Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

Situs inversus of donor or recipient in liver transplantation

Situs inversus is a rare anatomical abnormality that is often associated with multiple, complex malformations. In the past, patients with situs inversus were considered unsuitable candidates for transplantation or organ donation because associated visceral, and especially vascular, anomalies pose special technical difficulties. Recently, several cases of successful liver transplantation in recipients with situs inversus have been published using modified surgical techniques. This report reviews the literature and describes our own experience, including two liver graft recipients with complete and incomplete situs inversus, and one patient who underwent successful transplantation using a liver from a donor with situs inversus. Received: 10 October 1997 Received after revision: 22 December 1997 Accepted: 9 January 1998     

Arterialization of the portal vein in pediatric liver transplantation

Portal vein arterialization (PVA) is an acquired concept in shunt surgery for portal hypertension. This technique, recently described as both a temporary and permanent procedure in adult liver transplantation, is reported by the authors in two cases of pediatric transplantation. The indication was low portal blood flow after reperfusion with poor graft function due to persistence of spontaneous retroperitoneal venous shunts. In both cases described, PVA allowed for satisfactory macroscopic liver reperfusion. The increase in portal blood flow from 150 to 500 ml/min in the second patient enabled the liver to be reperfused correctly and led to successful transplantation. The graft function in both cases improved in the 1st postoperative week, but thrombosis of the PVA occurred in the 1st patient 2 months after transplantation. Signs of hepatic hyperarterialization occurred in the second patient and this necessitated a dearterialization of the portal vein 2 weeks later. Although the benefit of this procedure appears to be beyond doubt in the immediate postoperative period, we have no data on long-term arterialization. We do think that PVA can be performed in pediatric liver transplantation, but it may need to be done only in special, individual situations when no valid alternative can be proposed, such as in the absence of a mesenteric vein and/or the presence of spontaneous retroperitoneal venous shunts. Received: 24 June 1997 Received after revision: 27 November 1997 Accepted: 28 November 1997     

Two grams daily of oral acyclovir reduces the incidence of cytomegalovirus disease in CMV-seropositive liver transplant recipients

Our objective in this study was to determine the efficacy of 2 grams a day of oral acyclovir administered for 16 weeks after transplantation for the prevention of cytomegalovirus (CMV) infection and disease in CMV-seropositive liver transplant recipients. Seventy-three adult liver transplant recipients, seropositive for CMV, were randomized to receive either 2 grams a day of oral acyclovir for 16 weeks after transplantation or no prophylaxis. The incidence of CMV disease was significantly lower in the acyclovir group (5 %) than in the control group (27 %; P < 0.05). By log-rank analysis, the differences in the probability of presenting CMV disease over the first 16 weeks and over the 1st year were also significant (P < 0.05). We conclude that 2 grams a day of oral acyclovir provides effective prophylaxis against CMV disease in CMV-seropositive liver transplant recipients. Received: 14 March 1997 Received after revision: 30 May 1997 Accepted: 9 June 1997     

Internal hernia and volvulus of the small bowel following liver transplantation

Internal herniation with volvulus of the small intestine is an uncommon, but potentially fatal, complication after liver transplantation. We present here four cases in which the herniation occurred around the Roux-en-Y loop used for the biliary reconstruction. One patient died due to intestinal and liver allograft necrosis; another lost almost the entire small intestine and has since undergone successful intestinal transplantation. Two patients survived following surgery that involved reduction of the hernia and closure of the mesenteric defect. Clinical diagnostic implications emphasize early diagnosis and appropriate operative intervention. Received: 2 May 1996 Received after revision: 7 October 1996 Accepted: 28 October 1996     

Cadaveric small bowel/split liver transplantation in a child

Scarcity of size-matched grafts continues to be a major limiting factor for liver and combined liver/intestinal transplants in the pediatric population. It is reported that 29 % of pediatric patients listed for hepatic transplantation die while waiting for a donor. The reported mortality of pediatric patients awaiting intestinal transplantation is about 40 %. We report on a technique of segmental liver and intestinal transplantation in a child. To our knowledge, this is the first report of a combined split liver-intestinal transplantation. We used a cadaveric donor, but the technique can also be performed with a live donor. The adult recipient of one segment of the liver was discharged home without complications. The child who received the combined liver intestinal graft developed intestinal perforation and severe rejection and died. If this technique is applied successfully, the adverse effects and mortality of a long pretransplant waiting period in pediatric patients may be avoided. Received: 7 May 1998 Received after revision: 29 September 1998 Accepted: 12 October 1998     

Lipid abnormalities in stable liver transplant recipients – effects of cyclosporin, tacrolimus, and steroids

Dyslipidemia is common after liver transplantation, but the underlying mechanisms are largely unknown. We studied the lipid profile of 27 liver transplant recipients randomized to receive either cyclosporin (CyA, n = 14) or tacrolimus (n = 13) and compared them with 20 healthy, matched controls. Before transplantation, patients presented low total and low-density lipoprotein (LDL) cholesterol (as compared to controls) that increased shortly, i. e., 3 months, after transplantation. Eighteen months post-transplantation, total and LDL cholesterol levels decreased to pretransplant values but tended to remain higher in CyA-treated patients. However, at that time, prednisone treatment was more prevalent among CyA-treated than tacrolimus-treated patients and fully accounted for the difference in cholesterol levels. Indeed, regardless of therapy, patients not receiving prednisone exhibited lower cholesterol levels than prednisone-treated patients and controls. We conclude that prednisone therapy, rather than CyA or tacrolimus immunosuppression, seems to be the major determinant of increased cholesterol levels. Received: 19 June 1997 Received after revision: 24 October 1997 Accepted: 10 November 1997     

Reduced Size Liver Transplantation from a Donor Supported by a Berlin Heart

Patients on cardiac assist devices are often considered to be high-risk solid organ donors. We report the first case of a reduced size liver transplant performed using the left lateral segment of a pediatric donor whose cardiac function was supported by a Berlin Heart. The recipient was a 22-day-old boy with neonatal hemochromatosis who developed fulminant liver failure shortly after birth. The transplant was complicated by mild delayed graft function, which required delayed biliary reconstruction and abdominal wall closure, as well as a bile leak. However, the graft function improved quickly over the first week and the patient was discharged home with normal liver function 8 weeks after transplant. The presence of a cardiac assist device should not be considered an absolute contraindication for abdominal organ donation. Normal organ procurement procedures may require alteration due to the unusual technical obstacles that are encountered when the donor has a cardiac assist device.     

Auxiliary liver transplantation with arterialization of the portal vein for acute hepatic failure

Six adult patients suffering from acute hepatic failure and with a high urgent status underwent heterotopic auxiliary liver transplantation. In four of these patients, the portal vein of the liver graft was arterialized in order to leave the native liver and the liver hilum untouched and to be able to place the liver graft wherever space was available in the abdomen. The arterial blood flow via the portal vein was tapered by the width of the anastomosis. Two patients died, one of sepsis on postoperative day 17 (POD), the other after 3 months due to a severe CMV pneumonia. There were no technically related deaths. The native liver showed early regeneration in all cases. In one patient, the auxiliary graft was removed 6 weeks after transplantation. Four weeks later, he had to undergo orthotopic retransplantation due to a recurrent fulminant failure of the recovered native liver. This patient is alive more than 1 year after the operation. We conclude that heterotopic auxiliary liver transplantation with portal vein arterialization is a suitable approach to bridging the recovery of the acute failing native liver. Received: 15 September 1997 Received after revision: 4 February 1998 Accepted: 2 March 1998     

Donor des-gamma-carboxy prothrombin positivity is a risk factor for poor early graft function in liver transplantation

Des-gamma-carboxy prothrombin (DCP) is an abnormal prothrombin that lacks coagulating activity. The aim of this study was to determine if the presence of DCP in the donor could be used as a marker of post-transplant graft function. We collected data and serum samples on 90 organ donors. DCP level was correlated with donor-specific factors and with graft function intraoperatively and in the early post-transplant period. Twenty-seven donors (30.0 %) had positive DCP levels before harvesting. Although recipients were similar in demographics, preoperative liver function, and primary disease distribution, patients transplanted with livers from DCP-positive donors needed significantly more intraoperative transfusion. Furthermore, donor DCP positivity was identified as a preoperative risk factor for poor early graft function based on multivariate analysis (odds ratio = 6.58, P = 0.0032). Our findings suggest that DCP is another valuable marker for evaluating the quality of donor livers. Received: 30 June 1997 Received after revision: 14 October 1997 Accepted: 19 November 1997     

Recurrent postinfantile syncytial giant cell hepatitis after orthotopic liver transplantation

Syncytial giant cell hepatitis is a severe form of hepatitis characterized by diffuse giant cell transformation of hepatocytes. The disease may evolve to chronic cholestatic cirrhosis necessitating liver transplantation. We report the case of an adult liver transplant recipient presenting with early recurrent disease without concomitant clinicobiochemical syndrome. Early recurrence of giant cell hepatitis after liver transplantation favors the hypothesis of a transmissible agent as the etiology of the disease. Routine follow-up liver biopsy is necessary in these cases in order to gain more information about the precise incidence and aggressivity of disease recurrence in the allograft. Received: 4 July 1997 Received after revision: 12 January 1998 Accepted: 11 February 1998     

The characterization of reconstituted passenger leukocytes on the induction of tolerance in rat liver transplantation

The tolerance induced by orthotopic liver transplantation [DA (RT1^a) rats to PVG (RT1^c) rats] can be prevented by total body irradiation of the donor rat. Reconstitution of the irradiated donor with DA splenic leukocytes reintroduces this tolerance. To investigate the major histocompatibility complex (MHC) specificity of passenger leukocytes, irradiated DA donors were reconstituted by third-party BN (RT1ⁿ) splenic leukocytes. The reconstitution with BN splenocytes re-established DA-specific tolerance in PVG recipients, as confirmed by subsequent DA cardiac allografting, while BN hearts were rejected with second-set tempo. To determine which cell components play an important role in re-establishing liver graft tolerance, DA splenic leukocytes were further purified into three types: T, B, and adherent cells. Only “T-cell-enriched” preparations restored liver graft tolerance in three out of five PVG recipients. These results suggest that passenger leukocytes of differing MHC types can help to induce liver-specific tolerance and that T cells in the liver graft may be essential to regulate tolerance induction. Received: 31 December 1996 Received after revision: 14 April 1997 Accepted: 15 April 1997     

Bowel perforation after paediatric orthotopic liver transplantation

Bowel perforation is a well-recognized complication following orthotopic liver transplantation. Of 194 paediatric liver transplantations performed in our hospital, 13 patients (6.7 %) developed bowel perforation post-transplantation. Contributory factors included previous operation, steroid therapy and viral infection. The incidence was higher in children who underwent transplantation for biliary atresia after a previous Kasai portoenterostomy. Seven patients (53 % of this group) reperforated. Diagnosis may be difficult and a high index of suspicion is needed. Received: 8 December 1997 Received after revision: 17 February 1998 Accepted: 2 March 1998     

Hilar biliary cysts in hepatic transplantation. Report of three symptomatic cases and occurrence in resected liver grafts

Hilar cysts are infrequent post-transplant biliary tract complications. Thirteen cases were discovered among 493 consecutive liver transplants (2.6 %). Three (0.60 %) were symptomatic (obstructive jaundice) while the other ten were found by systematically searching in the hilum in a series of 129 consecutive, resected grafts at retransplantation or autopsy (n = 54). Two types of cysts were detected: in eight grafts (1.6 %), these were blind unilocular cavities with viscid mucous content, located adjacent to the biliary tract anastomoses. These had been inadvertently created as a result of the sequestered remnant cystic duct after cholecystectomies and biliary tract reconstructions, where a double-barreled common duct and long cystic duct had been present in the donor liver. These mucoceles ranged from 0.5 to 5.5 cm in diameter (median 1.7 cm). The three symptomatic cases were diagnosed by imaging techniques 3.5 years after transplantation; however, this type of cyst was found as early as the 2nd month post-transplantation when detected in lost liver grafts. Five livers (1 %), lost between 5 months and 2.8 years post-transplantation, showed cystically dilated peribiliary glands, sometimes with multilocular, and occasionally multiple, cavities ranging from 0.5 to 2 cm in diameter (median 0.8 cm). This type of cyst was asymptomatic and located adjacent to the left, right, or common hepatic ducts. Threads were found near four cysts, suggesting that surgical injury may have been responsible for obstructing the neck of the glands. With the increasing number of long-term survivors of liver transplantation, unless preventive surgical methods are implemented, the number of symptomatic cysts of these origins can be expected to grow. Transplantation teams should, therefore, be aware of these potential causes of biliary tract complications. Received: 3 June 1997 Received after revision: 21 October 1997 Accepted: 19 November 1997     

Delayed dynamic abdominal wall closure following multi-visceral transplantation

INTRODUCTION

Primary closure of the abdominal wall following intestinal transplantation or multivisceral transplantation could become a challenging problem in a significant number of patients.

PRESENTATION OF CASE

A 38-year-old woman with familial adenomatous polyposis (FAP) underwent a multi-visceral transplantation for short gut syndrome. She subsequently developed acute graft rejection that proved resistant to conventional treatment. She was relisted and underwent re-transplantation along with kidney transplantation. Abdominal wall closure could not be achieved because of the large size of the graft and bowel oedema. The wound was initially managed with laparostomy followed by insertion of the delayed dynamic abdominal closure (DDAC) device (Abdominal Retraction Anchor – ABRA^® system). Continuous dynamic traction to the wound edges resulted in gradual approximation and complete closure of the abdominal wound was achieved within 3 weeks.

DISCUSSION

Successful abdominal closure after multivisceral transplantation or isolated intestinal transplantation often requires biological mesh, vascularised flaps or abdominal wall transplantation. DDAC eliminated the need for a prosthetic mesh or skin graft and provided an excellent cosmetic result. Adjustment of the dynamic traction at the bedside minimised the need for multiple returns to the operating theatre. It resulted in a well-healed linear scar without a hernia.

CONCLUSION

Dynamic traction allows delayed closure of laparotomy resulting in strong and cosmetically sound wound healing with native tissue.     

Utilidad del trasplante de la pared abdominal en el trasplante de órganos. Nuestra experiencia inicial

Abdominal wall transplantation has been consolidated as an alternative to primary abdominal wall closure in intestinal and multiple organ transplant recipients. Given that it is feasible to obtain the visceral graft and the abdominal wall graft from the same donor, abdominal wall transplantation could offer satisfactory outcomes and be easily coordinated. Non-vascularized fascia is one of the alternatives for abdominal wall closure in transplantation. We report two cases of non-vascularized fascia transplantation in intestinal and multivisceral transplants, respectively. Both donors were young (23 and 18 years old). Both recipients had endured multiple previous surgeries, and no surgical alternatives for primary wall repair could be offered. In both cases, a complete abdominal wall flap was retrieved from the donor, however, due to the characteristics of the recipient's abdominal wall defect, only non-vascularized fascia was used after removing skin and subcutaneous cellular tissue from the graft. Abdominal wall transplantation is an option to consider for abdominal wall closure in patients with multiple previous surgeries and no alternatives for primary wall repair.     

Liver transplantation for alcoholic cirrhosis with anti-HCV antibodies

The results of orthotopic liver transplantation (OLT) in patients with alcoholic liver cirrhosis (ALC) are currently similar to those obtained in patients with other indications. However, the frequent association of ALC with hepatitis C virus (HCV) infection may impair these results. We retrospectively studied the consequences of HCV infection on survival and graft function in 59 patients with ALC undergoing OLT. Patients were classified into two groups depending on their HCV serology before transplantation: group 1 comprised 24 anti-HCV-positive patients, and group 2, 35 anti-HCV-negative patients. Patient and graft survival were similar in both groups. Liver function tests 1 and 4 years after OLT showed AST and ALT values that were significantly higher in group 1 patients and post-transplant histologically proven chronic hepatitis was found in 45 % and 61 % of these patients at 1 and 4 years, respectively. We conclude that pretransplant HCV infection in patients with ALC does not affect survival after OLT. However, one must bear in mind the high incidence of post-transplant chronic hepatitis secondary to recurrence of HCV infection and be cautious when drawing this conclusion. Received: 1 October 1996 Received after revision: 3 March 1997 Accepted: 17 March 1997     

Systemic liberation of interleukin-8 in the perioperative phase of liver transplantation

Serum levels of interleukin-8 (IL-8) were investigated in the perioperative phase of liver transplantation (LTx) in order to help determine whether this cytokine might serve as a parameter for preservation injury. In a study of 45 patients undergoing LTx, systemic IL-8 was estimated at the end of the anhepatic phase, at 30, 60, and 120 min after reperfusion of the graft, and 24 h and 7 days after LTx. A maximum mean concentration of 665 ± 135 pg/ml was seen 60 min after LTx. The minimum was found on the 1st postoperative day (POD 1): 328 ± 33 pg/ml. Significant changes were found between 60 min and PODs 1 and 7, as well as between 120 min and POD 1. Differences in cold ischemia time were not found to be significant. We conclude that monitoring of systemic IL-8 levels is not useful in the development of new liver preservation concepts. Received: 12 September 1996 Received after revision: 27 February 1997 Accepted: 3 March 1997     

Post-regraft supra-hepatic caval obstruction in liver transplantation: a successful outcome with expandable stents. A case report

Supra-hepatic inferior vena cava (IVC) obstruction is an unusual complication following an orthotopic liver transplantation (OLT) and is seen more often in hepatic regrafts. Dilatation of these stenotic lesions and the use of endovascular stents has been described in the past. Although the results of this technique are unquestionably superior to surgical correction, their use in the very early post-operative period is not without danger. Herein we describe a case where this modality was used successfully within 24 h of an OLT. Received: 17 June 1997 Received after revision: 30 September 1997 Accepted: 8 October 1997     

A validated technique for the analysis of biliary bile acid secretion in donor livers prior to transplantation

Many parameters currently used for the pre-transplant assessment of liver allografts, are not reliable enough in predicting the likelihood of early graft dysfunction or non-function. It is generally accepted that bile secretion is a sign of hepatic function post-transplant and that bile flow shows a close linear relationship to the secretion of bile acids (“apparent choleretic activity”). We have studied bile flow, biliary bile acid concentrations and composition and measured apparent choleretic activity from hepatic bile collected with a new technique under controlled conditions at the time of retrieval from 18 donor livers. More than three samples were collected from each of 13 donors and a total of 65 samples of hepatic bile were analysed. Of these, ten showed typical apparent choleretic activity with a positive slope in the regression line analysis (correlation coefficient of 0.9), validating our collection technique. Received: 1 September 1997 Received after revision: 15 December 1997 Accepted: 9 January 1998