Robert E. Kane

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

safety of Lansoprazole in the Treatment of Gastroesophageal Reflux Disease in Children

Objectives: To evaluate the safety of lansoprazole in children between 1 and 11 years of age. Methods: In a phase I/II, open‐label, multicenter (11 sites) study, children with symptomatic gastroesophageal reflux disease (GERD), erosive esophagitis (≥grade 2), and/or esophageal pH < 4 for > 4.2% of the 24‐hour period were assigned, on the basis of body weight, to lansoprazole 15 mg (≤30 kg) or 30 mg (>30 kg) once daily for 8 to 12 weeks. At the discretion of the investigator, the dosage of lansoprazole was increased up to 60 mg daily in children who continued to be symptomatic after 2 weeks of treatment. Safety for all study participants was monitored by adverse event reports and laboratory evaluations. Results: Sixty‐six children were enrolled in the study and were included in the safety analysis. Throughout the treatment period, no child discontinued therapy because of an adverse event and no. clinically significant changes in laboratory values were observed. Three of the 32 children (9%) who received lansoprazole 15 mg once daily (mean exposure 50.3 days) and 6 of the 34 children (18%) who received the 30 mg once‐daily dose (mean exposure 49.4 days) experienced one or more treatment‐related adverse events before any dose increase. The three children in the lansoprazole 15 mg treatment group were treated with doses of 0.6 mg to 1.2 mg/kg/day; those in the lansoprazole 30 mg treatment group were treated with doses of 0.7 mg to 0.9 mg/kg/day. Only one child experienced a new treatment‐related adverse event after an increase in lansoprazole dose to 1.3 mg/kg/day. Treatment‐related events experienced by two or more children were: constipation (lansoprazole 15 mg QD, two children; lansoprazole 30 mg QD, one child), and headache (lansoprazole 30 mg QD, two children). Mean fasting serum gastrin levels were significantly increased from 58.0 pg/mL at baseline to 112.4 pg/mL at week 2 and 121.9 pg/mL at the final visit (P ≤ 0.001 for each comparison). However, the median fasting serum gastrin levels at the week 2 and the final visit were within the normal range (25‐111 pg/mL). Conclusion: Lansoprazole, when administered on the basis of body weight in children between 1 and 11 years of age, is safe and well‐tolerated.

ENERGY AND RESPIRATORY METABOLISM IN CYSTIC FIBROSIS : THE INFLUENCE OF CARBOHYDRATE CONTENT OF NUTRITIONAL SUPPLEMENTS

The basal energy expenditure (BEE) in a group of adolescent and young adult patients with cystic fibrosis (CF) with mild lung disease was 97 +/- 6% of that predicted by the Harris-Benedict equation (which estimates BEE by age, sex, height, and weight). The BEE of a group with more severe lung disease was 117 +/- 5% of that predicted by the Harris-Benedict equation, due primarily to a 14% greater oxygen consumption (VO2) and 24% greater CO2 production (VCO2) compared with milder lung disease (p less than 0.05). The measured BEE in the patients with mild lung disease correlated well with the predicted BEE, but variably underestimated that of patients with more advanced lung disease. The influence of low carbohydrate (Pulmocare) and higher carbohydrate (Instant Breakfast) nutritional supplements on the energy and pulmonary metabolism was compared in 10 malnourished CF patients with moderate to severe lung disease. Their BEE before ingesting the supplements was 120% of that predicted by the Harris-Benedict equation. Their VCO2 increased 9-19% for the 3 h after ingesting 500 kcal/M2 of Pulmocare, and 25-30% after ingesting Instant Breakfast (p less than 0.05). The respiratory quotient (RQ) was significantly greater for Instant Breakfast than Pulmocare. The minute ventilation (VE) rose 10-13% for the 3 h after ingesting Pulmocare, versus 27-31% after ingesting Instant Breakfast, but the difference was not significant. The metabolic expenditure rose 13-16% for the 3 h after ingesting both formulas. We concluded that CF patients have increasing difficulty maintaining their nutrition as their pulmonary disease progresses, in part because of a 17-20% increase in their BEE.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulfation and glucuronidation of acetaminophen by cultured hepatocytes reproducing in vivo sex-differences in conjugation on Matrigel and type 1 collagen

SummaryThe sulfate and glucuronide conjugation of acetaminophen (APAP) by hepatocytes cultured on Matrigel or type 1 collagen was compared to APAP metabolism in vivo. The metabolic fate of low (15 mg/kg), medium (125 mg/kg), and high (300 mg/kg) doses of APAP injected intraperitoneally were determined in male and female rats. Males excreted more APAP as the sulfate conjugate than females, which correlated with the twofold greater APAP sulfotransferase activity in the male vs. females (301±24 vs. 156±18 pmol · mg−1 protein · min−1). Also, as sulfate conjugation became saturated, there was a dose-related shift in APAP metabolism from sulfate to glucuronide conjugation in both sexes. After death, the livers of the same animals were perfused with collagenase and the hepatocytes cultured in modified Waymouth’s medium on either Matrigel or rat-tail collagen, with various doses of APAP (0, 0.125, 0.25, 0.5, and 1.0 mM). Sex differences in APAP sulfation and glucuronidation persisted in culture for up to 4 days, with sulfation predominating in the male similar to in vivo. With increasing APAP concentration (dose), there was a saturation of sulfate conjugation and a shift to glucuronidation as observed in vivo. Sex differences in APAP sulfation and glucuronidation were no longer significant by Day 4 in culture. Sulfation, and to a lesser extent, glucuronidation, were more stable on Matrigel than collagen. We concluded that APAP metabolism of freshly isolated hepatocytes could replicate in vivo sex differences in conjugation, and that Matrigel was superior to collagen as substrate.

Glucose intolerance with low-, medium-, and high-carbohydrate formulas during nighttime enteral feedings in cystic fibrosis patients.

Ten young adult cystic fibrosis (CF) patients over 16 years of age (average 21.4 years) began nighttime enteral feedings as a method of nutritional rehabilitation to regain and maintain body weight. Patients received nighttime feedings of 1,000 kcal/M2 of a low- (Pulmocare), medium- (Ensure Plus), or high-carbohydrate (Vivonex) formula for at least 2 nights each with pancreatic enzyme therapy. Five of ten young adult CF patients developed nocturnal hyperglycemia (serum glucose >300 mg/dl) and glucosuria (1–3% glucose) with varying degrees of polyuria during enteral feedings. No patient developed ketonuria despite serum glucoses at times >600 mg %. There was no difference between the hyperglycemic and nor-moglycemic groups in median age, percent of ideal body weight, NIH score, Brasfield scores, pulmonary function tests, or family history of diabetes. All normoglycemic and four of five hyperglycemic patients had normal fasting blood sugars. The percent hemoglobin A1c was greater in the glucose intolerant group than the normoglycemic patients (11.2 ± 0.8% vs. 6.8 ± 1.1%, mean ± SE, p < 0.005). Twelve to 15 units of NPH insulin prior to initiation of feedings provided adequate therapy in most hyperglycemic patients. There was no apparent difference in the elevation of early morning serum glucoses with the low- medium- and high-carbohydrate formulas. We concluded that hyperglycemia requiring insulin therapy was common in young adult CF patients using nighttime enteral feedings. A hemoglobin A1c appeared to be a useful screening test before initiating such therapy.

Valproate use associated with persistent hyperammonemia and mitochondrial injury in a child with Down's syndrome.

Valproate is a commonly prescribed anticonvulsant drug that may cause potentially fatal hepatotoxicity, bone-marrow toxicity, and pancreatitis. Toxicity usually resolves, though, after discontinuation of the medication. We report a 9-year-old boy who had Downs syndrome and who developed valproate-associated bone marrow toxicity, and hepatotoxicity that persisted greater than 2 years after discontinuation of valproate therapy. Three years after starting valproate, he developed erythrocyte aplasia with a severe, normochromic, macrocytic anemia requiring several blood transfusions. Several months later while still receiving valproate, he developed progressive hyperammonemia and decreased hepatic synthetic function. The macrocytic anemia resolved and hepatic synthetic function improved after discontinuation of valproate therapy. However, hyperammonemia, steatosis, mitochondrial injury, and marked hepatic iron accumulation persisted greater than 2 years after the valproate was discontinued. The persistent hyperammonemia was responsive to lactulose therapy. A decrease in hepatic iron content by serial phlebotomies did not result in any improvement in the hyperammonemia or hepatic synthetic function. This is the first report of persistent hyperammonemia and hepatic mitochondrial injury after valproic acid therapy.

An examination of the relationship between race, skin color and a series of autonomic nervous system measures

In the total population of 75 subjects, the skin albedo correlated significantly with skin resistance, a relationship which was not maintained when the total population was separated into its component subgroups of whites, blacks and Indians. The Indians, “anthropologically Caucasians” but skin color more akin to the blacks, exhibited mean skin reflectance and skin resistance intermediate to that obtained in the black and white groups respectively. Other differences and significant correlations between the autonomic functions in the three groups indicated a higher level of sympathetic tone in the Indians, although this could be attributed to the older age of this group. It was suggested from the results that skin color rather than race has a greater influence on skin resistance.

Benzidine N-Glucuronidation by Human, Rat, and Dog Liver

Abstract Hepatic N-glucuronidation is proposed to be an important pathway for metabolism of aromatic amine carcinogens and was assessed in human, rat, and dog. Benzidine and its monoacetylated product N-acetylbenzidine were glucuronidated. The latter was identified as an N′-glucuronide. Both glucuronides were acid labile with t1/2s of approximately 5 min at pH 5.3 and 37 °C. In plasma, the stability of both glucuronides increased. Irrespective of the detergent used to increase microsomal activity, the relative amount of glucuronidation was human > dog > rat. N-Glucuronidation of N,N′-diacetylbenzidine was not detected. Following incubation with 3H-benzidine, liver slices from all three species produced N-glucuronides. However, only human and rat slices produced N-acetylbenzidine N′-glucuronide. The stability of these N-glucuronides in plasma and their lability in acidic urine provides a mechanism by which these detoxified products are transported to the bladder and then recycled to the arylamine. A model ...