M. Gamez

Long-term survival expectancy after liver transplantation in children

PURPOSE The aim of this study was to assess the long-term survival rate in children who have undergone orthotopic liver transplantation (OLT) in the last 13 years. METHODS The records of 198 consecutive patients under 18 years of age who underwent 249 OLTs between 1986 and 1998 were reviewed. Actuarial patient survival rates were assessed at 1, 3, 5, and 10 years in the whole series, in the last 5 years, and in patients surviving more than 1 year. Age, weight, and indications were analyzed, as well as type and incidence of posttransplant complications. The median follow-up period was 41 months (0 to 154 months). RESULTS Biliary atresia was the most common indication (41.9%) followed by alpha-1 antitrypsin deficiency (8.1%), Alagille syndrome (7.6%), and fulminant hepatic failure (6.6%). One hundred forty-six patients (58.6%) were below 5 years, and 46 patients were (18.5%) younger than 1 year at operation. Sixty-eight patients (27.3%) weighed less than 10 kg. One hundred seventy whole organs and 70 reduced, 5 living-related donor, and 4 split-liver allografts were used. Hepatic artery thrombosis (n = 18), primary nonfunction (n = 15), and chronic rejection (n = 14) were the most common causes for allograft failure. Fourteen patients (7%) had posttransplant lymphoproliferative disorders (PTLD) at a median time of 28 months (4 to 124 months) postoperation (3 died). The 1-, 3-, 5-, and 10-year actuarial patient survival rates are 80%, 76%, 74%, and 74%, respectively; over the last 5 years it is 88% at 1 year and 82% at 3 and 5 years. For patients surviving more than 1 year, 3-, 5-, and 10-year actuarial survival rates are 95%, 93%, and 93%, respectively. CONCLUSIONS (1) Overall results of OLT improve with increasing experience. (2) Children who survive more than 1 year after OLT have an excellent prognosis, although long-term complications of immunosuppression can be expected.

Late biliary complications in pediatric liver transplantation

PURPOSE The aim of this study was to review the biliary complications occurring in late follow-up after liver transplantation in children. METHODS The medical records of 135 children who received orthotopic liver transplantations (OLT) and had graft survival of more than 1 year were reviewed. Technical variants using a reduced-size graft were applied in 32 (23.7%). For biliary reconstruction, 15 patients had choledochocholedochostomy and 120 a Roux-en-Y loop. Biliary reoperation in the early post-OLT period was needed in 24 patients (17.7%). Routine checking of liver function and duplex Doppler ultrasonography (DDS) were performed during the follow-up period, which averaged 58 months. Late biliary complication was defined as that occurring after the first hospital discharge. RESULTS Late biliary complications occurred in 18 children (13.3%); 16 showed symptoms or analytical disturbances in liver function tests. The Diagnoses included uncomplicated cholangitis (n = 6), anastomotic biliary stricture (n = 7), ischaemic damage of the biliary tree (n = 3) including one late (28 months) hepatic artery thrombosis leading to an intrahepatic biloma. and bile leak after T-tube removal (n = 2). The six children with uncomplicated cholangitis had no repeat episodes in follow-up despite persistent aerobilia. Six patients affected by anastomotic strictures were treated successfully with percutaneous dilatation and, if present, stone removal. Persisting dysfunction and cholangitis occurred in one case affected by ischaemic biliary disease. Biliary leaks after T tube removal settled spontaneously. Risk factors for late biliary complications were determined. There was no relation to the cold ischaemia time, type of graft or biliary reconstruction, or previous early post-OLT biliary reoperation. Aerobilia (affecting 21.5% of OLT patients) was related to cholangitis (P = .001). CONCLUSIONS Anastomotic strictures, reflux of intestinal contents via the Roux-en-Y loop, and residual ischaemic damage led to late biliary complications in 12% of paediatric OLT patients. Evidence of biliary dilatation on DDS may be delayed in anastomotic strictures; in these cases the results of percutaneous treatment were excellent. Children with aerobilia have and increased risk of cholangitis.

Donor vascular grafts for arterial reconstruction in pediatric liver transplantation

The authors compared the results of 48 orthotopic liver transplantations (OLT) in which revascularization was achieved with a conduit interposed between the receptor aorta and the graft (vascular graft [VG] group) with those obtained for 56 OLT performed during the same period (1991 to 1994) in which end-to-end anastomosis (EEA) of the hepatic arteries or celiac trunk was used (EEA group). In the VG group, the interposed conduits were the cadaveric iliac artery (37) the living-donor saphenous vein (3), or nonthrombosed conduits from previous transplants (8) (7 iliac arteries, 1 saphenous vein). There were significant differences between the two groups with respect to recipient age, recipient weight, the retransplant:first transplant ratio, the number of emergency transplantations, the use of reduced-size grafts, and intraoperative transfusion requirements. Twenty-nine grafts in the VG group (60.4%) and 43 in the EEA group (76.7%) currently are functioning. The actuarial 3-year graft survival rates are 60% and 71.5% for the VG and EEA groups (P < .05), respectively. The rate of arterial thrombosis did not differ between the two groups. The authors conclude that, although EEA of the hepatic artery is still the preferred revascularization technique for OLT, revascularization of the liver graft by conduit interposition is safe when EEA is not possible. Reutilization of the interposed conduit during retransplantation proved to be safe in the absence of hepatic artery thrombosis.

Pediatric intestinal transplantation

AIM Analyze the results of a paediatric intestinal transplantation (IT) program in Spain. PATIENTS During an 5-year period, 18 children were included as candidates for IT. The causes for intestinal failure (IF) were short bowel syndrome (n=13), motility disorders (n=3), and congenital epithelial disorders (n=2). Nine children were admitted for a combined liver-small bowel transplant (LSBT), seven for an isolated intestinal transplantation (IIT) and two for a multivisceral transplantation (MVT). In three of the candidates for IIT the indication had to be changed to LSBT because of progression of the liver damage. RESULTS Eight candidates are on the waiting list: four for LSBT, two for IIT, and two for MVT. Four children died before transplantation. All were children under 1 year and candidates for LSBT. One child died during an attempted MVT. Five children underwent transplantation. Grafts were IIT in two and LSBT in three. Of these children, two are on a normal diet (respective follow-up times: 40 and 18 months), two died, both with functioning liver and intestinal grafts (hemorrage after liver biopsy and lymphoproliferative disease), and one developed an untreatable rejection that lead to loss of the intestinal graft; currently, she is on the waiting list for LSBT. CONCLUSIONS The morbidity and mortality of IT are high, but it is the only possible treatment for children in IF who cannot be adequately managed with parenteral nutrition. A severe problem is the the scarcity of suitable donors for the very low weight children who are candidates for LSBT.

Long-term follow-up of patients with biliary atresia successfully treated with hepatic portoenterostomy. The importance of sequential treatment

Abstract The outcome of 18 biliary atresia (BA) patients (5 male, 13 female; age range 10.7–22.5 years; mean 15.4±0.7 years) treated with hepatic portoenterostomy (HPE) and jaundice-free for more than 10 years without liver transplantation (LT) is analyzed retrospectively. Eight of these patients subsequently required LT (age at LT 12.8±0.5 years, range 10.5–15.2 years); 3 children (aged 11.6, 13.2 and 14.1 years, respectively) had episodes of gastrointestinal variceal bleeding associated with other signs of severe disease and are now candidates for LT; and among the 7 asymptomatic patients (age range 11.2–22.5 years; mean 15.9±2.1 years), 5 had sonographic and biochemical signs of moderate portal hypertension (PH). In order to analyze whether the age at transplantation influences the survival of children transplanted for BA, we also reviewed the outcome of 71 BA patients transplanted at our hospital between 1986 and 1996. All the children older than 10 years at the time of LT were alive; only patients younger than 10 years died following LT (n= 15). We conclude that the natural outcome of extrahepatic BA is toward PH, fibrosis, and cirrhosis, even in those cases successfully treated with HPE. In our experience, the results of sequential treatment with HPE and LT were excellent.

Variant techniques for liver transplantation in pediatric programs.

INTRODUCTION Several variant techniques have been developed as alternatives to whole liver transplantation to improve size matching, timing, or simply to increase the pool of donors. The aim of this study was to assess the requirements of these techniques and their outcomes in a pediatric transplant program. PATIENTS AND METHOD A retrospective analysis of children on the waiting list in the last 4 years was carried out. Data of patients who died while on the waiting list (WL) were recorded. Transplanted patients were divided according to the type of graft: whole liver, split, living donor and reduced liver. The analyzed outcome variables were: age, weight, UNOS status, cause of liver failure, complications and graft and patient survival. Comparisons between types of graft were performed by using Kaplan-Meier, log-rank, chi (2) and Kruskal-Wallis tests. RESULTS During the period studied, 116 children were listed for liver transplantation. Of these 116 children, nine (7.7 %) died after a mean period of 40.5 (5-175) days waiting for a suitable graft. Their median age at inclusion was 214 (35-1607) days, and median weight was 7.2 (12.3-3.6) kg. The cause of liver failure in this group was: 1 hemochromatosis, 1 hepatoblastoma, 2 biliary atresia, 2 acute liver failure, 2 primary non-function (PNF) and 1 chronic rejection. Liver transplantation was performed in 103 children: 25 (24 %) whole livers, 17 (16.5 %) split, 29 (28 %) living donor, 32 (31 %) reduced and 4 remain on the waiting list. Recipient age and weight were significantly lower in those receiving split and living donor than in those who given whole livers. Patient and graft survival were similar in all groups although there was a trend to lower graft survival in patients receiving whole livers. More than 50 % of patients with UNOS status I received a split graft and 5/6 children with hepatoblastoma underwent living donor transplantation. There were no differences in the rate of acute vascular complications, but long-term biliary complications were more frequent in split and living donor grafts. CONCLUSIONS As long as the goal of zero mortality for children on the waiting list is not achieved, variant techniques will be necessary in pediatric liver transplantation programs. Split and living donor were employed mostly to treat younger children and particularly those with a higher UNOS status. Children with tumors were treated mainly with living donor grafts. Variant techniques, which are absolutely necessary in a pediatric program, need to be improved in order to avoid long-term biliary complications.

Supraceliac aortic clamping during the anhepatic phase of experimental orthotopic liver transplantation

BACKGROUND The pig tolerates simultaneous clamping of the liver pedicle and inferior vena cava poorly, so venovenous bypass has to be used during the anhepatic phase of experimental orthotopic liver transplantation (OLT). The aim of this work is to assess whether clamping of the supracoeliac aorta during the anhepatic phase (AP) of experimental OLT in pigs allows transplantation in stable hemodynamic conditions. METHODS Fourteen pigs (weight, 16 to 18 kg) received whole liver grafts from 14 age-matched donors and were subsequently divided into two groups: group I, OLT without venovenous bypass during the AP, group II, OLT with supracoeliac aortic clamping during the AP. Variables analyzed were cardiac output (CO) and related variables, mean systemic arterial pressure (MAP), mixed venous oxygen saturation (SvO2), hepatic artery and portal vein blood flow, systemic and hepatic O2 supply and uptake (SDO2, SVO2, HDO2, HVO2, respectively), liver enzymes, glucose, creatinine, and electrolytes. RESULTS In group I, CO, MAP, and SvO2, decreased during the AP (anhepatic) in comparison with baseline (preanhepatic) values (CO, 3.60+/-0.74, preanhepatic, v. 1.21+/-0.25 L x min(-1), anhepatic; P<.05. MAP, 97+/-12, preanhepatic, v. 43+/-17 mm Hg, anhepatic; P<.05. SvO2, 91.6+/-5.6, preanhepatic v. 70.0+/-12.5%, anhepatic; P<.05), and SDO2/SVO2 increased by 16% (preanhepatic) to 33% (anhepatic; P<.05). In group II, CO decreased during the anhepatic phase by only 21% (3.82+/-0.81, preanhepatic, v. 3.07+/-0.99 L x min(-1), anhepatic; not significant), the MAP increased significantly (100+/-8, preanhepatic, v. 135+/-4 mm Hg, anhepatic; P<.05), and SVO2, SDO2, SVO2, and SDO2/SVO2 remained unchanged. After revascularization, none of these variables differed significantly between groups, and levels of liver enzymes, glucose, creatinine, urea, and electrolytes were similar in both groups, both before and aftertransplantation. CONCLUSIONS Experimental OLT can be carried out in pigs without venovenous bypass, but it leads to severe hemodynamic disturbances. Clamping of the supraceliac artery during the AP is well tolerated and results in excellent hemodynamic stability, so it may prove to be a useful technique in liver transplantation in animals, such as dogs or pigs, that do not tolerate simultaneous clamping of the liver pedicle and inferior vena cava as well as human beings.

Cyclosporine monitoring in the early post-transplant period in pediatric liver transplant recipients

Abstract:  Monitoring of CsA blood levels two h post‐dose (C2) has shown a higher correlation to drug exposure than monitoring of trough levels (C0) at least in adults, but initial doses and target blood levels of CsA have yet to be established in pediatric transplant patients. The objectives of the study were to describe the pharmacokinetics of CsA administered by NGT in the first days after transplantation and the dose of Sandimmun Neoral® required to achieve minimum therapeutic range blood levels. This study included 20 pediatric liver transplant recipients (mean age of 3.2 yr) treated with CsA administered by NGT from day one post‐transplant until they were able to ingest oral medication. The study was continued until one yr of post‐transplant follow‐up. Eight h pharmacokinetic profiles were performed on days one, three, and five post‐transplant to determine the minimum dose required to achieve the therapeutic range. All children received an initial dose of 15 mg/kg/day of CsA by NGT. Mean CsA doses administered on days one, three, and five were 16.8, 29.5, and 36.5 mg/kg/day, respectively. Mean C0 levels of 119, 310, and 337 ng/mL and mean C2 levels of 213, 753, and 888 ng/mL were obtained. No correlation was found between C0 and C2 levels and the AUC0–8 h. Intravenous administration of CsA was required in 55% of patients. The biopsy‐confirmed acute rejection rate was 45%, with graft and patient survival rates of 95 and 100%, respectively. Conclusions: Poor absorption of CsA in small children requires a considerable increase in dose. CsA exposure cannot be estimated by single C0 or C2 determinations in the early post‐transplant period.

Pediatric living donor liver transplantation

AIM The aim of this study was to analyze the results of living donor in a pediatric liver transplantation program. PATIENTS Twenty-six living donor liver transplantations were performed in children from 0.5 to 14.8 years of age. The main indication was biliary atresia (72%) followed by tumors (2 hepatoblastomas and 1 hepatocarcinoma). Left lateral segments were used in 23 (1 transformed into a monosegment), 1 left lobe was used in 1, and right lobes were used in 2. Arterial reconstruction employed saphenous venous grafts in the first 3 cases and end-to-end anastomoses with a microsurgical technique in the following 22 cases. RESULTS There has been no major morbidity in the donors, with a median hospitalization of 6 days. Four grafts have been lost; 2 in the first 3 cases. In only 1 case, the graft loss was related to the procedure saphenous venous graft thrombosis). Early biliary complications were frequent (23%). Six month, 1 year, and 5 year graft and patient survival rates were 91%, 85%, and 85% and 100%, 96%, and 96%, respectively. CONCLUSIONS Living donor liver transplantation is an excellent option for transplantation in children.

Tacrolimus for steroiD‐resistant liver rejection in children

Abstract Eighteen pediatric liver transplant recipients were converted from cyclosporine‐based immunosuppression to tacrolimus for refractory rejection episodes affecting 21 grafts. Before conversion, steroid boluses were applied to all episodes followed by OKT3 monoclonal antibodies in 3 of them. Baseline biopsy showed cellular rejection in 18 patients and ductopenia in 3 cases. Thirteen episodes initiated within the first 2 postoperative weeks, and 8 occurred beyond the 21st day. A previous steroiD‐responsive episode of rejection was noted in 4 patients. Tacrolimus was administered by the oral route to obtain trough blood levels in the range 6–15 ng/ml. Reversal of rejection was obtained in 15 patients (71.4%). Complete normalization of liver function tests was achieved in 10 out of 12 patients who were followed for more than 6 months. A refractory evolution affected 6 patients (28.5 %). Significant factors predictive for tacrolimus‐resistant rejection were identified as ductopenia on baseline biopsy, previous episodes of acute rejection, late onset rejection (beyond 21st posttransplant (day), and a longer time of evolution of rejection prior to conversion.