Causes and management of portal hypertension in the pediatric population.

Therapeutic options for children with portal hypertension now include a broad range of pharmacologic, endoscopic, and surgical procedures. Thoughtful application of all of these options can improve quality of life by decreasing the complications of portal hypertension and can decrease mortality by preventing the consequences of variceal hemorrhage. The development of portal hypertensive gastropathy following palliative procedures such as endoscopic sclerotherapy and band ligation may limit their long-term success in children. The excellent results now obtained with selective portosystemic shunts and liver transplantation assure that definitive surgical treatments will continue to be important components in the treatment of children with portal hypertensive complications or progressive liver disease. Evolving procedures, such as TIPS, represent excellent short-term life-preserving techniques to stabilize critically ill patients while awaiting liver transplantation. Their role in the future, long-term management of children is yet to be defined.

Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study.

Prostaglandin E1 (PGE1) and N-acetylcysteine (NAC) have been used as single agents to decrease reperfusion injury and improve outcome after solid-organ transplantation (Tx). We hypothesized that combined treatment with NAC and PGE1 would be safe and reduce reperfusion injury. We therefore carried out a pilot study to assess the safety of this drug combination and gain information regarding the efficacy of treating pediatric liver transplant recipients with NAC and PGE1. The pilot study took the form of an open-label study incorporating 25 pediatric liver transplant recipients (12 children in the treatment group and 13 children as controls). NAC (70 mg/kg) was given intravenously over 1 h following reperfusion and then every 12 h for 6 days. PGE1 (0.4 mg/kg/h) was given as a continuous intravenous infusion for 6 days, starting after the first NAC dose. The primary outcome was the safety of combined treatment with NAC and PGE1. Patient survival, graft survival, allograft rejection within the first 90 days after Tx, peak post-transplant serum alanine aminotransferase (ALT) concentration, post-transplant length of hospitalization, and post-operative complications were secondary outcomes. Post-operative complications occurred at similar rates in both control and treated groups. No complications or adverse events occurred in the treated group as a result of study drugs. The 3-month patient survival rate was 100% for both groups. For the group treated with NAC and PGE1, peak serum ALT was lower and median length of stay was shorter but the differences did not reach statistical significance. The proportion of patients with allograft rejection was not significantly different between the two groups. However, rejection was more severe in the control group than in the treated group. In summary, infusions of NAC and PGE1 were safely administered to pediatric liver transplant recipients. However, a randomized controlled study is needed to determine the efficacy of treatment with NAC and PGE1.

Predictors of cost of liver transplantation in children: a single center study.

OBJECTIVE: Efforts to decrease the cost of orthotopic liver transplantation (OLT) must address the impact of specific interventions on clinical outcome. We hypothesized that an intervention designed to decrease the length of hospitalization would reduce costs without jeopardizing clinical outcome. We further sought to identify predictors of length of stay and cost for hospitalization after liver transplantation. METHODS: The study group included 47 children who underwent OLT from September 1996 to April 1999, and the control group included 36 children who underwent OLT from March 1994 to August 1996. The intervention was a transition to home program in which patients were discharged to a family living center when they met established clinical criteria and their families met predefined educational goals. We analyzed patients who survived 3 months after OLT. RESULTS: For the intervention group, the mean length of stay, total costs, and surgical costs were 29%, 36%, and 34% lower, respectively. Organ type, height z score, race, hepatic artery thrombosis, early allograft rejection, and participation in the transition to home program predicted length of stay and total costs. CONCLUSION: An early discharge program based on defined criteria can be used to decrease length of stay and cost after OLT without jeopardizing clinical outcome.

Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis.

BACKGROUND: Chronic intrahepatic cholestasis is associated with severe pruritus that is often refractory to maximal medical management and leads to significantly impaired quality of life. The hypothesis in this study was that partial external biliary diversion (PEBD) can substantially improve intractable pruritus secondary to intrahepatic cholestasis with subsequent improvement of functional quality of life. METHODS: Parents' and/or patients' clinical rating of pruritus, growth percentiles, biochemical parameters, and liver biopsies performed before and after surgery were compared in a retrospective medical record review. RESULTS: Eight children underwent PEBD from 1990 through 1997. Complete follow-up data were available for seven patients. Before surgery, all patients had intense pruritus, which was not responsive to maximal medical therapy. Specimens obtained in preoperative liver biopsies showed moderate (n = 1), minimal (n = 6), or no (n = 1) portal fibrosis. After PEBD, all patients received ursodeoxycholic acid (10-15 mg/kg/dose two to three times daily) until resolution of pruritus. Of the seven patients with complete follow-up data, six had complete resolution of pruritus and sustained resolution up to 8 years after surgery. The patient with mild to moderate residual pruritus was the youngest to undergo PEBD. Growth improved from below the 5th percentile before surgery to the 5th through the 25th percentiles for five of six patients with more than 6 years' follow-up. All families reported improved quality of life, defined by school attendance and ability to resume normal activity with peers. There has been no clinical evidence of progression of liver disease. CONCLUSION: Partial external biliary diversion is effective in the long-term treatment of pruritus refractory to medical therapy and provides a favorable outcome in a select group of patients with chronic intrahepatic cholestasis without cirrhosis.

Long-term survival after liver transplantation.

BACKGROUND: Liver transplantation (LT) remains a high-risk operation, especially during the first months after LT when technical complications and preexisting illness exert their influence on survival. However, there are late deaths. The authors have reviewed their experience to identify factors impacting on long-term survival. METHODS: A total of 150 patients who had undergone liver transplantation over an 11-year period were reviewed. Thirty-three patients died after LT (22%). Of these, 18 of 33 (55%) died in the first 3 postoperative months. One hundred thirty-two patients survived beyond 3 months, and 15 patients (11%) suffered late deaths. This review concentrates on the latter group. RESULTS: The primary cause of death was sepsis in 11 of 15 (73%). In two, sepsis complicated retransplantation in chronically debilitated patients. Two additional patients had late-presenting postoperative complications (bile leak or abscess, intestinal obstruction with perforation). In two cases, pneumocystis carinii pneumonia occurred; noncompliance or unplanned discontinuation of prophylaxis was directly responsible. Multiple organ system failure from presumed immunoincompetence developed in four patients; one had undergone bone marrow transplantation for aplastic anemia (AA) after fulminant hepatic failure (FHF). Lymphoproliferative disease (LPD) was the cause of death in 3 of 15 cases (20%). In only three cases was the cause of death related to the patient's primary disease (chronic hepatitis, Alper's syndrome or seizures, and AA with FHF). Pretransplant diagnosis, and UNOS status at the time of LT did not influence the long-term survival. CONCLUSIONS: Long-term survival in patients who have undergone LT was compromised by immunosuppressive complications and sepsis. Early mortality factors, such as UNOS status, age at LT, primary diagnosis, and technical complications do not predict late deaths. In children who adhere to their medical regimen and have good initial allograft function, late postoperative infection, especially with Ebstein-Barr virus, accounts for most of the late mortality. Improved and decreased immunosuppression may further improve these long-term results.

Pediatric burn patients with respiratory failure: predictors of outcome with the use of extracorporeal life support.

Extracorporeal life support (ECLS) for pediatric burn patients is a viable option for respiratory failure that is unresponsive to maximal conventional therapy. No criteria have been identified that are predictive of the success of the use of ECLS for these patients. This article presents a retrospective review of the pediatric burn patients placed on ECLS at a single pediatric medical center. It was found that 12 patients (mean age, 30.3 months; range 6 to 69 months) were placed on ECLS because of profound pulmonary failure that was unresponsive to aggressive ventilatory support. The mean size of the burns of these patients was 50.2% of the total body surface area (average size of full-thickness burns, 41.8% total body surface area), with 6 patients having scald burns and 6 having flame burns. The overall survival was 67% (8 of 12). Nonsurvivors had greater positive end-expiratory pressure, mean airway pressure, peak inspiratory pressure, and oxygenation index before ECLS. It is felt that ECLS is a life-saving therapy for pediatric patients with thermal injury. Greater ventilator requirements before ECLS are associated with nonsurvival. Early institution of ECLS in pediatric burn patients with severe respiratory failure may prevent excessive barotrauma and thus discourage the onset of irreversible lung injury.

Biliary atresia: pathogenesis and treatment.

Biliary atresia is a disorder of infants in which there is obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow. Untreated, the resulting cholestasis leads to progressive conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. Biliary atresia has an incidence of approximately one in 10,000 live births worldwide. Evidence to date supports a number of pathogenic mechanisms for the development of biliary atresia. An infectious cause, such as by a virus, would seem most pausible in many cases. The clinical observation that biliary atresia is rarely encountered in premature infants would support an agent acting late in gestation. However, no infectious or toxic agent has been conclusively implicated in biliary atresia. Genetic mechanisms likely play important roles, even regarding susceptibility to other specific causes, but no gene whose altered function would result in obstruction or atresia of the biliary tree has been identified. The variety of clinical presentations support the notion that the proposed mechanisms are not mutually exclusive but may play roles individually or in combination in certain patients. Biliary atresia, when untreated, is fatal within 2 years, with a median survival of 8 months. The natural history of biliary atresia has been favorably altered by the Kasai portoenterostomy. Approximately 25 to 35% of patients who undergo a Kasai portoenterostomy will survive more than 10 years without liver transplantation. One third of the patients drain bile but develop complications of cirrhosis and require liver transplantation before age 10. For the remaining one third of patients, bile flow is inadequate following portoenterostomy and the children develop progressive fibrosis and cirrhosis. The portoenterostomy should be done before there is irreversible sclerosis of the intrahepatic bile ducts. Consequently, a prompt evaluation is indicated for any infant older than 14 days with jaundice to determine if conjugated hyperbilirubinemia is present. If infectious, metabolic, endocrine disorders are unlikely and if the child has findings consistent with biliary atresia, then exploratory laparotomy and intraoperative cholangiogram should be done expeditiously by a surgeon who has experience doing the Kasai portoenteostomy. Biliary atresia represents the most common indication for pediatric liver transplantation, representing more than 50% of cases in most series. Transplantation is indicated when symptoms of end stage liver disease occur, including recurrent cholangitis, progressive jaundice, portal hypertension complications, ascites, decreased synthetic function, and growth/nutritional failure.

Current concepts in pediatric liver transplant.

Orthotopic liver transplantation has significantly improved the survival rate of children with end-stage liver disease. Efforts to correct abnormalities existing prior to transplantation coupled with improved surgical techniques and immunosuppression have led to better quality of life and 1-year survival rates approaching 90% in many centers. Despite this success the expanding waiting list population of all ages has driven development of operative techniques to expand the donor pool. Building on the success of reduced-size transplantation, split-liver and living-donor transplantation are now suitable alternatives, especially when used in candidates with satisfactory clinical stability. In the post-operative period, infectious complications represent an important cause of morbidity and mortality. Although antimicrobial regimens are effective in the immediate post-operative phase, acquisition of viral infections represents a major concern particularly in the young liver recipient. Early detection and development of new anti-viral agents are likely to decrease occurrence of post-transplant proliferative disorders and optimize longterm transplantation outcome.

Biliary atresia--surgical management and treatment options as they relate to outcome.

Results show that the use of sequential surgical treatment, employing Kasai portoenterostomy in infancy, followed by selective liver transplantation for children with progressive hepatic deterioration yields improved overall survival. All children with successful Kasai portoenterostomy procedures who do not require OLT are survivors. Using newer transplant techniques, the 5-year survival rate for children who receive transplants with a primary diagnosis of biliary atresia was 82%. This yields an overall survival rate of 86% in this entire study population. Limited donor availability and increased complications after liver transplantation in infants less than 1 year of age mitigate against the use of primary liver transplantation without prior portoenterostomy for infants with biliary atresia. At present, these two operative procedures should be used as sequential and complementary modes of treatment rather than as competitive procedures. When biliary atresia is not recognized in infancy and established cirrhosis has resulted, primary transplantation should be offered as the initial surgical treatment.

Liver transplantation in Ohio.

BACKGROUND: Since its inception in 1984, the Ohio Solid Organ Transplantation Consortium has tracked liver transplantation outcomes for its five member institutions. Presented herein is a 12-year summary of this data analyzed to determine whether, with increasing experience, outcomes have improved in a cost-effective manner. METHODS: Between July 1984 and June 1996, 1,063 liver transplants were performed in Ohio in 943 patients (772 adults and 171 children), of which 943 were primary and 120 were retransplants (13%). Outcome comparisons were made for three eras: 1984-1988, 1988-1992, and 1992-1996. RESULTS: The percentage of urgent (United Network for Organ Sharing status 1 and 2) transplants has decreased (62% to 41%), whereas that of homebound patients has increased (38% to 59%). Average time on the waiting list has increased from 39 to 165 days, and the average length of stay has decreased from 44 to 27 days. Patient survival at 1-year increased in each era (64%, 80%, and 82%, respectively). Although actual hospital charges have remained relatively constant, they have decreased substantially when compared in 1985 dollars as corrected for inflation. CONCLUSIONS: Patients undergoing liver transplantation in Ohio are now listed earlier in the course of their disease and wait longer for their transplant, but enjoy a better chance of survival, have a shorter hospital stay, and a relatively less expensive operation. These data indicate that with increased experience, the Ohio Solid Organ Transplantation Consortium liver transplantation teams perform liver transplantation in a more cost-effective manner.

Biliary atresia: current concepts and research directions. Summary of a symposium.

Biliary atresia (BA) is the end result of a destructive, inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tract with the development of biliary cirrhosis. It is the commonest cause of chronic cholestasis in infants and children, and therefore is the most frequent indication for liver transplantation in this age group. The disease occurs worldwide, affecting an estimated 1 in 8,000 to 12,000 live births. At present, there is no specific therapy for BA; however, sequential surgical therapy begins with creation of a hepatoportoenterostomy (HPE); in those with end-stage liver disease, liver transplantation is indicated. Since most candidates are young children of small size, there is a shortage of size-matched donors for liver transplantation. At present, an increased awareness to ensure early diagnosis and development of methods to prevent progressive fibrosis are needed. These considerations are dependent on detailed studies of the pathogenesis of BA. Recent studies have focused on normal and altered bile duct morphogenesis and the role of various factors (infectious or toxic agents and metabolic insults) in isolation or in combination with a genetic or immunologic susceptibility in the etiology of BA.

The use of extracorporeal life support in pediatric burn patients with respiratory failure.

Respiratory failure is the most common cause of death after thermal injury and may be caused by inhalation injury, acute respiratory distress syndrome (ARDS) or pneumonia. ARDS is usually associated with sepsis; however, it may also occur during burn shock, especially in patients that have a delayed or inadequate fluid resuscitation. During the past 24 months, five pediatric burn patients underwent extracorporeal life support (ECLS) for respiratory failure unresponsive to optimal medical management. The mean age of the patients was 26 months (range, 8.5 to 48 months), with a mean burn size of 46% TBSA (> 95% third degree). The etiology of the respiratory failure included severe bronchospasm in a 22-month-old former premature infant with bronchopulmonary dysplasia; three patients with ARDS; and one patient with a severe inhalation injury. All five patients required greater than 56 cm H2O peak pressures and 100% FIO2 at the time of beginning ECLS. The oxygenation index (OI) ranged from 45 to 180. Three (60%) of the patients survived. In the three patients who ultimately survived, significant improvements in pulmonary and hemodynamic parameters occurred within 96 hours of ECLS. The two patients who died showed no improvement and were removed from ECLS at 10 and 11 days; both expired within hours. The patients who expired developed significant hemodynamic instability, coagulopathy, and hemorrhage from their burn wounds. The extent and degree of burn injury did not seem to alter the outcome. Indications for considering ECLS in the pediatric burn patient are unmanageable, life threatening pulmonary insufficiency in patients that undergo a relative short course of pre-ECLS ventilator support.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction therapy with OKT3 in pediatric liver-transplant recipients.

The goal of any posttransplant immunosuppressive regimen is to prevent allograft rejection while minimizing infectious complications. We hypothesized that sequential induction immunotherapy using the monoclonal antibody ORTHOCLONE OKT3 (muromonab-CD3) would meet these objectives effectively. We have therefore used such a protocol since July 1988 for all pediatric patients undergoing liver transplantation at Children's Hospital Medical Center of Cincinnati. Initial immunotherapy consisted of OKT3, administered preoperatively and then QD, methylprednisolone, and azathioprine. Cyclosporine was begun on POD 3-5, and OKT3 was discontinued when therapeutic cyclosporine levels were achieved for 48 hours. Rejection has not occurred throughout the lifetime of the allograft in 55% of long-term survivors. In the 28 patients who experienced rejection episodes, 71% had a single episode, 21% had two episodes, and 7% had a single episode, 21% had two episodes, and 7% had more than two. Rejection occurring after more than 120 days was invariably associated with noncompliance or subtherapeutic cyclosporine levels. The use of an OKT3-based sequential induction protocol resulted in a decreased incidence of acute rejection. Renal function was preserved, and the incidence of infection was not increased. Long-term outcome analysis of this protocol shows excellent patient survival and the near absence of late or chronic rejection.

Catheter-induced urinary bladder rupture presenting with pneumoperitoneum.

Neonatal bladder injury is rare and usually associated with umbilical artery catherization. Patients may present with apparent renal failure, abdominal distension, and respiratory distress. Treatment involves operative closure of the perforation and bladder drainage. A case of Foley catheter-induced bladder rupture in a premature infant, not previously reported in the literature, is detailed.

Soluble interleukin-2 receptor monitoring during bacterial and viral infections in liver transplant recipients: a comparative evaluation.

We evaluated the significance of serial sIL-2R serum levels as a differential marker of immune activation during bacterial versus viral infections in liver transplant recipients. A comparative evaluation of sIL-2R levels was performed in 76 liver transplant recipients (51 pediatric and 27 adult) during bacterial versus viral infections at 7 days prior to infection diagnosis (DAY-7), the day of diagnosis (DAY 0), peak sIL-2R level and at the end of therapy (END). There were no significant elevations at any time point during bacterial infections in either adult or pediatric transplant recipients. However, adult recipients demonstrated significant elevations during viral infections when comparing DAY-7 to PEAK (3840 +/- 830 vs 7225 +/- 2814 p = 0.03), with PEAK levels significantly higher during viral versus bacterial infections in this population (7225 +/- 2814 vs 4195 +/- 1819). Pediatric recipients demonstrated similar increases in sIL-2R serum levels during viral infections from DAY-7 to PEAK (4932 +/- 887 vs 11323 +/- 2794 p = 0.0012). Significant decreases from PEAK to END were noted during viral infections in both adult and pediatric recipients (7225 +/- 2814 vs 2911 +/- 1376 p = 0.01 and 11323 +/- 2794 vs 5214 +/- 2403 p = 0.006). Pediatric recipients had higher mean sIL-2R levels than adult recipients at all time points during viral infections. In conclusion, significant elevations in mean sIL-2R serum levels were observed during viral but not bacterial infections in pediatric and adult liver transplant recipients. This suggests that serial sIL-2R monitoring is a valuable immunologic marker of viral pathogenesis and may be useful in monitoring the progression of viral infections as well as response to antiviral therapy.

Effect of orthotopic liver transplantation on bone mineral content and serum vitamin D metabolites in infants and children with chronic cholestasis.

Almost all infants and children with chronic cholestasis have osteopenia. We evaluated the effect of orthotopic liver transplantation on bone mineral content and serum 25(OH)-vitamin D-[25(OH)D]-of nine infants and children (five girls; age, 6 to 21 mo at the time of orthotopic liver transplantation) with end-stage liver disease resulting from chronic cholestasis. We hypothesized that after orthotopic liver transplantation, decreased bone mineral content will recover and the serum 25(OH)D level will either normalize or remain normal in those who were previously vitamin D deficient or sufficient, respectively. All had subnormal bone mineral content before transplant. On long-term follow-up (> 4 mo) of seven patients, bone mineral content normalized in all between 6.5 and 19 mo after transplant, with a mean of 11.2 +/- 4.5 mo. In six patients with normal serum 25(OH)D levels before orthotopic liver transplantation, the serum 25(OH)D levels had declined markedly 1 to 2 mo after transplant, followed by return to normal by 3 to 6 mo. Low serum 25(OH)D levels (< 15 ng/ml) in three patients before orthotopic liver transplantation normalized after transplant. Although there was no correlation between bone mineral content and serum 25(OH)D level before transplant, sustained normal serum 25(OH)D and 1,25(OH)2D levels preceded or accompanied normalization of bone mineral content in the seven patients available for long-term follow-up. We conclude that (a) in infants and children younger than 2 yr with chronic cholestasis, bone mineral content normalizes approximately 11 mo after orthotopic liver transplantation. This normalization is preceded by a sustained period of normal serum 25(OH)D levels.(ABSTRACT TRUNCATED AT 250 WORDS)