Split-liver transplantation: Past, present, and future

Split-Liver Transplantation: Past, Present, and Future Hasan Yersiz, John F. Renz, and Ronald W. Busuttil Split-liver transplantation, a procedure in which one cadaver liver is divided to provide for 2 recipients, has existed for over 15 years. Although SLT offers an immediate expansion of the cadaver-donor pool and decreased reliance on living-donation, SLT has not been widely applied within the United States. The continuing shortage of cadaver organs, coupled with the increasing realization of the limits of living donor liver transplantation in adults, has renewed interest in expanding SLT techniques to include 2 adult recipients from one adult cadaver donor. Significant obstacles to the widespread application of SLT exist and must be resolved by the transplant community before greater application of these techniques can be realized. This manuscript reviews current SLT results and how SLT may be further applied to alleviate the current organ shortage. © 2004 Elsevier Inc. All rights reserved.

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plit-liver transplantation (SLT) was simultaneously reported by Pichlmayr et al1 and Bismuth et al2 in 1989. Their technique involved the ex vivo division of an adult cadaver liver into a pediatric allograft and a remnant adult allograft. Transplantation of a partial-liver allograft for children was advocated by Smith3 in 1969 and was initially performed through the surgical reduction of a larger child or adult cadaver allograft, termed reducedliver transplantation by Bismuth and Houssin4 and Broelsch et al5 in 1984. These efforts were an attempt to satisfy an increasing demand for pediatric cadaver allografts that had resulted in prolonged waiting periods and a wait-list mortality of approximately 50% at major pediatric referral centers.6,7 Although increasing pediatric organ supply, reducedliver transplantation only shifted competition between adult and pediatric candidates for the same donor pool.6-9 Thus, to expand the donor pool, the surgical techniques of reduced-liver transplantation were modified to create 2 allografts suitable for transplantation of a child and adult.

From the Dumont-UCLA Transplant Center, University of California Los Angeles, Los Angeles, CA; and Center for Liver Disease and Transplantation, Columbia College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY. Address reprint requests to John F. Renz, MD, PhD, Center for Liver Disease and Transplantation, Columbia College of Physicians and Surgeons, 622 West 168th St, Room PH14C, New York, NY 10032. 0955-470X/$ - see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2004.02.001

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Technical Considerations Excellent manuscripts exist detailing the technical performance of SLT.10-14 These techniques require only standard surgical facilities with no specialized equipment and have been performed concomitant with additional abdominal and thoracic organ procurements. The anatomic classification system of Couinaud15 refined by Bismuth16 (Fig 1) has been universally accepted by the transplant communities of Europe, Asia, and North America as the reference for describing functionally distinct split-liver allografts (Fig 2). Division of the hepatic parenchyma at the falciform ligament yields a Couinaud segment II/III graft, termed a left lateral segment allograft, of approximately 250 mL volume for pediatric recipients17 and a remnant Couinaud segment I, IV-VIII right trisegment allograft of approximately 1,100 mL for transplantation of an adult.18 The left lateral segment allograft can be further reduced to a “monosegment allograft” (segment III) for very small infants and neonates.19 For transplantation of 2 larger individuals from one adult cadaver donor, the liver can be divided along the middle hepatic vein to create 2 nearly equal-sized allografts (Fig 2). Left lobe allografts of approximately 400 mL volume can be created with (Couinaud segments I-IV) or without the caudate lobe (Couinaud segments II-IV) for recipients typically less than 60-kg body mass. Right lobe allografts (Couinaud segments I, V-VIII, or V-VIII) have a typical volume of approximately 800 to 1,000 mL and are generally suitable for candidates ⱕ80 kg.10,12,13,20

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Figure 1. Segmental liver anatomy. The segmental anatomy of the liver as described by Couinaud15 and Bismuth.16 Each anatomic segment (roman numeral) receives a unique portal pedicle (light blue) consisting of a portal venous branch, hepatic arterial inflow, and bile duct. Individual segments are drained by unique hepatic venous outflow branches (dark blue) and separated by connective tissue scissurae.

SLT can be performed as an ex vivo procedure after a routine donor procurement at the recipient institution or as an in situ procedure with the entire dissection performed within the heart-beating cadaver. Ex vivo SLT requires a dedicated “benching” period that increases cold ischemia time and may expose the graft to potential rewarming through manipulation. The in situ SLT technique, introduced by Broelsch et al21 and Busuttil,22 incorporates hilar and parenchymal dissection in the cadaver donor before aortic cross-clamp and organ cold perfusion. In situ SLT reduces cold ischemia, simplifies identification of biliary and vascular structures,21,23 facilitates organ sharing, eliminates unintentional graft rewarming during ex vivo manipulation, and reduces hemorrhage on graft reperfusion23,24; however, in situ SLT mandates substantial logistics coordination and the provision of experienced procurement personnel. The prolonged operating time, blood loss, and volume replacement incurred during in situ SLT has prompted concerns regarding the quality of thoracic organs.25 However, data from centers with a commitment to in situ SLT suggest the impact on thoracic or additional abdominal organ function is negligible.26-28 Appropriate donor and recipient selection is critical to the success of SLT. Typically, donor selection is restricted to optimal candidates with respect to age, ABO compatibility, size match, liver function tests (⬍3⫻ upper normal limit), minimal vasopressor requirements, absent/scant arrest period, and

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serum sodium concentration.23,28,29 Accurate donor assessment from the recovery team is equally important because results of SLT are affected by vascular and biliary anatomy as well as parenchymal quality. Successful SLT requires recognition that partialliver grafts predispose to unique complications resulting from anatomic variations as well as recipient physiology. Technical challenges include the creation of sufficient liver volume to meet the metabolic demands of the recipient, graft positioning to optimize vascular flow and biliary drainage, and an appreciation of anatomic variations that necessitate complex biliary or vascular reconstruction. Frequent complications among SLT recipients include parenchyma bile leak, hepatic arterial thrombosis, hepatic venous outflow obstruction, infection from remnant necrotic tissue, and poor graft function secondary to insufficient hepatic volume. Graft mass is a critical variable affecting outcomes and a limitation to the extension of SLT between 2 adults. Adequate graft mass has been extensively explored in living donor liver transplantation with minimal graft thresholds advocated30-33; however, these data are not directly applicable to SLT because parenchyma quality and immediate function of living donor grafts exceeds that of cadavers.34,35 Our preference is a graft mass of at least 1% recipient body weight; however, grafts below 0.8% recipient body weight have been used with success.29,36,37 Inadequate graft mass for the recipient manifests as a pattern of dysfunction associated with

Figure 2. Surgical division of the liver. Surgical division of the liver along the middle hepatic vein (yellow line labeled “A”) yields a left lobe (segments I-IV) and right lobe (segments V-VIII) graft that can be used in SLT between 2 adults. Division along the falciform ligament (white line labeled “B”) yields the pediatric left lateral segment graft (segments II-III) and the remnant adult right trisegment graft (segments I, IV-VIII).

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portal hyperperfusion with prolonged cholestasis and gradual recovery, termed “small-for-size syndrome.”30,36 Pathologic evaluation reveals a pattern of diffuse ischemic injury characterized by hepatocyte ballooning, steatosis, centrilobular necrosis, and parenchymal cholestasis that may be misinterpreted as preservation injury.30

Current Results Early data from North America and Europe showed a high incidence of biliary complications and retransplantation among SLT recipients with outcomes inferior to cadaver, whole-liver transplantation.38,39 These procedures were typically performed ex vivo at the recipient facility with a dedicated “benching” period that increased cold ischemia time and exposed the graft to rewarming through manipulation. Broelsch et al21 and Busuttil22 separately introduced a technical modification by performing the split technique in situ incorporating hilar and parenchymal dissection in the donor before aortic cross-clamp and organ cold perfusion. Series data from the University of California Los Angeles22 and University of Hamburg40 showed in situ SLT procedures yielded pediatric as well as adult recipient graft and patient survival that equaled or exceeded whole, cadaverorgan data. Furthermore, de Ville de Goyet41 reported an experience of 100 grafts from the European Split Liver Registry followed over 5 years showing significantly improved outcomes that approached European Liver Transplant Registry survival data for cadaver whole-organ, liver transplantation. SLT had become a practical therapeutic option for patients requiring liver transplantation. The absence of a dedicated SLT registry has limited data to individual center reports. The American Society of Transplant Surgeons (ASTS) has performed a data protected, self-reporting survey of SLT application and outcomes from North American transplant centers.42,43 The ASTS survey reported data on 207 left lateral segment, 152 right trisegment, 15 left lobe, and 13 right lobe grafts.43 SLT was most frequent in the setting of at least one urgent recipient with the majority of each graft type applied to United Network for Organ Sharing (UNOS) status I and IIA recipients. Experience was concentrated among 13 centers reporting 5 or more SLT procedures that accounted for 221 grafts or 57% of the cumulative data. The majority of groups reporting experience with SLT

(63%) had performed less than 5 procedures. Furthermore, cadaver whole-liver transplantation volume correlated with the application of SLT.43 Complications were frequent in all graft types with biliary and vascular complications equally distributed between grafts split by either ex vivo or in situ techniques. Primary nonfunction, graft failure, and recipient death correlated with recipient UNOS status at transplantation.43 The relative contribution of complication type varied with vascular complications more frequently in critically ill recipients, and biliary complications were more common among nonurgent recipients. Primary nonfunction and graft failure occurred principally in urgent status recipients. Recipient mortality was more frequent in urgent status recipients with the majority of deaths attributed to graft-related complications. The University of California Los Angeles has reported the largest series on SLT to date encompassing 100 procedures and 190 allografts.28 Retrospective analysis comparing outcomes and the incidence of complications between SLT, living donor, and whole-organ recipients receiving liver transplantation during the same time period was performed. The incidence of biliary and vascular complications observed in SLT recipients of left lateral segment grafts was not statistically different from recipients of left lateral segment grafts created from living donation or children receiving whole-organ grafts from pediatric donors. Kaplan-Meier survival estimations of left lateral segment graft and recipient survival also showed no statistical difference between split-liver, living donor, and whole-organ recipients. SLT right trisegment allografts showed a 10% incidence of biliary and 7% incidence of vascular complications with excellent long-term graft function. Patient and graft survival were equal to 1,086 recipients of cadaver whole-organ grafts transplanted during the same time period.28 Independent predictors of SLT graft and recipient survival identified by multivariate analysis included UNOS status at transplantation, indication, the occurrence of a complication, donor creatinine, and donor length of hospitalization.28 The authors applied in situ SLT to all indications and categories of medical urgency for initial as well as retransplantation when suitable donors were available. SLT accounts for approximately 15% of grafts at University of California Los Angeles,26 but only 2% of all transplants performed nationally over the past decade.42 At University of California Los Angeles, SLT is an effective mechanism for immediate expansion of the cadaver donor

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Table 1. Summary of Adult and Pediatric Split-Liver Transplantation Center Adult/pediatric split-liver transplantation left lateral segment graft data Los Angeles28 Hamburg44 Birmingham45 Berlin46 Milano47 Houston48 Los Angeles18 London49 Los Angeles22 Hamburg21 Adult/child split-liver transplantation right trisegment graft data Los Angeles28 Hannover50 Hamburg44 Birmingham45 Berlin46 Milano47 Houston48 Los Angeles18 London49 Los Angeles22 Hamburg21

Author

Year

n

Recip (%)

Graft (%)

Comp (%)

Yersiz Broering Noujaim Sauer Maggi Kilic Ghobrial Rela Goss Rogiers

2003 2001 2001 2001 2001 2001 2000 1998 1997 1996

94 49 49 18 11 8 55 22 12 7

78 82 N/A 93 89 100 76 86 100 86

68 76 N/A 87 66 100 N/A 82 80 71

32 28 ⬎8 44 23 25 N/A 45 25 57

Yersiz Nashan Broering Noujaim Sauer Maggi Kilic Ghobrial Rela Goss Rogiers

2003 2001 2001 2001 2001 2001 2001 2000 1998 1997 1996

71 78 49 37 18 16 8 55 22 14 7

78 80 N/A N/A 90 86 100 80 95 86 100

69 N/A N/A N/A 90 80 100 N/A 95 93 100

27 N/A N/A ⬎15 39 12 12 N/A 27 19 28

Abbreviations: n, graft number; Recip, recipient survival; Graft, graft survival; Comp, reported overall complication rate; N/A, data not reported.

pool that has reduced dependence on living donation in adults and children. Additional single-center outcomes for the performance of adult/pediatric SLT are summarized in Table 1. Sparse data exist on SLT between 2 adults because these techniques have been cautiously implemented among select transplant centers. Bismuth has the largest series on adult/adult SLT with excellent results of 1-year patient and graft survival of 79% and 78%, respectively.11,23,37 Furthermore, the routine application of ex vivo SLT has increased overall graft availability at their center by 28%.23 A later series compared 1- and 2-year SLT patient and graft survival to adults receiving cadaver whole-organ transplantation over the same time period.37 Although no significant difference between whole-organ and SLT recipient 1-year survival was identified, the increased incidence of complications observed in SLT grafts contributed to a significantly decreased incidence of graft survival at 1 year, particularly among left-SLT recipients. SLT was performed in 15% of available donors, yielding a 62% net increase in adult recipients. The authors concluded SLT between 2 adults can yield good outcomes, provided

recognition of donor and recipient limitations and surveillance for complications unique to the procedure.37 The University of Minnesota has reported the largest North American center data on adult/adult SLT. Humar et al51 have reported 9 procedures yielding 18 grafts with a mean follow-up of 18 months. Seventeen of the 18 recipients were UNOS status IIB and one was UNOS status IIA. Patient and graft survival were 89% for right lobe versus 78% for left lobe grafts. Biliary complications were most frequent (27%), followed by an 11% incidence of vascular complications that resulted in 2 deaths. There was one primary nonfunction in an unspecified graft. SLT has also been performed in Asia with organ sharing among Asian countries, although the total number of procedures is low.52,53 Data from the ASTS survey did not permit meaningful analysis but did indicate an overall incidence of complications in each allograft type exceeding 20%. Primary nonfunction and graft failure were 7% and 9% for left lobe versus 9% and 14% for right lobe grafts, respectively.43 Additional series data on adult/adult SLT are summarized in Table 2.

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Table 2. Adult/Adult Split-Liver Transplantation Center

Author

Year

n

Recip (%)

Graft (%)

Comp (%)

Minneapolis51 Villejuif 37 Minneapolis29 Hamburg54 Genoa55 Bergamo56 Eppendorf 57 Villejuif 23

Humar Azoulay Humar Broering Andorno Colledan Gundlach Azoulay

2001 2001 2001 2001 2001 2000 2000 1996

18 34 12 12 10 8 4 27

89 81 83 93 100 87 100 79

89 75 83 85 80 63 100 78

43 24 58 N/A N/A 75 N/A 37

Abbreviations: n, graft number; Recip, recipient survival; Graft, graft survival; Comp, reported overall complication rate; N/A, data not reported.

Discussion Organ scarcity and increasing wait-list morbidity have fueled the development of SLT. Unfortunately, the discrepancy between organ supply and recipient demand has never been greater. Herculean efforts by a select group of centers around the world have generated a decade of data showing left lateral segment grafts applied to pediatric recipients yield excellent outcomes with significant decreases in pediatric wait-list times, wait-list morbidity, and lower utilization of living donation at centers that routinely implement these techniques.28,44,58 Despite these efforts, SLT remains an infrequent procedure that only a handful of US transplant centers routinely perform with substantial obstacles preventing the wider application of SLT.59 Interest in SLT is high among North American transplant centers as shown by the recent ASTS survey response,43 and the success of traditional adult/pediatric SLT has stimulated interest in the extension of SLT to include 2 adults. SLT requires substantial logistical planning and superior surgical technique. To date, most SLT have been performed in large centers that can support at least 2 concurrent recipient operations with experienced surgical teams. Technical considerations complicating SLT are still in evolution and must be further disseminated throughout the surgical community before any appreciable increase above current activity. The lack of an organized registry or mechanism for information sharing to date has impeded utilization. Until this occurs, data on these procedures will remain extremely limited and dissemination inefficient. The current UNOS organ allocation policy also impedes SLT.59 Recipient selection is fundamental to the successful application of the procedure and is limited by available hepatic mass. To implement

SLT between 2 adults, the team contemplating the procedure must have access to a diversity of recipients of different sizes that can be paired. This flexibility may require centers to collaborate for the benefit of the overall donor pool and compromise on individual access for global benefit. In Europe, where cadaver organs are allocated to centers, rather than specific patients, increased flexibility is available for recipient selection and coordination.59 The result has been standing agreements between centers for sharing of partial grafts that have been quite successful.25,60 The past UNOS policy permitting the unrestricted use of remnant grafts by the SLT center was a direct incentive for the application of SLT; however, in regions in which multiple centers are competing for each donor, rigid allocation policies have impeded SLT application. Furthermore, disappointing results in decompensated cirrhotics with living donor and SLT grafts have made it apparent that critically ill patients fare poorly from these complex technical variants.18 Complications are more frequent and poorly tolerated by the decompensated cirrhotic. Ironically, these are the patients to whom livers are preferentially allocated under the patientdriven system in the United States.59 Requirements for consent with respect to SLT have not been defined. In contrast to the extensive ethical analyses that preceded living donor liver transplantation,61 relatively little discussion of the ethics surrounding SLT has occurred. Because increased risk is inherent in the performance of SLT, it is customary to obtain specific informed consent for the procedure. In our practice, SLT is addressed with the patient prospectively, when the patient is placed on the wait list. SLT has the potential to immediately impact the waiting list. With greater information sharing and relatively small changes to current organ allocation

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policy, SLT application can significantly increase. SLT and living donation are complementary, not competitive, strategies for expansion of the donor pool; however, because SLT preserves the benefits of living-donor liver transplantation without incurring donor risk, it is the authors’ procedure of choice.26,28,44

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