David A. Gremse

Gastroesophageal Reflux: Management Guidance for the Pediatrician

Recent comprehensive guidelines developed by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition define the common entities of gastroesophageal reflux (GER) as the physiologic passage of gastric contents into the esophagus and gastroesophageal reflux disease (GERD) as reflux associated with troublesome symptoms or complications. The ability to distinguish between GER and GERD is increasingly important to implement best practices in the management of acid reflux in patients across all pediatric age groups, as children with GERD may benefit from further evaluation and treatment, whereas conservative recommendations are the only indicated therapy in those with uncomplicated physiologic reflux. This clinical report endorses the rigorously developed, well-referenced North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines and likewise emphasizes important concepts for the general pediatrician. A key issue is distinguishing between clinical manifestations of GER and GERD in term infants, children, and adolescents to identify patients who can be managed with conservative treatment by the pediatrician and to refer patients who require consultation with the gastroenterologist. Accordingly, the evidence basis presented by the guidelines for diagnostic approaches as well as treatments is discussed. Lifestyle changes are emphasized as first-line therapy in both GER and GERD, whereas medications are explicitly indicated only for patients with GERD. Surgical therapies are reserved for children with intractable symptoms or who are at risk for life-threatening complications of GERD. Recent black box warnings from the US Food and Drug Administration are discussed, and caution is underlined when using promoters of gastric emptying and motility. Finally, attention is paid to increasing evidence of inappropriate prescriptions for proton pump inhibitors in the pediatric population.

Comparison of Polyethylene Glycol 3350 and Lactulose for Treatment of Chronic Constipation in Children

Polyethylene glycol (PEG) 3350 and lactulose were compared in an unblinded, randomized, crossover design for treatment of constipation in 37 children aged 2 to 16 years. Subjects received lactulose (1.3 g/kg/d divided twice daily up to 20 g) or PEG 3350 (10 g/m2/day) for 2 weeks. PEG 3350 significantly decreased the total colonic transit time compared to lactulose (47.6 +2.7 vs 55.3 ±2.4 hours, mean ±SE, PEG 3350 vs lactulose, respectively, p = 0.038). The stool frequency, form, and the ease of passage were similar for each laxative. Polyethylene glycol 3350 is an effective laxative for the treatment of chronic constipation in children.

Comparison of oral sodium phosphate to polyethylene glycol-based solution for bowel preparation for colonoscopy in children.

Thirty-four patients, aged 3 to 17 years, were randomized to receive oral sodium phosphate solution or a polyethylene glycol-based solution in preparation for elective colonoscopy. Nineteen patients received two doses of oral sodium phosphate solution (45 mL/1.7 m2/ dose) and 15 received polyethylene glycol-based solution (4 L/1.7 m2). Compliance with oral sodium phosphate solution was judged as easy or tolerable in 15 of 19 patients, but only in 5 of 15 who were given polyethylene glycol-based solution. The quality of colon cleansing was rated by an endoscopist who was blinded to the colon preparation method used. The bowel preparation was excellent or good (only liquid remaining in the colonic lumen) in 18 of 19 patients who received oral sodium phosphate solution and in 6 of 15 who received polyethylene glycol-based solution. The incidence of vomiting was similar in both groups, but abdominal pain occurred more frequently in the polyethylene glycol-based solution group. Hyperphosphatemia developed in patients who received oral sodium phosphate solution (serum phosphorus = 2.3 +/- 0.7 mmol/L (7.2 +/- 2.2 mg/dL; mean +/- SD), but only in 1 of 15 patients in the polyethylene glycol-based solution group. Patients did not exhibit symptoms of hyperphosphatemia and serum calcium concentrations were similar in both groups. In summary, oral sodium phosphate solution is better tolerated than polyethylene glycol-based solution for bowel preparation in children. However, hyperphosphatemia occurred frequently in patients who received oral sodium phosphate solution. Further studies are needed to determine the optimal dose for safety and efficacy for the use of these solutions in children.

Age-specific Questionnaires Distinguish Gerd Symptom Frequency and Severity in Infants and Young Children: Development and Initial Validation

Two gastroesophageal reflux disease (GERD) symptom questionnaires were developed and tested prospectively in a pilot study conducted in infants (1 through 11 months) and young children (1 through 4 years) with and without a clinical diagnosis of GERD. A pediatric gastroenterologist made the clinical diagnosis of GERD. Parents or guardians at 4 study sites completed the questionnaires, providing information on the frequency and severity of symptoms appropriate to the 2 age cohorts. In infants, symptoms assessed were back arching, choking or gagging, hiccups, irritability, refusal to feed and vomiting or regurgitation. In young children, symptoms assessed were abdominal pain, burping or belching, choking when eating, difficulty swallowing, refusal to eat and vomiting or regurgitation. Respondents were asked to describe additional symptoms. Symptom frequency was the number of occurrences of each symptom in the 7 days before completion of the questionnaire. Symptom severity was rated from 1 (not at all severe) to 7 (most severe). An individual symptom score was calculated as the product of symptom frequency and severity scores. The composite symptom score was the sum of the individual symptom scores. The mean composite symptom and individual symptom scores were higher in infants (P < 0.001 and P < 0.05, respectively) and young children (P < 0.001 and P < 0.05, respectively) with GERD than controls. Vomiting/regurgitation was particularly prevalent in infants with GERD (90%). Both groups with GERD were more likely to experience greater severity of symptoms. We found the GERD Symptom Questionnaire useful in distinguishing infants and young children with symptomatic GERD from healthy children.

Collagenous colitis in children

Collagenous colitis, a disorder characterized by increased subepithelial collagen deposition associated with an inflammatory infiltrate in the lamina propria, has been reported infrequently in children. An 8-year-old girl with collagenous colitis is described who presented with chronic watery diarrhea and abdominal pain. Biopsy specimens of the colonic mucosa showed the pathological features of collagenous colitis. The patients symptoms resolved following corticosteroid therapy. Collagenous colitis should be considered in the differential diagnosis of children with chronic diarrhea.

Identification of a Novel Gene Encoding the Yeast Mitochondrial Dicarboxylate Transport Protein via Overexpression, Purification, and Characterization of Its Protein Product

A gene encoding the mitochondrial dicarboxylate transport protein (DTP) has been identified for the first time from any organism. Our strategy involved overexpression of putative mitochondrial transporter genes, selected based on analysis of the yeast genome, followed by purification and functional reconstitution of the resulting protein products. The DTP gene from the yeast Saccharomyces cerevisiae encodes a 298-residue basic protein which, in common with other mitochondrial anion transporters of known sequence and function, displays the mitochondrial transporter signature motif, three homologous 100-amino acid sequence domains, and six predicted membrane-spanning regions. The product of this gene has been abundantly expressed in Escherichia coli where it accumulates in inclusion bodies. Upon solubilization of the overexpressed DTP from isolated inclusion bodies with Sarkosyl, 28 mg of DTP was obtained per liter of E. coli culture at a purity of 75%. The purified, overexpressed DTP was then reconstituted in phospholipid vesicles where both its kinetic properties (i.e. Km = 1.55 mM and Vmax = 3.0 μmol/min/mg protein) and its substrate specificity were determined. The intraliposomal substrates malonate, malate, succinate, and phosphate effectively supported [14C]malonate uptake, whereas other anions tested did not. External substrate competition studies revealed a similar specificity profile. Inhibitor studies indicated that the reconstituted transporter was sensitive to inhibition by n-butylmalonate, p-chloromercuribenzoate, mersalyl, and to a lesser extent pyridoxal 5′-phosphate but was insensitive to N-ethylmaleimide and selective inhibitors of other mitochondrial anion transporters. In combination, the above findings indicate that the identified gene encodes a mitochondrial transport protein which upon overexpression and reconstitution displays functional properties that are virtually identical to those of the native mitochondrial dicarboxylate transport system. In conclusion, the present investigation has resulted in identification of a gene encoding the mitochondrial DTP and thus eliminates a major impediment to molecular studies with this metabolically important transporter. Based on both structural and functional considerations, the yeast DTP is assignable to the mitochondrial carrier family. Additionally, the development of a procedure that enables the expression and isolation of large quantities of functional DTP provides the foundation for comprehensive investigations into the structure/function relationships within this transporter via site-directed mutagenesis, as well as for the initiation of crystallization trials.

The Yeast Mitochondrial Citrate Transport Protein PROBING THE ROLES OF CYSTEINES, Arg181, AND Arg189 IN TRANSPORTER FUNCTION

Utilizing site-directed mutagenesis in combination with chemical modification of mutated residues, we have studied the roles of cysteine and arginine residues in the mitochondrial citrate transport protein (CTP) from Saccharomyces cerevisiae. Our strategy consisted of the sequential replacement of each of the four endogenous cysteine residues with Ser or in the case of Cys73 with Val. Wild-type and mutated forms of the CTP were overexpressed in Escherichia coli, purified, and reconstituted in phospholipid vesicles. During the sequential replacement of each Cys, the effects of both hydrophilic and hydrophobic sulfhydryl reagents were examined. The data indicate that Cys73 and Cys256 are primarily responsible for inhibition of the wild-type CTP by hydrophilic sulfhydryl reagents. Experiments conducted with triple Cys replacement mutants (i.e. Cys192 being the only remaining Cys) indicated that sulfhydryl reagents no longer inhibit but in fact stimulate CTP function 2–3-fold. Following the simultaneous replacement of all four endogenous Cys, the functional properties of the resulting Cys-less CTP were shown to be quite similar to those of the wild-type protein. Finally, utilizing the Cys-less CTP as a template, the roles of Arg181 and Arg189, two positively charged residues located within transmembrane domain IV, in CTP function were examined. Replacement of either residue with a Cys abolishes function, whereas replacement with a Lys or a Cys that is subsequently covalently modified with (2-aminoethyl)methanethiosulfonate hydrobromide, a reagent that restores positive charge at this site, supports CTP function. The results clearly show that positive charge at these two positions is essential for CTP function, although the chemistry of the guanidinium residue is not. Finally, these studies: (i) definitely demonstrate that Cys residues do not play an important role in the mechanism of the CTP; (ii) prove the utility of the Cys-less CTP for studying structure/function relationships within this metabolically important protein; and (iii) have led to the hypothesis that the polar face of α-helical transmembrane domain IV, within which Arg181, Arg189, and Cys192 are located, constitutes an essential portion of the citrate translocation pathway through the membrane.

Effectiveness of nasogastric rehydration in hospitalized children with acute diarrhea.

The American Academy of Pediatrics recommends oral rehydration and early refeeding for management of infants with diarrhea and mild to moderate dehydration. However, intravenous rehydration is still widely used for treatment of infants hospitalized for dehydration. The administration of oral rehydration solution via continuous infusion through a nasogastric tube facilitates its delivery in hospitalized children. The purpose of this study is to compare intravenous and nasogastric rehydration in children hospitalized for mild to moderate dehydration. Infants who failed attempts at oral rehydration and were hospitalized for dehydration due to acute diarrheal illness were randomized to receive intravenous or nasogastric rehydration. Following rehydration, infants received soy formula and a maintenance oral electrolyte solution to replace ongoing stool losses, as directed by the attending physician. Patients were discharged from the hospital once oral feeding was tolerated, and the vomiting and diarrhea resolved. Twenty-four patients, from 2 to 19 months of age, were enrolled in the study. Rehydration was successful in 11 of 12 patients in the nasogastric rehydration group and in all 12 patients who received intravenous rehydration. The degree of dehydration, severity of vomiting and diarrhea, and duration of rehydration were similar in both groups. The duration and cost of hospitalization were less for patients receiving nasogastric rehydration compared to those who were rehydrated intravenously. Rehydration by infusion of oral rehydration solution via a nasogastric tube is a safe and effective treatment for infants with mild to moderate dehydration. Rehydration with infusion of oral rehydration solution through a nasogastric tube should be considered for in-patient management of infants with diarrhea.

Lansoprazole in adolescents with gastroesophageal reflux disease: Pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability

Objectives: To evaluate the pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability of lansoprazole in adolescents between 12 and 17 years of age with gastroesophageal reflux disease (GERD). Methods: Adolescents with symptomatic, endoscopically and/or histologically proven GERD were enrolled in this multicenter, double‐blind trial and randomized to lansoprazole 15 mg or 30 mg once daily for 5 days. Results: Sixty‐three adolescents were enrolled in the study. After lansoprazole administration, Tmax occurred at 1.6 hours in those treated with lansoprazole 15 mg and at 1.7 hours in those treated with lansoprazole 30 mg. Dose‐proportional increases in lansoprazole Cmax and AUC were observed in the treatment groups. Age, weight, and gender had no significant effect on Tmax, Cmax, or AUC. Lansoprazole produced significant increases (P ≤ 0.05) in mean 24‐hour intragastric pH and the percentages of time intragastric pH was above 3 and 4. The majority of adolescents treated with lansoprazole 15 mg (69%, 22/32) or lansoprazole 30 mg (74%, 23/31) demonstrated improvement in their reflux symptoms after 5 days of treatment. Adolescents in both dosage groups exhibited reductions from baseline in the percentage of days and nights with heartburn (or other predominant symptom of GERD), the severity of heartburn, the percentage of days antacids were used, and the number of antacid tablets used per day. Pharyngitis and headache were the most commonly reported side effects among adolescents treated with lansoprazole 15 mg and 30 mg, respectively. Five patients experienced adverse events considered to be possibly treatment‐related. One patient with a history of environmental allergies experienced a mild allergic reaction after 3 days of treatment with lansoprazole 15 mg. Among those treated with lansoprazole 30 mg, 4 patients each reported one occurrence of pain (toothache), diarrhea, dizziness, and rash. Conclusion: The pharmacokinetic parameters of lansoprazole observed in this study of adolescents are similar to those observed in studies of healthy adults. Lansoprazole 15 mg or 30 mg once daily for 5 days produces significant increases in intragastric pH, effectively relieves symptoms of reflux disease, and is well tolerated in adolescents with GERD.

Hypertension associated with naloxone treatment for clonidine poisoning

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