ORIGINAL ARTICLES

Extensive Use of Split Liver for Pediatric LiverTransplantation: A Single-Center ExperienceMarco Spada, Bruno Gridelli, Michele Colledan, Andrea Segalin,

Alessandro Lucianetti, Wanda Petz, Silvia Riva, and Giuliano Torre

The results of the extensive use of in situ liver splitting ina pediatric liver transplant program are presented. Allreferred donors were considered for split liver, and whenthe donor-recipient body weight ratio (DRWR) wasgreater than 2, the grafts were split. A modified split-livertechnique was adopted when the DRWR was 2 or less.Eighty liver procurements were attempted and 72 (90%)were performed, enabling 65 children to receive 42 split,22 whole, and 8 reduced-size livers. The right portions ofthe grafts were transplanted by other centers into adults.Median patient waiting time was 22 days, with nomortality on the waiting list. After a median follow-up of14 months, overall patient and graft survival rates were85% and 81%, respectively. Fifty-eight children received asingle allograft, whereas 7 children required retransplan-tation. Two-year actuarial survival rates were 85% forsplit-liver recipients, 84% for whole-liver recipients, and67% for reduced-size liver recipients. Vascular complica-tions developed in 18% of the patients, with no differenceamong the 3 groups with different technique. Biliarycomplications developed in 25% of the children, mainlyin reduced-size and split-liver recipients. Patient and graftsurvival rates for right split-liver grafts were 84% and79%, respectively. Adopting a liberal policy of liversplitting provides allografts of optimal quality for pediat-ric transplantation, allowing a dramatic decrease in thewaiting list time. The in situ split-liver technique shouldbe considered the method of choice for expanding thecadaveric liver donor pool. (Liver Transpl 2000;6:415-428.)

T he majority of Italian children with end-stageliver disease, and their families, have had to go to

foreign transplant centers for the last 15 years to receivecare. One of the objectives we pursued, first at theMaggiore Hospital of Milan and then at the RiunitiHospital of Bergamo, was to make pediatric livertransplantation a readily available therapy in Italy.

We started a pediatric liver transplant program inMilan in 1988, and for the first 6 years, the annualnumber of transplantations was less than 10. In 1994,for a number of reasons, including increased donoravailability and referral of candidates from pediatriccenters, the transplant activity increased significantly(Fig. 1). To better meet the needs of the children underour care, we moved to the Bergamo hospital inOctober 1997, where we expanded the use of split-livertransplantation.

Because the number of pediatric transplant donors

is less than the number of pediatric transplant recipi-ents, and the majority of the recipients are agedyounger than 2 years, it has been common practice touse reduced-size livers from adult donors, discardingthe excess liver parenchyma, particularly in the 1980sand early 1990s.1-4 This practice shifted the imbalancebetween need and availability of liver grafts from thepediatric to the adult population of transplant candi-dates. The incidence of end-stage liver failure requiringtransplantation in the pediatric age group is 2 in10,000 live births5; therefore, approximately 100 of the500,000 children born each year in Italy will requireliver transplantation.

In Italy, there are currently 3 organ procurementtransplant agencies that allocate cadaver donor organs.Our center is linked to North Italy Transplant (NITp),which coordinates the activity of 7 liver transplantcenters. Six of these centers provide care mainly toadults, whereas the Bergamo center mainly focuses onpediatric recipients. In 1998, the NITp organized theorgan procurement of approximately 300 cadaverorgan donors.6 We therefore reasoned that the exten-sive use of the liver-splitting procedure would generateenough liver grafts for children without interferingwith the waiting lists of adult patients.

We report the impact of the adoption of a liberalpolicy of in situ liver splitting on our pediatric livertransplant program.

Patients and Methods

Study PopulationBetween October 1997 and October 1999, a total of 72pediatric liver transplantations were performed in 65 chil-

From the Liver Transplantation Center, Ospedali Riuniti diBergamo, Bergamo, Italy.

Address reprint requests to Marco Spada, MD, PhD, CentroTrapianti di Fegato, Chirurgia III, Ospedali Riunuti, Largo Barozzi 1,24128 Bergamo, Italy. Telephone: 39 035 269363; FAX: 39 035266898; E-mail: mspada@ospedaliriuniti.bergamo.it

Copyright r 2000 by the American Association for the Study ofLiver Diseases

1527-6465/00/0604-0013$3.00/0doi:10.1053/jlts.2000.7570

Liver Transplantation, Vol 6, No 4 (July), 2000: pp 415-428 415

dren at the Liver Transplantation Unit of the OspedaliRiuniti of Bergamo, Italy.

The transplant recipients were 32 boys and 33 girls,ranging in age from 0.1 to 21 years (mean 6 SD, 4.1 6 4.9years; median, 1.6 years). Body weight ranged from 2.8 to 62kg (mean, 16 6 14 kg; median, 10.5 kg). Figure 2 showstransplant recipient distribution by age: 39% of the trans-plant recipients were aged younger than 1 year, and 66%were aged younger than 3 years. Two patients aged 19 and 21years were included on the study because they were referredto our center for liver failure secondary to extrahepatic biliaryatresia.

The original liver diseases of the patients are listed inTable 1. Sixty-three children underwent primary liver trans-plantation, whereas 2 patients who previously underwenttransplantation elsewhere received a second graft because ofchronic rejection of the first transplanted liver.

Of 65 transplant recipients, 4 patients (6%) were UnitedNetwork for Sharing Organs (UNOS) status 1, 6 patients(9%) were UNOS status 2, and 55 patients (85%) wereUNOS status 3.

Splitting Criteria and Donor Procedures

Since the beginning of the Bergamo pediatric liver transplan-tation program, we adopted a liberal policy of liver splitting.The decision of whether to split a graft was based mainly onrecipient rather than donor criteria. We did not excludechildren who required retransplantation or who had fulmi-nant hepatic failure.

In the NITp area, cadaver liver donors are allocated on arotation basis to the 7 transplant centers. The liver of everydonor assigned to our center was evaluated for electivetransplantation when at least 1 blood group type A, type B,type O (ABO)-compatible recipient with a donor-recipientbody weight ratio (DRWR) of 12 or less was wait listed.Gross pathological findings at the procurement were themain criteria for organ acceptance or refusal. Donor evalua-tion did not require special or additional invasive or noninva-sive tests. Particular care was applied to the evaluation of liverfunction, hemodynamic and metabolic status, and livermacroscopic appearance of donors aged older than 50 years,but age alone was not an exclusion criterion. Every accepted

Figure 1. Number of pediat-ric liver transplantations per-formed in Milan between1988 and 1997.

Figure 2. Recipient distribu-tion by age.

Spada et al416

graft was attributed to the most urgent recipient on thewaiting list. Time on the waiting list was an allocationcriterion for patients with the same UNOS status.

The liver was procured and transplanted as a whole liverwhen the DRWR was 2 or less. Donor procedures wereperformed using the standard technique of rapid multiorganprocurement. When the DRWR was between 2 and 12, theorgan was considered for split liver. Of the 2 grafts obtainablewith the splitting procedure, as a rule, the right was offered toanother center, with the agreement of a restitution of the splitliver at the first opportunity. The allocation of the left graftsreceived from other centers according to this agreement wasperformed using the same criteria previously described.

Standard surgical facilities for multiorgan procurementwere used, and no special equipment was required from thedonor hospital. When possible, the splitting procedure wasperformed in situ as described by Rogiers et al7 by a surgicalteam composed of members of both centers involved in thetransplantation. Briefly, the procedure consists of sectioningthe liver along the falciform ligament, dividing the left lateralsegment ([LLS] segments II and III of Couinaud) fromsegments IV to VIII and the caudate lobe. The left graftincluded the left hepatic vein, left branch of the portal vein,and left branch of the hepatic artery, along with the commonhepatic artery and celiac axis. The right graft included thevena cava, right branch of the hepatic artery, and portal vein.

During procurement, the following variations in hepaticartery anatomy were encountered: left hepatic artery comingfrom the left gastric artery with no left branch originatingfrom the proper hepatic artery (2 cases); left hepatic arterycoming from the left gastric artery and right hepatic arteryoriginating from the superior mesenteric artery, with absenceof the proper hepatic artery (1 case); accessory left hepaticartery coming from the left gastric artery (1 case); anomalous

left gastric artery originating from the left hepatic artery (1case); and right hepatic artery originating from the superiormesenteric artery, with no right branch coming from theproper hepatic artery (3 cases).

We recently used and described an alternative in situsplitting technique that results in left grafts substantiallylarger than those obtained with the standard technique.8 Thistechnique consists of sectioning the liver along a planedirected from the right border of the gallbladder fossa to thedivision of the portal vein and to the right margin of themedian hepatic vein. The left graft (segments I to IV)includes the vena cava with the left and median hepatic veins,portal vein, and left branch of the hepatic artery along withthe common hepatic artery and celiac axis. The right graft(segments V to VIII) includes the right hepatic vein with apatch of vena cava, right branch of the hepatic artery, andright branch of the portal vein.

This alternative splitting technique was recently adoptedfor patients with a DRWR of 2 or less and a graft-recipientweight ratio of 0.8 or greater. We estimated the left graftvolume (segments I to IV) using a formula for calculating thestandard liver volume in the donors from their body surfacearea9 and assuming that the left lobe volume was 40% of thedonor’s estimated liver mass.10

The splitting procedure was performed ex situ only whenrequired for hemodynamic instability of the donor or logisticreasons. In all cases, an effort was made to limit ischemic timeas much as possible. When a center with a suitable recipientfor the right graft could not be found, the liver was reducedon the back table using the standard technique.3

Organ procurements were performed in 72 donorsranging in age from 0.1 to 65 years (mean 6 SD, 24 6 19years; median, 17.5 years). Body weight ranged from 3.8 to105 kg (mean, 54 6 24 kg; median, 60 kg).

Recipient ProceduresSplit and reduced grafts were transplanted using the piggy-back technique, with retention of the recipient vena cava inall but 1 case. In 1 child with hepatic hemangiosarcoma, theinferior vena cava was removed with the liver and a neocavawas created on the back table using the donor iliac vein.

During split-liver transplantation, attention was given toprevent venous outflow obstruction, leaving the left hepaticvein short and using the triangulation technique described byEmond et al.11 Direct end-to-end anastomosis of the portalvein was performed in 38 cases (90%). In 4 cases (10%) ofbiliary atresia, when the recipient portal vein was severelyhypoplastic, the portal vein of the graft was anastomosed tothe confluence of the splenic vein and superior mesentericvein of the recipient with an interposition graft. As previouslydescribed, the entire hepatic artery and celiac axis were keptwith the LLS. Arterial reconstruction was performed byanastomosing the celiac axis or the common hepatic artery ofthe graft to the celiac axis, common hepatic artery, or aorta ofthe recipient. In 4 cases, arterial reconstruction was accom-plished by means of an arterial interposition graft. When a

Table 1. Original Liver Disease of the Patients

DiagnosesNo. of

Patients %

Extrahepatic biliary atresia 43 66Intrahepatic cholestatic disease* 5 8Secondary cirrhosis† 5 8Tumor‡ 4 6Fulminant hepatitis 2 3Chronic rejection§ 2 3Metabolic disease\ 2 3Others¶ 2 3

*Alagille syndrome, Byler disease.†Cryptogenetic cirrhosis, Langerhans’ cells histiocytosis,autoimmune hepatitis.‡Hepatocarcinoma, hemangiosarcoma, rhabdomyosarcoma.§Patients who previously underwent transplantation else-where.\Crigler-Najjar disease, perinatal hemochromatosis.¶Budd-Chiari syndrome, arteriohepatic fistula.

Split Liver for Pediatric Liver Transplantation 417

unique or accessory anomalous left hepatic artery originatingfrom the left gastric artery was present, no particular benchreconstruction was required because the entire celiac axis waswith the LLS graft. Details of the arterial reconstruction arelisted in Table 2.

Left graft biliary reconstruction was always with aRoux-en-Y hepaticojejunostomy. When possible, small bileducts were enlarged by anterior incision. Inclusion of morethan 1 ductal orifice in the biliary enterostomy was requiredin 13 cases. All vascular and biliary reconstructions wereperformed using surgical loupe magnification (original mag-nification 33.5). Whole livers were transplanted with thestandard technique, without preservation of the vena cava.

Postoperative ManagementNo special posttransplantation care was required for recipi-ents of split grafts. All patients were managed according tothe established protocol for pediatric liver transplantation,including Doppler ultrasound performed daily for the firstpostoperative week to evaluate hepatic artery, portal vein, andhepatic vein flow. Immunosuppression consisted of oralcyclosporine microemulsion and steroids in 41 patients andoral cyclosporine microemulsion, steroids, and azathioprinein 4 children. Thirteen children were administered oralcyclosporine, basiliximab, and steroids, and another 7 pa-tients were administered tacrolimus and steroids.

Statistical AnalysisValues are expressed as mean 6 SD or median and range. Forstatistical comparison, log-rank test for Kaplan-Mayer sur-vival analysis, Mann-Whitney test, or Kruskal-Wallis test forcontinuous data, Chi-squared test, and/or Fisher’s exactprobability test for categorical data were used. P less than .05is considered statistically significant.

Results

Donor Procedure

Eighty liver procurements were begun: in 4 cases, theliver was not used because of steatosis. In 4 donorsconsidered for split liver, the procedure could not becompleted because the donor became hemodynami-cally unstable (n 5 1) or because of anatomic and/ordimensional reasons (n 5 3). In these cases, the wholeliver was procured and transplanted at another center.Of 72 procurement procedures, 42 procedures (58%)were split livers. In all but 2 cases, the splittingprocedures were performed using the in situ technique,and in 36 cases, consisted of the procurement of theLLS, in 3 of the left lobes (segments I to IV), and in 1case, of the right segments I and IV to VIII. In 8 cases(11%), a transplant center with a suitable recipient forthe right graft could not be found, and the liver,procured as a whole, was reduced on the back table. In22 donors (31%), the liver was procured and trans-planted as a whole organ. No procurement procedureswere abandoned because of intraoperative technicalcomplications, and no extrahepatic organs were jeopar-dized, allowing the regular procurement of kidneys,pancreases, hearts, and lungs. Blood transfusion wasneeded in some cases during the splitting, mainly indonors with low preoperative hemoglobin levels. Thesplit-liver procedures added 156 6 33 minutes to theprocurement when the LLS was procured, whereasusing the alternative technique required 185 6 50more minutes. In the case of procurement of the rightsegments I and IV to VIII, the LLS was used by ourcenter for a combined split-liver and small-boweltransplantation, performed in a 1.3-year-old patient.

The demographics of the 72 donors, classified bythe adopted procurement technique, are listed inTable 3.

Patient and Graft Survival

Patient median time on the waiting list was 22 days,with a significant decrease from 60 days (Octoberthrough December 1997) to 7 days (August throughOctober 1999). No patient died on the waiting list.

Of the 65 transplant recipients, 39 patients (60%)received a split liver; 35 patients, an LLS; 3 patients, aleft lobe; and 1 patient, a right graft (segments I and IVto VIII). Six children (9%) received a reduced-size liver(LLS), and the remaining 20 patients (31%) received awhole organ. Patient demographics classified by grafttype are listed in Table 4.

At a median follow-up of 17 months (range, 2 to 28

Table 2. Type of Arterial Reconstruction in the 42Split-Liver Transplantations

Arterial Anasomosis No. ofCases

No. ofGraftsSplit Liver Recipient

Celiac axisCeliac axisCommon hepatic

artery

215

02

Aorta 5 0

Common hepaticartery

Celiac axisCommon hepatic

artery

117

00

Aorta 2 2

Spada et al418

months), 55 patients (85%) are currently alive. Overall1-year and 2-year actuarial patient survival rates are84% and 84%, respectively (Fig. 3). The 1-year and2-year actuarial graft survival rates are 78% and 78%,respectively (Fig. 3). Fifty-eight patients (89%) re-ceived a single allograft and 7 children (11%) requiredretransplantation, one from an ABO-incompatibledonor. Three patients were recipients of a whole liver(15%), whereas 4 children were in the split-liver group(10%). Data for patients who underwent retransplanta-tion are listed in Table 5.

The 1-year and 2-year actuarial patient survivalrates of patients who underwent transplantation with asplit liver are 85% and 85%, respectively; for patients

who received a reduced-size liver, 67% and 67%,respectively; and for patients who received a wholeliver, 85% and 85%, respectively (Fig. 4). The actuarialallograft survival rates at 1 and 2 years are 76% and76% for split livers, 63% and 63% for reduced livers,and 78% and 78% for whole livers, respectively.

For patients who received a split liver, actuarialsurvival rate based on UNOS status at the time oftransplantation was determined. The 1-year and 2-yearsurvival rates of patients with UNOS status 2 and 3were 100% and 100% and 90% and 90%, respectively(Fig. 5). Of the 4 patients with UNOS status 1, 2patients died at 9 months and at 17 days aftertransplantation, whereas 2 patients are alive.

Table 3. Profiles of Donors Classified by the Adopted Procurement Technique

Surgical Technique

PWhole Reduced

Split

II-III I-IV

No. of donors 22 8 39 3Age (yr) 15 6 17 21 6 23 30 6 18 27 6 7 ,.05*

(0.1-59) (6-62) (3-65) (20-33)Weight (kg) 36 6 25 38 6 16 67 6 15 70 6 13 ,.01†

(3.8-90) (20-64) (30-105) (60-85)Ischemia (min) 423 6 90 473 6 89 349 6 97 320 6 50 ,.05*

(240-638) (310-580) (180-615) (285-355)

NOTE. Data reported as mean 6 SD (range).*Whole and reduced liver v split II-III.†Whole and reduced liver v split II-III; reduced v split I-IV.

Table 4. Profiles of Recipients Classified by Graft Type

Surgical Technique

PWhole Reduced

Split

II-III I-IV

No. of recipients 20 6 36 3Age (yr) 8 6 5 0.9 6 0.7 1.7 6 1.7 15 6 6 ,.01*

(0.5-19) (0.4-2.3) (0.1-7) (10-21)Weight (kg) 27 6 16 7 6 2 10 6 4 47 6 9 ,.01†

(6-62) (4-11) (3-20) (38-55)DRWR 1.4 6 0.7 4.9 6 1.9 8.0 6 3.2 1.5 6 0.1 ,.01‡

(0.4-3.1) (3.1-8.6) (3.1-17.6) (1.4-1.6)RBC§ (mL/kg) 21.1 6 21.7 30.5 6 18.8 19.6 6 17.5 — NS

(2.6-77.8) (5-63.1) (2-88.1)

Abbreviations: RBC, red blood cells; NS, not significant.*Whole versus reduced and split liver II-III; split II-III versus split I-IV.†Whole versus reduced, split liver II-III, and split I-IV; reduced versus split I-IV; split II-III versus split I-IV.‡Each group versus the others.§Intraoperative RBC transfusion.

Split Liver for Pediatric Liver Transplantation 419

Recipient Mortality and Morbidity

Perioperative mortality occurred in 8 patients (12%)after transplantation. Four children underwent retrans-plantation for technical complications and eventuallydied, whereas the procedure was successful in 3patients (Table 5). Four patients died within 1 monthof the primary transplantation. Data concerning theselatter patients and 2 other children who died 39 and287 days after transplantation are listed in Table 6.

Of the 2 patients who developed primary nonfunc-tion (PNF), 1 patient was a 12-year-old boy withBudd-Chiari syndrome and protein C, protein S, andantithrombin III deficiency who received a whole liverand died 3 days after transplantation with disseminatedintrahepatic thrombosis, possibly related to his originaldisease. Postmortem examination showed dissemi-nated intravascular coagulation. The second child wasa 14-month-old girl with hepatoportal sclerosis and

multiple arteroportal intrahepatic fistulas who under-went transplantation with an LLS from a split liverwith a DRWR of 7.78 and died 2 days after surgery.Her liver graft failed possibly because of insufficientportal inflow.

Three other children died after primary split-livertransplantation. The first, a 2-month-old boy, receivedan urgent LLS for acute hepatic failure of unknownorigin. Allograft function in the posttransplantationperiod was excellent, but the patient did not show aneurologic recovery, and a brain computed tomo-graphic scan and magnetic resonance imaging showeddiffuse cerebral edema with multiple intracerebralcollections. The boy eventually died 9 months aftertransplantation with normal liver function.

The second patient, a 2-month-old girl weighing3.4 kg, received an urgent split-liver transplant foracute hepatic failure of unknown origin from a donor

Figure 3. Kaplan-Meier survival curve showing 1- and2-year actuarial overall patient (X) and graft (n) survivalrates.

Table 5. Profiles of Transplant Recipients Who Required Retransplantation

PatientNo.

Age(yr)

1st TXTechnique DRWR Cause of Failure

2nd TXTechnique DRWR Status

1 12 Whole 1.3 HA thrombosis Whole 0.5 Alive2 1 Reduced 4.4 PV 1 HV thrombosis Split (II-III) 10.0 Dead3 1.6 Whole 2.7 HA 1 PV thrombosis Reduced 7.1 Dead4 1.3 Split (II-III) 7.6 HV thrombosis Reduced 3.2 Alive5 0.5 Whole 0.6 HA 1 PV thrombosis Split (II-III) 9.7 Dead6 1 Split (right) 1.7 HA thrombosis Split (II-III) 6.5 Dead7 21 Split (I-IV) 1.5 HA thrombosis Whole 1.6 Alive

Abbreviations: HA, hepatic artery; PV, portal vein; HV, hepatic vein; TX, transplantation.

Figure 4. Kaplan-Meier survival curve showing 1- and2-year actuarial patient survival rates for recipients ofsplit-liver (X) allografts, reduced-size liver (n) allografts,and whole livers (e).

Spada et al420

with a DRWR of 17.6. The oversized graft precludeddirect closure of the abdomen, and a polypropyleneprosthesis was used. The patient developed respiratoryfailure requiring prolonged mechanical ventilation andsepsis, and on day 17, portal vein thrombosis wasdiagnosed. Revision of the anastomosis was attempted,but during surgery, the child became hemodynamicallyunstable, had a cardiac arrest with resuscitation, and atthe end of the procedure was transferred to thepediatric intensive care unit (ICU) in unstable condi-tion and died soon after.

A 16-month-old girl who received an LLS forextrahepatic biliary atresia developed acute and fatalgastrointestinal bleeding after a liver biopsy performedon postoperative day 35 to confirm clinical suspicionof acute rejection.

The last patient who died after primary liver

transplantation was a 5-month-old boy who received areduced liver for extrahepatic biliary atresia. Allograftfunction in the immediate postoperative period wasgood; however, on day 11 he developed aspirationpneumonia and eventually had a fatal cardiac arrest.Postmortem examination showed nonspecific liverdamage related to preservation injury and bilateralsevere pneumonia.

Four patients experienced early vascular complica-tions and underwent unsuccessful retransplantation.Two girls aged 20 months and 6 months underwentwhole-liver transplantation for extrahepatic biliaryatresia. Both grafts were from pediatric donors aged 8years and 10 days, weighing 24 and 3.8 kg, respectively.The first patient developed acute intraoperative throm-bosis of the interposition graft, which was placedbetween the recipient aorta and the common hepaticartery of the graft, with acute graft nonfunction. Thechild underwent retransplantation with a reduced grafton day 1. She was transferred to the pediatric ICU instable condition, became hypotensive a few hours later,and had a fatal cardiocirculatory arrest. Postmortemexamination showed hepatic necrosis with thrombosisof the portal vein, dissection of the hepatic artery,necrosis of the right kidney, and pulmonary edema.

The second girl developed acute hepatic artery andportal vein thrombosis on day 3 and underwentrevision of the anastomosis with the use of an interpo-sition vein graft and subsequent split-liver retransplan-tation. Liver recovery was regular, but the patientdeveloped sepsis and died on day 9 after primarytransplantation. Postmortem examination showed bac-terial bilateral pneumonia and meningitis.

A 1-year-old girl who underwent transplantationfor Byler’s disease with a reduced-size liver graft from apediatric donor (age, 9 years; weight, 35 kg) developedacute thrombosis of the left hepatic vein and portalvein and underwent urgent retransplantation with a

Figure 5. Kaplan-Meier survival curve showing 1- and2-year actuarial split-liver recipient survival rates forpatients with UNOS status 1 (e), UNOS status 2 (X), andUNOS status 3 (n). There is a statistically significantdifference (P F .05) between UNOS status 2 and 3patients compared with UNOS status 1 patients.

Table 6. Profiles of Transplant Recipients Who Died After Primary Transplantation

PatientNo.

Age(yr)

TransplantTechnique

UNOSStatus DRWR Cause of Death

PODay

1 0.4 Reduced 3 8.6 Pneumonia 112 12 Whole 3 1.4 PNF 33 1.1 Split (II-III) 3 7.8 PNF 24 0.2 Split (II-III) 1 6.4 Neurological complication 2875 1.2 Split (II-III) 3 8.4 GI hemorrhage 396 0.2 Split (II-III) 1 17.6 Sepsis 17

Abbreviations: GI, gastrointestinal; PO, postoperative.

Split Liver for Pediatric Liver Transplantation 421

split-liver graft. During the procedure, the hemody-namically unstable patient experienced a fatal cardiocir-culatory arrest.

Finally, a 20-month-old boy with extrahepaticbiliary atresia underwent transplantation with a rightgraft (segments I and IV to VIII) from a pediatricdonor (age, 2 years; weight, 14 kg). Acute hepaticartery thrombosis was diagnosed on day 3, and anurgent retransplantation was performed the next daywith an LLS. The liver showed a normal recovery offunction; however, the boy developed progressive braindamage and died on day 7 after primary transplanta-tion.

Vascular complications occurred in 13 patients(20%), with hepatic artery thrombosis developing in 6patients (9%), portal vein thrombosis in 7 patients(11%), and venous outflow obstruction in 4 patients(6%). Complications were equally distributed in whole-liver (20%), split-liver (21%), and reduced-liver (17%)recipients. Arterial occlusion was diagnosed in 2 split-liver recipients (5%), 1 who received a right graft andthe other a left lobe, and in 4 whole-liver recipients(20%). Portal vein complications occurred in 4 split-liver recipients (10%), 1 reduced-size liver recipient(17%), and 2 whole-liver recipients (10%). Two chil-dren (5%) who received split livers experienced venousoutflow obstruction compared with 1 patient with a

reduced-size liver (17%). Details regarding vascularcomplications and their treatment are listed in Table 7.

Biliary complications developed in 16 children(25%), primarily in patients who received a split liver(11 of 39 patients) or reduced liver (4 of 6 patients)compared with the whole-liver recipients (1 of 20patients). Biliary complications included anastomoticstricture (n 5 7), anastomotic leak (n 5 3), or cut-edge leak (n 5 5). Stenoses were successfully treated inall but 1 patient with percutaneous transhepatic cholan-giography, drainage, and balloon dilatation. One pa-tient required revision of the anastomosis. Cut-edgeleaks were treated with percutaneous drainage in 4patients and surgical revision in 1 patient. Anastomoticleaks always required surgical intervention on theanastomosis. A 10-month-old boy who underwenttransplantation with an LLS for extrahepatic biliaryatresia developed progressive intrahepatic biliary treedistension 3 months after transplantation. Percutane-ous transhepatic cholangiography showed a patenthepaticojejunostomy with an intestinal stricture a fewcentimeters below the bilioenterostomy, where anintestinal valve had been created at the time of Kasaiportoenterostomy. The child underwent laparotomywith resection of the intestinal loop and redo of thehepaticojejunostomy. No biliary complications directly

Table 7. Profiles of Transplant Recipients With Vascular Complications

PatientNo.

Recipient Donor

TransplantTechnique Complication Treatment Status

Age(yr)

Weight(kg)

Age(yr)

Weight(kg)

1 0.5 10 49 85 Split (II-III) Venous outflowobstruction

Balloon dilatation Alive

2 12 40 49 50 Whole HA thrombosis Retransplantation Alive3 2.3 12 22 70 Split (II-III) PV thrombosis Observation Alive4 1 8 9 35 Reduced LHV 1 PV throm-

bosisRetransplantation Dead

5 1.6 9 8 24 Whole HA thrombosis* Retransplantation Dead6 12 40 16 55 Whole LHV 1 HA 1 PV

thrombosisRevision anastomoses Dead

7 1.3 11 18 84 Split (II-III) Venous outflowobstruction

Retransplantation Alive

8 0.7 7.2 43 75 Split (II-III) PV thrombosis Revision anastomosis Alive9 0.5 6.2 0.1 3.8 Whole HA 1 PV thrombosis Retransplantation Dead

10 0.7 7.5 33 80 Split (II-III) PV thrombosis* Observation Alive11 0.2 3.4 18 60 Split (II-III) PV thrombosis* Revision anastomosis Dead12 1 8.1 2 14 Split (right) HA thrombosis Retransplantation Dead13 21 55 29 85 Split (I-IV) HA thrombosis Retransplantation Alive

Abbreviations: HA, hepatic artery; PV, portal vein; LHV, left hepatic vein.*Anastomosis performed with an interposition graft.

Spada et al422

resulted in graft or patient loss. Details for biliarycomplication are listed in Table 8.

Eight children required reexploration for intestinalperforation, 4 children among the split-liver recipients(10%), 1 child in the reduced-size liver group (17%),and 3 children among the whole-liver recipients (15%).Two patients, 1 in the split-liver group and the other inthe reduced-liver group, required reexploration forintra-abdominal hemorrhage. All cases of intestinalperforation and hemoperitoneum were diagnosed early,and none led to graft loss or death.

Early Postoperative Course

Forty-eight patients required intraoperative blood trans-fusion, 17 patients (85%) in the whole-liver group, 6patients (100%) in the reduced-size liver group, and 25

patients (64%) in the split-liver group. Overall intraop-erative blood transfusion requirements were 21.3 618.7 mL of red blood cells per kilogram of recipient’sbody weight (median, 16.6 mL; range, 2 to 88 mL).No statistically significant differences in terms of bloodtransfusion were observed among the different trans-plantation techniques, although reduced-size liver re-cipients required more transfusions than the otherpatients (Table 4).

Posttransplantation graft function recovery tendedto be slower in split-liver recipients compared withchildren who received a whole liver. Table 9 lists thechronologic changes in values for serum alanine amino-transferase, serum total bilirubin, and prothrombininternational normalized ratio according to the 2 typesof grafts transplanted.

Overall median hospitalization was 22 days, with a

Table 8. Profiles of Transplant Recipients With Biliary Complications

PatientNo.

Recipient

DRWRTransplantTechnique

ColdIschemia

(min)

No. ofDuctalOrifices Complication

PODay Treatment

HospitalStay (d)

Age(yr)

Weight(kg)

1 19 54 1.39 Whole 476 — Stenosis 639 PTC dilatation andstenting

14

2 2 11 5.91 Split (II-III) 278 2 Cut-edge leak 12 Percutaneous drainage 503 2 13 5.00 Split (II-III) 315 2 Stenosis 78 PTC dilatation and

stenting30

4 0.4 4.2 4.76 Reduced 420 1 Stenosis 21 PTC dilatation andstenting

58

5 0.6 7 10.00 Split (II-III) 615 1 Stenosis 251 Revision of anasto-mosis

14

6 1.3 11 3.18 Reduced 420 1 Stenosis 34 Revision of anasto-mosis

13

7 0.8 7.8 9.62 Split (II-III) 300 2 Roux limb stenosis 115 Revision of anasto-mosis

19

8 13 48 1.35 Split (I-IV) 355 1 Cut-edge leak 8 Surgical treatment 249 2.5 13 5.00 Split (II-III) 240 2 Anastomotic leak 23 Revision of anasto-

mosis35

10 4 19.5 3.24 Split (II-III) 285 1 Stenosis 148 PTC dilatation andstenting

34

11 10 38 1.58 Split (I-IV) 285 1 Cut-edge leak andstenosis

6101

Percutaneous drainage,PTC dilatation, and

stenting

17

12 0.5 6.6 3.79 Reduced 520 1 Anastomotic leak 8 Revision of anasto-mosis

25

13 1 8.1 9.88 Split (II-III) 480 1 Cut-edge leak 8 Percutaneous drainage 2414 6 14.6 1.02 Split (II-III) 305 1 Stenosis 36 Revision of anasto-

mosis27

15 0.8 7.8 8.33 Split (II-III) 330 1 Cut-edge leak 16 Percutaneous drainage 3116 0.8 7.5 4.67 Reduced 580 1 Anastomotic leak 5 Revision of anasto-

mosis21

Abbreviations: PO, postoperative; PTC, percutaneous transhepatic cholangiography.

Split Liver for Pediatric Liver Transplantation 423

median ICU stay of 7 days. Patients who underwenttransplantation with a whole liver had a medianhospital stay of 15 days; those who underwent trans-plantation with a reduced-size liver, 21 days; and thosewho received a split liver, a median of 24 days.

Right Grafts

Of the right grafts obtained by in situ split liver(segments I and IV to VIII in 37 cases and segments Vto VIII in 3 cases), 1 graft was transplanted by ourcenter into a pediatric recipient and is included in ourstudy, whereas the others were transplanted by othercenters, as well as the 2 right grafts obtained by ex situsplit liver. Nine liver transplant centers collaboratedwith us, sharing the split-liver grafts. Seven centerswere in the NITp area, 1 center was an Italian centeraffiliated with a different organ procurement agency,and 1 center was a European center in Germany.

Data concerning the right lobe grafts from in situsplit livers were presented by us at the 1999 Meeting ofthe Nord Italia Transplant.12 Briefly, 36 grafts wereused for primary liver transplantation, whereas 3 rightlivers were used for retransplantation of patients whopreviously underwent transplantation with whole livers(n 5 2) or right split livers (n 5 1). The patientpopulation included 24 men and 15 women with amedian age of 52 years (range, 19 to 63 years). Themost common causes of end-stage liver disease werechronic active hepatitis C (n 5 12) and B (n 5 7). Atthe time of primary transplantation, 9 patients (25%)were UNOS status 3, 26 patients (72.2%) were UNOSstatus 2, and 1 patient (2.8%) was UNOS status 1.Overall actual patient and graft survival rates after

primary right graft in situ split-liver transplantationwere 84% and 79%, respectively. One graft (3%) waslost because of PNF.

Discussion

The use of a liberal policy of liver splitting, madepossible by strict collaboration with other transplantcenters, allowed us to meet the needs of all the pediatricpatients referred to our center, with no mortality on thewaiting list. The consensus-based policy adopted byseveral liver transplant centers in the NITp area to splitall suitable donor livers had a significant impact onreducing waiting time for pediatric patients. In a fewmonths, the waiting list time for our pediatric patientsdecreased from 60 to 7 days.

We started to use the split-liver technique on aregular basis at the end of 1997. In 1998, this policyhad a significant impact on the liver transplant activityin the NITp area: although the increase in the numberof donors per million of inhabitants from 1997 to1998 was 11% (from 16.5 to 18.3 donors/millioninhabitants), the number of liver transplantations hada 17% increase (from 243 to 284 transplantations).6

The formula used allowed us to share grafts withcollaborating adult transplant programs located notonly in our areas, but also in other areas of the countryand in Europe.

The collaborating centers obtained good results interms of patient and graft survival rates, similar to theones reported by the European Split Liver Registry foradult patients.13

No definitive study comparing the advantages of insitu versus ex situ techniques have been performed.

Table 9. Changes in Serum ALT, Serum Bilirubin, and INR Values in Split-Liver and Whole-Liver Transplant Recipients

TimeAfter

TX (d)

Split Liver (n 5 39) Whole Liver (n 5 20)

ALT(IU/L)

Bilirubin(mg/dL) INR

ALT(IU/L)

Bilirubin(mg/dL) INR

0 108 6 92 12.1 6 12.2 1.21 6 0.17 139 6 51 10.1 6 9.9 1.16 6 0.1711 1,050 6 1,289* 5.2 6 2.9* 1.93 6 0.63* 349 6 140* 3.0 6 1.3* 1.37 6 0.30*13 1,296 6 1,509* 5.9 6 2.7* 1.60 6 0.43* 360 6 193* 2.7 6 1.3* 1.17 6 0.12*15 577 6 527 5.2 6 3.5* 1.21 6 0.69 303 6 205 2.2 6 1.0* 1.14 6 0.1017 271 6 170 5.9 6 5.4* 1.13 6 0.80 424 6 315 2.1 6 2.2* 1.41 6 0.76

114 91 6 182 2.8 6 2.5 1.05 6 0.57 147 6 349 1.7 6 1.9 1.43 6 0.46121 81 6 21 2.0 6 2.1 1.18 6 0.21 75 6 104 1.2 6 1.1 1.27 6 0.26128 42 6 28 0.5 6 0.4 1.19 6 0.14 37 6 21 0.6 6 9.4 1.09 6 0.03

NOTE. Data reported as mean 6 SD.Abbreviations: TX, transplantation; ALT, alanine aminotransferase; INR, international normalized ratio.*P , .05, split-liver recipients versus whole-liver recipients.

Spada et al424

Although excellent results have been reported with theex situ technique,14 we share the view of the inventorsof the in situ technique that this method has severaladvantages,15,16 and in particular, it facilitates thesharing of split grafts between collaborating centers.The overall patient and graft survival rates of our seriesof in situ split-liver transplantations showed an improve-ment over the ex situ pediatric split-liver transplanta-tion experience.5,17-23 By in situ splitting of the liver, wewere able to have short ischemia times, resulting ingood liver allograft function and a low incidence ofPNF. The sharing of the 2 split grafts between 2 centersallowed the transplantation of both at approximatelythe same time, with a reduction of the ischemic timecompared with sequential transplantation, which issometime performed in a single center. This canexplain the low incidence of PNF in the adult recipi-ents compared with other reported series.13 With the insitu technique, good hemostasis of the cut surface atthe time of allograft procurement was obtained, result-ing in reduced intraoperative blood transfusion require-ments during transplantation compared with reduced-size liver grafts. Only 1 split-liver recipient (2%)required reexploration for intra-abdominal hemor-rhage compared with 13% of the reduced-size liverrecipients. It has been claimed that with the in situsplit-liver technique, increasing the operation time inthe donor hospital might have a negative effect onorgan donation.14 The widespread use of in situsplit-liver transplantation in the NITp area did notreduce the number of donor referrals and resulted in anet increase of 6% in the total available liver allografts.6

The formula adopted to select the pediatric recipi-ents according to DRWR was accurate in predictingthe size compatibility of the left lateral segment. In ourseries, all the LLS split livers chosen according to theformula fit in the recipients’ abdomens without compli-cations. Regarding the lower size limit of the split graft,we transplanted the liver as a whole liver when theDRWR and the recipient were small because we werenot able to find a pediatric transplant center to acceptthe right graft, not because of the low dimension of theLLS. Moreover, experience with the use of right graftsfrom split livers for pediatric transplantation is anec-dotal, and the only case that we performed developed afatal vascular complication related to the small caliberof the right branch of the hepatic artery. For largechildren, we described and adopted a modified split-liver technique that generates 2 grafts more similar insize, both of which are transplantable in adults or largechildren with a graft-recipient weight ratio of 0.8 orgreater.

The upper limit of a DRWR of 12 was exceeded in2 cases. In the first, an LLS from a donor with aDRWR of 17.6 was transplanted into a UNOS status 12-month-old girl with acute hepatic failure of un-known origin. Because of the large volume of the graft,the abdomen was closed by means of a polypropylenemesh after further nonanatomic parenchymal reduc-tion. The child developed portal vein thrombosis,respiratory failure, and sepsis and died 17 days aftertransplantation. The second patient, a UNOS status 212-month-old boy with Alagille syndrome received anLLS from a donor with a DRWR of 16.7. He did notdevelop major postoperative complications and is well4 months after the procedure.

The reported incidence of hepatic artery thrombosisfor pediatric reduced-liver transplantation ranges from6% to 25%.13,16,17,19,24 Arterial complications in ourpatients (9%) were in this range. Recent series reporteda lower incidence of arterial occlusion (0% to 6%)obtained with the use of microsurgical techniques.16,24,25

In our series of 39 split-liver transplantations, therehave been 2 cases of hepatic artery thrombosis, 1 in achild with a right graft (segments I and IV to VIII) andthe other in a patient with a left lobe. No recipients ofconventional split livers experienced hepatic arterythrombosis. This complication occurred in 4 patientswith a whole liver, in 1 child with acute recurrence ofBudd-Chiari syndrome, and in 2 patients aged youngerthan 2 years who received whole grafts from a neonataland a pediatric donor. Published series have docu-mented a greater incidence of arterial thrombosis andinferior survival in small transplant recipients if theyreceived a full-size liver allograft.25,26

The first split-liver recipient in our series developedvenous outflow obstruction caused by stenosis of theleft hepatic vein anastomosis. The stenosis was treatedsuccessfully by balloon dilatation. After the adoptionof the triangulation technique of Emond et al,11 we didnot observe venous outflow obstructions, except in 1child who underwent transplantation with an LLSgraft with 2 independent hepatic veins from segmentsII and III that did not allow for the creation of acommon anastomotic stump. The patient developedacute graft congestion with PNF and underwentsuccessful retransplantation with a reduced-size graft.

The incidence of portal vein thrombosis varied inseveral reported series from 4% to 13%.13,19,24,25 Portalcomplications in our series of split-liver transplanta-tions (10%) were in the upper range, all in smallchildren. The triangulation technique adopted for theleft hepatic vein anastomosis decreased the graft’srotation to the right, reducing the risk for portal vein

Split Liver for Pediatric Liver Transplantation 425

strictures. Moreover, we used to dissect the recipient’sextrahepatic portal vein, even if slightly sclerotic, pastthe primary portal branches, obtaining an adequatelength of portal vein to anastomose to the graft leftbranch of the portal vein. We limited the use ofinterposition venous grafts to very sclerotic and smallportal veins of patients with biliary atresia, performingthe anastomosis to the confluence of the splenic veinand superior mesenteric vein. Three of 4 split-liverrecipients who developed portal vein thrombosis under-went transplantation for extrahepatic biliary atresia,and 2 patients required an interposition graft.

Another possible risk factor in the development ofportal vein thrombosis is the volume of the trans-planted graft. Tight closure of the abdomen after verylarge-for-size liver grafts, particularly in small children,can result in impaired perfusion of the graft, highintrahepatic vascular resistance, and portal vein throm-bosis. In our series, 1 patient who underwent transplan-tation for acute liver failure of unknown cause with anLLS from a donor with a DRWR of 17.6 developedportal vein occlusion. The extensive use of delayedabdominal closure adopted by others might helpaddress this issue.24

The overall incidence of biliary complication in ourseries was 25%. Whereas only 1 whole-liver recipient(5%) developed a biliary complication, the incidenceof biliary complications was greater in reduced-size andsplit-liver recipients. In the split-liver group, 2 of the 3patients who received a graft obtained with the modi-fied split-liver technique (segments I to IV) experi-enced a biliary leak at the cut edge, and 1 of thesepatients subsequently developed a biliary structuresecondary to fibrosis. To date, we adopted the modifiedsplit-liver technique in selected cases, and much moreexperience must be gained with this method to be ableto evaluate the type and incidence of biliary complica-tion. After conventional in situ split-liver transplanta-tion (LLS), 9 of 36 patients developed biliary complica-tions. In 1 previously discussed case, biliarycomplication was related to the ileal loop stenosisrather than to the split-liver technique itself. In another2 cases (patients 2 and 5 in Table 8), the developmentof a biliary complication followed an episode of bowelperforation with sepsis. In the reduced-size liver group,hemoperitoneum in 1 patient and bowel perforationwith sepsis in another patient preceded the develop-ment of 2 anastomotic leaks (patients 12 and 16 inTable 8). Sanchez-Urdazpal et al27 reported increasedbile duct complications in liver transplantation acrossthe ABO barrier. This could be the cause of the biliary

stricture observed in reduced-size graft recipients previ-ously discussed (patient 6 in Table 8).

The incidence of biliary complications varied inseveral reports, from 0% to 28% in pediatric split-livertransplantation14,17,19-21,28 and 10% to 38% in pediat-ric living related liver transplantation.29-32 This seemsto be related to the technical and anatomic problemsassociated with the procedure33 and ischemic injurycaused by prolonged cold preservation,27 especially inthe ex situ technique; hepatic artery thrombosis32-34;sepsis33; and underlying pathological conditions.32

Several measures have been proposed to reduce theincidence of biliary complications: reduce cold isch-emia time,34 extensively use bench cholangiography toidentify anomalous biliary anatomy,14,19 meticulousligation of bile duct radicles on the cut surface,14

routinely use T-tubes,14 and avoid the dissection of thebile duct bifurcation.17,19,29 We did not use benchcholangiography because it increases the benching timeand needs manipulation of the graft. In our series,preservation time was limited, and we did not observe adifference in cold ischemia time between patients whodeveloped and did not develop strictures of the bileducts (383 6 79 v 384 6 101 minutes in the entirepopulation, respectively; 380 6 157 v 339 6 82 min-utes in the split-liver group, respectively). We recentlystarted using an ultrasound dissector for parenchymaltransection, and since then, we have not observedcut-edge biliary leaks (data not reported).

Timely diagnosis and correction of biliary complica-tions is crucial to avoid graft loss or patient mortality.Reichert et al33 proposed routine planned explorationwith open liver biopsy to avert morbidity caused bybiliary complications. Our protocol was to closelysurvey the development of biliary leaks with Dopplerultrasound and perform cholangiography when biliarystricture was suspected, even without significant intra-hepatic biliary dilatation. In this way, we were able toproperly diagnose biliary complications and treat themwithout graft or patient loss.

The length of hospital stay after transplantation forthe patients with split livers was 24 days opposed to 15days for whole grafts. The greater incidence of biliarycomplications in the former group does not explainthis difference by itself. In the split-liver group, medianhospitalization of children experiencing biliary compli-cations was similar to those with no biliary problems(26 v 24 days; P 5 .4).

Urgent transplantation of high-risk patients is thedominant factor influencing poor outcome in ourexperience, as well as that of other investigators.13,19,23

Nevertheless, split livers are used by us as well as

Spada et al426

others34 in urgent conditions because split-liver graftsprovide function similar to whole or reduced-sizedgrafts. In our experience, all the patients referred to ourcenter with acute or fulminant liver failure (n 5 4)underwent transplantation with a split liver. Onepatient previously described died with poor graftfunction. The other 3 patients showed a normalpattern of graft function recovery. Two patients arealive 1 and 3 months after transplantation with normalliver function; 1 patient died 9 months after transplan-tation of brain death with normal liver function. Only1 patient among the adult recipients of a primary rightsplit liver was a high-risk, UNOS status 1 patient. He iswell 6 months after transplantation.

The split-liver technique has the potential to com-pletely meet the needs of pediatric liver transplanta-tion, and its further technical evolution to generate 2liver grafts with greater similarity in size could greatlycontribute to meet the needs of adult patients.8 One ofthe major benefits of living related liver transplantationis to perform transplantation on pediatric patients onan elective basis, early in the course of the originaldisease.35,36 In our experience, split-liver transplanta-tion matched this advantage, greatly reducing therecipient waiting time.

In conclusion, our report shows that the adoptionof a liberal policy of liver splitting provides allografts ofoptimal quality for pediatric transplantation. The insitu technique of split liver shortened the ischemiatimes with a low incidence of PNF and reexplorationfor intra-abdominal hemorrhage and facilitated thesharing of split grafts with other centers. The extensiveuse of split livers has dramatically decreased thepediatric waiting list time, allowing us to performtransplantation on all the children referred to ourcenter, with no mortality on the waiting list. Theextensive use of the alternate technique of in situsplit-liver transplantation might help meet the needs ofadult patients, further expanding the graft pool.

Acknowledgment

The authors thank the Nord Italia Transplant for its effort incoordinating the split-liver program and all the liver trans-plant centers that collaborated with this program.

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