between the two groups. The median total bilirubins in the WLT group on postoperative days 3, 7, and 14 were 5.4 mg/dl (range 0.7 to 31.5 mg/dl), 4.7 mg/dl (range 0.9 to 40.8 mg/dl), and 3.3 mg/dl (range 0.4 to 19.4 mg/dl), respectively; it was 6.8 mg/dl (range 0.1 to 17.4 mg/dl), 7.2

7 mg/dl (range 1.5 to 29.5 mg/dl), and 3.8 mg/dl (range 0.9 to 26.1 mg/dl) in the SLT group (p = 0.54, 0.08, and 0.47, respectively). Discussion A shortage of suitable donor organs was especially problematic in the pediatric population because of the difficulty in finding size-matched organs [9]. The development of reduced-size liver transplantation provided an answer to this particular problem [2-5,20]. The disadvantage, however, was that it shifted grafts from the adult donor pool to children. With improved surgical confidence, it was possible to develop techniques to split the liver into two transplantable grafts, one for a child and one for an adult recipient. Using SLT and living donor liver transplantation, most pediatric liver transplantation centers managed to reduce pretransplant mortality to near zero [21-24]. After an initial learning phase, the results of liver transplantation in children with these innovative techniques became equal to those of WLT [14-18,25]. In contrast, the initial patient and graft survival (67% and 50%, respectively) after transplantation of the right graft in the adult recipient were clearly inferior to those of whole liver transplants [4,9]. These poor results raised the conclusion that in SLT one plus one does not always equal two [26]. Improvements in technique and better donor and recipient selection led to a revival in the latter half of the 1990s [14,16]. Despite several publications showing favorable results [14,15,17,18], the procedure remained largely restricted to centers with mixed pediatric and adult populations. Other centers argued that the favorable results were either not comparable with those of WLT or were the result of systematic biases in patient and graft selection. Between 1988 and 1999, only 3% of transplants carried out in Europe were performed as SLTs [27]. Systematic application of SLT requires sufficient evidence of results comparable with those of WLT. The customary way to provide this evidence would be in the context of a prospective randomized trial. The ethical acceptability of this would be questionable. So, we performed a retrospective matched-pairs analysis on our patient population. The matching was based on the most important, generally recognized risk factors in liver transplantation [27-33]. To balance the influence of technical improvements in both groups, the year the transplantation took place was also used as a matching criterion. Although matching for donors was not initially intended when planning the study, we ended up with similar donors in each group. A recent study from the UCLA group concluded that donor length of stay was an independent predictor of survival after SLT [34]. In our study, a difference in donor characteristics was found for length of stay in the ICU, but this, surprisingly, to the disadvantage of the SLT group. The right extended liver lobe accounts for 80% of the standard liver volume in humans, which comprises 2.0% of the body weight. From experience in adult living donors, transplantation of grafts with more than 1% of the recipient s body weight can achieve results comparable with those with whole organ transplantation [35]. So size reduction from left lateral splitting does not affect size matching between donor and adult recipient. This is confirmed by similar rates of primary nonfunction and primary poor function in our study. There was no difference in postoperative graft function in either group.

8 In our series, neither portal vein thrombosis nor venous outflow problems were identified in either group. Two patients (5%) in the SLT group developed arterial stenosis; after whole organ grafting no arterial stenosis developed. This is consistent with reports in the literature from whole organ grafting [27,30]. The rate of biliary complications within 3 months of transplantation was low in both groups (SLT, 12.5% versus WLT, 10%). In 1994, Greif and associates [36] reported a biliary complication rate of 11.5% after 1,792 whole organ transplantations. Bile leakage either from the cut surface or the bile duct anastomosis was found in 5% of our SLT group, compared with a 2.5% rate of leakage of the bile duct anastomosis after WLT. In the Kings College split series [15], a biliary complication rate of 14.6% was reported. In a series of in-situ splitting, Busuttil and Goss [18] reported a bile leakage rate of 2.5%. In this study, no bile leakage was found after in situ splitting. Until the eighth postoperative day, the level of transaminases was higher in the SLT group than that in the WLT group. A difference was found only for the glutamate dehydrogenase peak on the second postoperative day. The higher transaminase level in the split group results from the physical trauma of splitting in addition to hypoperfusion of segments 1 and 4 of the right extended graft. This hypoperfusion does not lead to either increased intraperitoneal infection or septicemia. There is no major difference in the total number of relaparotomies in either group So, the assumption that SLT leads to more postoperative bleeding cannot be supported by our results. The main causes of death after SLT are similar to those reported after WLT. Twentysix percent of deaths in patients undergoing transplantation for primary sclerosing cholangitis were related to sepsis [37]. In this analysis, 12-month patient and graft survival rates after SLT were comparable with those after WLT. Data from UNOS show that the 1-year patient and graft survival rates of liver transplants performed between January 1997 and December 1998 were 85.6% and 79.8%, respectively [38]. The 1-year patient survival rate of patients receiving transplants in Europe in 1997 was 83% [39]. In our group of highly urgent recipients, the patient survival rate of 66.7% (4 of 6) after SLT was lower, but not significantly different from that in the WLT group. This survival rate is comparable with the 61% survival rate of all highly urgent recipients in Europe [27]. In conclusion, SLT provides a unique opportunity to eliminate pretransplant mortality in children. Transplantation of right extended grafts and full-size livers does not differ notably with regard to patient and graft survival, initial graft function, or postoperative complications. SLT of the extended right lobe does not put the adult recipient at higher risk, provided the procuring center has sufficient technical expertise and provided the choice of the recipient can be adapted to the available graft. Adequate training for the procuring surgeons is necessary to safely establish such programs. Our results question the ethical acceptability of not splitting suitable donor livers. These results provide additional scientific and ethical justification for mandatory liver-splitting programs. Good quality cadaveric livers should be considered paired organs. Implementation of routine liver splitting for two adult recipients on a national basis would be the next major step [40-42]. Splitting every splittable organ for two adult recipients using full-right and full-left lobes could eventually increase the number of available grafts by 20% to 30%, decreasing the need for living-related liver transplantation between adults.

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