The first liver transplant in a human was performed

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1 Liver Transplantation With Monosegments. Technical Aspects and Outcome: A Meta-Analysis Marcelo Enne, 1 Lucio Pacheco-Moreira, 1 Elizabeth Balbi, 2 Alexandre Cerqueira, 1 Giuseppe Santalucia, 3 and José Manoel Martinho 1 The shortage of organ donors for low-weight liver transplant recipients, especially small children, has led to the development of new surgical techniques to increase the donor pool. Almost all of these techniques use the left lateral segment (Couinaud s segments II and III), but even this graft could be too large for children under 10 kg, and further reduction could be necessary. Few articles address the issue of monosegmental liver transplantation. Available articles are with small sample sizes or even case reports, which makes it difficult to draw conclusions about indication and outcome for monosegmental grafts. A search of the MEDLINE databases using the terms Liver Transplantation and Monosegmental or Monosegments limited to title or abstract with publication in the English language was conducted. The data from each study were selected and analyzed, regarding donor status (living or cadaveric), donor weight, surgical techniques used in left lateral further reduction, recipient indication for liver transplantation, age and recipient weight, graft-to-recipient body weight ratio, segment utilized, type of abdominal closure, postoperative complications, and survival. Seven publications were identified from 1995 to 2004 and fulfilled the criteria. A total of 27 pediatric patients who received a monosegment transplant were identified, median age 211 days (range, 27 to 454 days) and median weight 4.6 kg (range, 2.45 to 7.4 kg). Segment III was utilized in 21 (78%) and segment II in 6 (22%). Patient survival was 85.2%. In conclusion, monosegment liver transplantation appears to be a satisfactory option for infants weighing less than 10 kg who require a liver transplant. (Liver Transpl 2005;11: ) The first liver transplant in a human was performed in a 3-year-old child 40 years ago. However, the development of pediatric liver transplantation has been associated with the introduction of some techniques to solve the problem of disparity between available donors and the exponential increase of patients on the waiting Abbreviations: LRD, living related donor; MLT, monosegmental liver transplantation. From the Liver Transplantation Program, Services of 1 Surgery, 2 Hepatology, and 3 Pediatrics, Hospital Geral de Bonsucessa, Ministry of Health, Rio de Janeiro, Brazil. Address reprint requests to Marcelo Enne, Hospital Geral de Bonsucesso, Av Londres 616, Bonsucesso, Rio de Janeiro, , Brazil. Telephone and FAX: ; marceloenne@ ig.com.br or txhepatico@hgb.rj.saude.gov.br Copyright 2005 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience ( DOI /lt list. Reduced-size, split-liver, and living related donors are all capable of reducing the deficit of organs for pediatric patients. 1-4 Almost all of these techniques use the left lateral segment (Couinaud s segments II and III) of the liver, but this graft may be too large for infants under 10 kg. To overcome a weight discrepancy of more than 10:1 from donor to recipient, a further reduction of the left lateral segment to a monosegment may be necessary, as has been done with cadaveric 5-8 and living related donors (LRD) The subsequent reduction could be performed in situ, at the donor operation 7,9,12 or at the back table procedure, 5,6,8 with the utilization of the segment II 6,8,9 or III 5,7,12,13 as grafts. The small sample size of reported data from each study on monosegmental liver transplantation (MLT), different donor status (cadaveric or living), and technical reduction of segment II or III make it difficult to draw conclusions about indication and outcome of monosegmental grafts. To date, no large trials are available, and the medical literature has progressively relied on meta-analysis, a helpful tool that synthesizes data from multiple small studies to obtain significant conclusions. Patients and Methods A MEDLINE literature search from 1984 to September 2004 using the terms Liver Transplantation and Monosegmental or Monosegments limited to title or abstract with publication in the English language was conducted. The bibliographies of the recovered articles were also examined to find supplementary references of data. When articles describing the same patients were reviewed, only the one containing the most complete information was included The data from each study were extracted and analyzed regarding donor and recipient data as follows: donor status (living or cadaveric), donor weight, donor operative details (surgical techniques used in left lateral further reduction), recipient indication for liver transplantation, age and recipient weight, graft-to-recipient weight ratio, segment utilized, recipient operative details (primary or secondary abdominal closure), and outcome (postoperative complications and survival). Results Nine publications were identified from 1995 to A total number of patients from 7 publica- 564 Liver Transplantation, Vol 11, No 5 (May), 2005: pp

2 Monosegmental Liver Transplantation 565 Table 1. Donor and Graft Characteristics Reference and patient no. Year Donor status Technical (reduction), segment utilized Donor weight (kg) Donor-torecipient weight relation Graft weight GRWR Strong et al Cadaveric Back table-iii 65 14:1 NR NR Mentha et al Cadaveric Back table-ii 78 11:1 NR NR Sirinivasan et al NR NR 1 Cadaveric In situ-iii 16 4:1 2 Cadaveric In situ-iii 35 11:1 3 Cadaveric In situ-iii 26 8:1 4 Cadaveric In situ-iii 46 8:1 5 Cadaveric In situ-iii 60 24:1 6 Cadaveric In situ-iii 20 8:1 Santibanes et al Living donor In situ-ii 64 8:1 170 g 2.3% 2 Living donor In situ-ii 56 8:1 160 g 2.2% Noujain et al NR NR 1 Cadaveric Back table-ii 65 25:1 2 Cadaveric Back table-ii 65 6:1 Kasahara et al Median, 61.1; range, Median, 11.9; range, Median, 215 g; range, g Median, 4.18%; range, 2.5%-5.2% 1 Living donor In situ-iii 2 Living donor In situ-iii 3 Living donor In situ-iii 4 Living donor In situ-iii 5 Living donor In situ-iii 6 Living donor In situ-iii 7 Living donor In situ-iii 8 Living donor In situ-ii 9 Living donor In situ-iii 10 Living donor In situ-iii 11 Living donor In situ-iii 12 Living donor In situ-iii 13 Living donor In situ-iii 14 Living donor In situ-iii Enne et al Living donor In situ-iii 68 11:1 231 g 3.8% Abbreviation: NR, not reported. tions were analyzed, because 2 publications from the same institution appeared to represent partial data from other publications by the same team. 10,11 Of the selected articles, 2 publications 8,9 reported 2 patients, while 3 articles were case reports, 5,6,13 and 2 publications 7,12 reported 6 and 14 cases, respectively. With the exception of the graft weight and graft-to-recipient body weight ratio, the magnitude and type of information disclosed in each publication were not remarkably variable. A total of 27 pediatric patients who received a monosegment transplant were identified, median age 211 days (range, 27 to 454 days) and median weight 4.6 kg (range, 2.45 to 7.4 kg). Donor Data The donor data are listed in Table 1. Four publications described the utilization of 10 cadaveric donors, while 3 papers reported a total of 17 living donors. The technical further reduction of the left lateral segments was in the back table procedure in 4 cases (4 of 27; 15%), all of them with cadaveric donors. In 23 donors (85%), the reduction was in situ; 6 cases received from a cadaveric donor, while 17 received from a living donor. Segment III was used in 21 children (78%) and segment II in 6 (22%). When segment II was used, half were of cadaveric origin. Segment III was used in 21, 14 (66%) from

3 566 Enne et al. Table 2. Recipient Characteristics, Complications, Type of Abdominal Closure, and Outcome Reference and Abdominal patient no. Year Indication Age Weight (kg) Complication closure Outcome Strong et al Biliary atresiaretransplantation Mentha et al Biliary atresiaretransplantation 4 mo 4.7 Pleural effusion Secondary Alive 10 mo 6.9 Diaphragmatic Primary Alive paralysis Sirinivasan et al Median, 10 days All secondary 1 FHF, neonatal 3.9 None Alive 2 FHF, neonatal 2.98 None Alive 3 FHF, neonatal 3.0 None Alive 4 FHF, hepatitis B 5.46 None Alive 5 Retransplantation HAT 2.45 None Died 6 FHF, neonatal 2.90 None Alive Santibanes et al Biliary atresia 8 mo 7.25 Biliary stenosis Primary Alive 2 Biliary atresia 11 mo 7.0 Bile leak Primary Alive Noujain et al NR 1 FHF NR 2.6 None Alive 2 FHF NR 4 None Alive Kasahara et al Median, 211 days; range, days Median, 5.95; range, kg 1 HAT, 1 PVT, 2 bile leaks 70% secondary 1 Biliary atresia Alive 2 FHF Died 3 Hepatic Alive hemangioendothelioma 4 Liver cirrhosis Died 5 Biliary atresia Alive 6 FHF Alive 7 Biliary atresia Alive 8 FHF Alive 9 Biliary atresia Alive 10 Biliary atresia Alive 11 Biliary atresia Alive 12 Biliary atresia Alive 13 Biliary atresia Alive 14 FHF Died Enne et al Biliary paucity 8 mo 6.1 g None Primary Alive Abbreviations: FHF, fulminant hepatic failure; HAT, hepatic artery thrombosis; NR, not reported; PVT, portal vein thrombosis. living donors. The median donor weight was 51.7 kg (range, kg) and the median donor-recipient weight ratio was 12:1 (range, 4:1-25:1). The median graft weight reported in 3 publications was 194 g (range, g), and the graft-to-recipient body weight ratio reported in the same papers was 3.12% (range, 2.2%-5.2%). Recipient Data The recipient characteristics are listed in Table 2. The reasons leading to liver transplantation were biliary atresia in 10 patients, fulminant hepatic failure in 11 (neonatal in 4, hepatitis B virus-related in 2, unknown origin in 3, and not reported in 2),

4 Monosegmental Liver Transplantation 567 retransplantation in 3 (hepatic artery thrombosis in 2 and primary nonfunction in 1), and infantile hepatic hemangioendothelioma, liver cirrhosis, and biliary paucity in 1 each. In 14 patients (52%), the indication for liver replacement was medical urgency (e.g., fulminant liver failure or the need for retransplantation). The median recipient age was 211 days (range, days). The median weight was 4.6 kg (range, kg). The type of abdominal closure was reported in 25 of 27 patients. Primary closure was achieved in 30%. Reported surgical complication rate was 22% (pleural effusion, diaphragmatic paralysis, biliary stenosis, bile leak, hepatic artery thrombosis, portal vein thrombosis). Vascular complication was 7.4%, with 1 portal vein thrombosis and 1 hepatic artery thrombosis. In addition, there were no retransplantations, and overall patient survival was 85% after a median follow-up of 21 months. Discussion In liver transplantation for small infants, the problem is large-for-size grafts, and the left lateral segment could exceed a 5% to 6% graft-to-recipient body weight ratio. When the estimated graft-to-recipient body weight ratio is more than 4% on preoperative volumetry, a further graft reduction could be necessary to overcome the large-for-size graft syndrome. 14 The problems of large-for-size grafts are the insufficient blood flow to the revascularized liver and the small size of the recipient s abdominal cavity, with inadequate tissue oxygenation and graft compression. 11,12 In some small infants, the use of monosegmental liver transplantation could allow for an easier abdominal wall closure and avoid an insufficient blood supply to the graft. Avoiding the use of synthetic mesh and secondary closure can also reduce the chance of abdominal-wall infectious complications. 6,9 In the 1990s, Houssin et al. 2 described a new reduction technique. Only 1 segment with the resection of segment III from the left lateral segment was used, to avoid the inability of closing the abdominal cavity. This further reduction was performed after implanting the graft, and a liver resection of a recently revascularized graft was technically complicated by hemostasis disorders. Strong et al. 5 described a case in which only segment III was implanted. The reduction was at the back table from the left lateral segment of a cadaveric donor. Mentha et al. 6 implanted segment II, also from a cadaveric donor, and the reduction was also performed at the back table, aided by the injection of methylene blue in the portal branch of segment III. Srinivasan et al. 7 Figure 1. (A) Schematic left lateral segment. The dashed line represents the cut line, which is far from pedicle elements. (B) Schematic segment III ready to be implanted. described 6 cases of segment III grafts from cadaveric donors transplanted in patients with acute liver failure, and at that time, they stated that this technique could also be potentially extended to living related liver transplantation. At that time, MLT was used only in urgent conditions for fulminant hepatic failure or retransplantation. Prior to 2000, there were no reports of MLT from an LRD. Santibañesetal. 9 were the first to describe a pediatric MLT using a liver segment resected in situ from an LRD. They published 2 cases in children weighing 7 kg, using segment II. Noujain 8 reported on a study of 15 patients weighing less than 5 kg using 2 MLTs from a cadaveric donor with back table reduction of segment II as a graft. Despite the few cases of segment II liver reduction, the paper from Santibañes reported 100% of biliary complications, while the paper from Noujain reported no vascular or biliary complications. The small sample of segment II liver reduction makes it difficult to draw conclusions about the rate of complications, in comparison to segment III liver reduction. The larger single-center experience with MLT was at Kyoto University, especially with segment III, with 14 cases reported between September 2000 and November 2002 by Kasahara et al. 12 They were the first to perform and to highlight the advantage of MLT with segment III in an elective setting. The Kyoto team also accented the utilization of the intraoperative ultrasonography to determine the transection plane between segment II and III. The transection line in segment III was made to preserve the entire length of the hepatic vein (Fig. 1). In another paper, they also emphasized the associated anatomical disadvantages of a large graft. 14 The concept of

5 568 Enne et al. Figure 2. Segment III ready to be implanted. large-for-size graft is estimated in infants whose graftto-recipient body weight ratio is evaluated in over 4.0% by preoperative volumetry. Kiuchi et al. describe some anatomical and even immunological disadvantages of the large-for-size grafts. 14 They describe a higher rate of vascular complications and more acute rejection episodes, in the first month, in recipients of large-for-size grafts. Despite these drawbacks, the negative impact of the large-for-size grafts is less pronounced in comparison to the lower survival rate of the small-for-size grafts in adults. Our group also reported on MLT using segment III from an LRD. 13 Segment II was resected in situ and discarded. This resection is not difficult and does not represent any danger to the pedicle vessels or to the left hepatic vein. The cut line was far enough from the pedicle elements that needed to be preserved, and we avoided some ischemic areas in the monosegmental graft (Fig. 2). With the help of intraoperative ultrasonography, the segment III hepatic vein could be preserved. Furthermore, with this technique the anastomosis was the same as performed when the left lateral segment from an LRD is implanted. 4 Additionally, since the first case, we have performed 3 other MLTs from an LRD in small children with a median weight of 6.0 kg. To create the segment II graft in situ, it is necessary to identify and to not injure the portal pedicle, with a hazardous dissection at the base of the umbilical fissure. Since the publication from Sirinivasan et al., 7 MLT with segment III appears to be technically easier and safer than segment II MLT. The in situ reduction at the donor operation is a safe procedure with no more than 15 to 20 additional minutes needed and with no additional blood loss. The monosegmental reduction at the back table will increase cold ischemia time. The procedure to remove segment II after the graft revascularization in the recipient could be hazardous because of coagulation disorders in the recipient of the recently reperfused graft. Available publications of liver transplantation in small infants, especially those weighing less than 10 kg, not using MLT reported a complication rate (required reoperation) between 25 and 46% The vascular complication and retransplantation rate in those papers seem to be higher than our findings with MLT in this meta-analysis, but the overall survival was comparable (Table 3). MLT does not avoid a secondary closure of the abdominal wall and the use of synthetic mesh. The Table 3. Patient Characteristics, Complications, Retransplantation, and Survival Rates in Reported Series of Liver Transplantations in Small Infants Not Using MLT Author Year n Urgent basis Age Weight (kg) Complication (reoperation) Vascular complications Retx (early) 1-year survival Colombani / mo (mean) % 15% 3/13 (23%) 85% et al. 15 (7%) (mean) Cacciarelli % 1 yr NR NR 14% 11/73 (15%) 76% et al. 16 Woodle et al % 37 days (median) 3.8 NR 14% None 60% (mean) Saing et al None 9.6 mo (mean) % None None 100% (mean) Iglesias et al % 7.4 mo (median) 5.8 (median) 25% 25% (HAT) 2/16 (12%) 82% Grabhorn /43 et al. 20 (20%) 136 days (median) 5.8 (median) Abbreviations: Retx, retransplantation; NR, not reported; HAT, hepatic artery thrombosis. 27.9% 4.7% 6/43 (15%) 90%

6 Monosegmental Liver Transplantation 569 majority of the patients (70%) were submitted to a secondary closure. It seems that the major concern of MLT is not the possibility of achieving a primary abdominal-wall closure, but rather a sufficient vascular inflow and tissue oxygenation in a graft-to-recipient body weight ratio under 4%, with lower vascular complication and graft dysfunction. The MLT has been recently introduced as a routine option for elective liver transplantation in small infants, especially with segment III from a living donor. In an MLT from a living donor, monosegmentectomy seems to be as safe as standard left lateral segmentectomy, with no increased complication rate at the donor operation. It seems that MLT does not increased morbidity and mortality in small recipients. Patient survival was 85.2% (median follow-up time, 21 months), despite almost half of the patients undergoing transplantation under an urgent fashion. The survival was comparable with that of patients weighing less than 10 kg who received a transplant of grafts other than MLT (Table 3). The incidence of postoperative bleeding and bile leakage from the 2 transected surfaces was null, whereas hepatic artery and biliary complications were potentially lower without retransplantations in this metaanalysis. Acknowledgment The authors thank Prof. Mureo Kasahara and his colleagues from the Department of Transplant Surgery for the information provided about their experience of monosegmental liver transplantation in Kyoto University, Japan. References 1. Bismuth H, Houssin D. Reduced size orthotopic liver graft in hepatic transplantation in children. Surgery 1984;104: Houssin D, Soubrane O, Boillot O, Dousset B, Ozier Y, Devictor D, et al. Orthotopic Liver transplantation with reduced size grafts: an ideal compromise in pediatrics? Surgery 1992;111: Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1989;21: Emre S. Living-donor liver transplantation in children. Pediatr Transplant 2002;6: Strong R, Lynch S, Yamanaka J, Kawamoto S, Pillay P, Ong Th. Monosegmental liver transplantation. Surgery 1995;118: Mentha G, Belli D, Berner M, Rouge JC, Bugmann P, Morel P, Le Coultre C. Monosegmental liver transplantation from an adult to an infant. Transplantation 1996;62: Srinivasan P, Vilca-Melendez H, Muiesan P, Prachalias A, Heaton D, Rela M. Liver transplantation with monosegments. Surgery 1999;126: Noujaim HM, Mayer DA, Buckles JA, Beath SV, Kelly DA, McKiernan PJ, et al. Techniques for and outcome of liver transplantation in neonates and infants weighing up to 5 kilograms. J Pediatr Surg 2002;37: Santibanes E, McCormack L, Mattera J, Pekolj J, Sivori J, Beskow A, et al. Partial left lateral segment transplant from a living donor. Liver Transpl 2000;6: Kasahara M, Kiuchi T, Haga H, Uemoto S, Uryuhara K, Fujimoto Y, et al. Monosegmental living-donor liver transplantation for infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38: Kasahara M, Kaihara S, Oike F, Ito T, Fujimoto Y, Ogura Y, et al. Living-donor liver transplantation with monosegments. Transplantation 2003;76: Kasahara M, Uryuhara K, Kaihara S, Kozaki K, Fujimoto Y, Ogura Y, et al. Monosegmental living donor liver transplantation. Transplant Proc 2003;35: Enne M, Pacheco-Moreira LF, Cerqueira A, Balbi E, Halpern M, Luiz Pereira J, et al. Liver transplantation with monosegment from a living donor. Pediatr Transplant 2004;8: Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 1999;67: Colombani PM, Cigarroa FG, Schwarz K, Wise B, Maley WE, Klein AS. Liver transplantation in infants younger than 1 year of age. Ann Surg 1996;223: Cacciarelli TV, Esquivel CO, Moore DH, Cox KL, Berquist WE, Concepcion W, et al. Factors affecting survival after orthotopic liver transplantation in infants. Transplantation 1997;64: Woodle ES, Mills JM, So SKS, McDiarmid SV, Bussutil RW, Esquivel CO, et al. Liver transplantation in the first three months of life. Transplantation 1998;66: Saing H, Fan ST, Chan KL, Lo CM, Wei WI, Tsoi NS, et al. Liver transplantation in infants. J Pediatr Surg 1999;34: Iglesias J, López JA, Ortega J, Roqueta J, Asensio M, Margarit C, et al. Liver transplantation in infants weighing under 7 kilograms: Management and outcome of PICU. Pediatr Transplant 2004;8: Grabhorn E, Shulz A, Helmke K, Hinrichs B, Rogiers X, Broering DC, et al. Short- and long-term results of liver transplantation in infants aged less than 6 months. Transplantation 2004; 78: