Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial.

BACKGROUND: Gastro-oesophageal reflux afflicts up to 7% of all infants. Histamine-2 receptor antagonists are the most commonly prescribed medications for this disorder, but few controlled studies support this practice. AIM: To evaluate the safety and efficacy of famotidine for infant gastro-oesophageal reflux disease. METHODS: Thirty-five infants, 1.3-10.5 months of age, entered an 8-week, multi-centre, randomized, placebo-controlled, two-phase trial: first 4 weeks, observer-blind comparison of famotidine 0.5 mg/kg and famotidine 1.0 mg/kg; second 4 weeks, double-blind withdrawal comparison (safety and efficacy) of each dose with placebo. RESULTS: No serious adverse events were reported. Eleven patients had 16 non-serious, possibly drug-related adverse experiences: 6 patients with agitation or irritability (manifested as head-rubbing in two), 3 patients with somnolence, 2 patients with anorexia, 2 with headache, 1 patient with vomiting, 1 patient with hiccups, and 1 patient with candidiasis. Of the 35 infants, 27 completed Part I. There were significant score improvements for famotidine 0.5 mg/kg in regurgitation frequency (P = 0.04), and for famotidine 1.0 mg/kg in crying time (P = 0.027) and regurgitation frequency (P = 0.004) and volume (P = 0.01). Eight infants completed Part II on double-blind treatment, which was insufficient for meaningful comparisons. CONCLUSIONS: Histamine-2 receptor antagonists may cause agitation and headache in infants. A possibly efficacious famotidine dose for infants is 0.5 mg/kg (frequency adjusted for age). As 1.0 mg/kg may be more efficacious in some, the dosage may require individualization based on response. Further sizeable placebo-controlled evaluations of histamine-2 receptor antagonists in infants with gastro-oesophageal reflux disease are warranted.

The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children.

OBJECTIVES: Eosinophilic esophagitis, previously confused with esophageal inflammation due to gastroesophageal reflux, has recently begun to be distinguished from it. We undertook this analysis of our large series of children with the condition to clarify its spectrum: its presenting symptoms; its relation to allergy, respiratory disease, and reflux; its endoscopic and histological findings; and its diagnosis and therapy. METHODS: We analyzed the details of our clinical series of 30 children with eosinophilic esophagitis, defining it as > or =5 eosinophils per high power field in the distal esophageal epithelium. Retrospective chart review was supplemented by prospective, blinded, duplicate quantitative evaluation of histology specimens, and by telephone contact with some families to clarify subsequent course. Presentation and analysis of the series as a whole is preceded by a case illustrating a typical presentation with dysphagia and recurrent esophageal food impactions. RESULTS: Presenting symptoms encompass vomiting, pain, and dysphagia (some with impactions or strictures). Allergy, particularly food allergy, is an associated finding in most patients, and many have concomitant asthma or other chronic respiratory disease. A subtle granularity with furrows or rings is newly identified as the endoscopic herald of histological eosinophilic esophagitis. Histological characteristics include peripapillary or juxtaluminal eosinophil clustering in certain cases. Association with eosinophilic gastroenteritis occurs, but is not common. Differentiation from gastroesophageal reflux disease is approached by analyzing eosinophil density and response to therapeutic trials. Therapy encompasses dietary elimination and anti-inflammatory pharmacotherapy. CONCLUSION: Awareness of the spectrum of eosinophilic esophagitis should promote optimal diagnosis and treatment of this elusive entity, both in children and in adults.

Isolated lower esophageal sphincter relaxation as "wave-suppressed" secondary peristalsis.

Esophageal venting following air insufflation may occur by secondary peristalsis or by isolated transient lower esophageal sphincter relaxation (TLESR). To identify factors determining venting by these two mechanisms, we analyzed the responses to esophageal air insufflation in 4 infants and in 2 adults. We used a nine-lumen dual-Dent-sleeve manometric catheter with an air insufflation esophageal side hole, identifying swallowing by pharyngeal manometry or submental electromyography. The time from the venting lower esophageal sphincter relaxation (whether part of a secondary peristalsis or an isolated TLESR) to the next swallow (whether spontaneous, in the infants, or on command, in the adults) was characterized as > or = 15 sec or < 15 sec. Of the 25 evaluable trials, the subsequent swallow was > or = 15 sec after the venting response in 9 instances and < 15 sec afterward in 16 instances. Eight of the 9 trials with delayed swallows (> or = 15 sec) were vented by secondary peristalsis, whereas 11 of the 16 with early swallows (< 15 sec) were vented by TLESR (X2 p < 0.01). TLESRs may be induced by esophageal stimuli, in which case they may represent "wave-suppressed" secondary peristaltic complexes.

Reflux symptoms in 100 normal infants: diagnostic validity of the infant gastroesophageal reflux questionnaire.

To identify the prevalence of reflux symptoms in normal infants, to characterize the diagnostic validity of a previously described 138-item Infant Gastroesophageal Reflux Questionnaire (I-GERQ) for separating normal infants from those with gastroesophageal reflux disease (GERD), and to identify potentially provocative caretaking practices, we administered the questionnaire to 100 infants attending a well-baby clinic (normals) and to 35 infants referred to the Gastroenterology Division for evaluation for GERI) and testing positive on esophageal pH probe or biopsy (GERD infants). Differences were analyzed by Chi-square, and odds ratios were defined. The diagnostic validity of a 25-point I-GERQ GERD score based on 11 items on the questionnaire was evaluated by calculating its sensitivity, specificity, and positive and negative predictive values. We found that normal infants had a high prevalence of reflux symptoms, such as daily regurgitation (40%), respiratory symptoms, crying more than an hour a day (17%), arching (10%), or daily hiccups (36%) but that many symptoms were significantly more prevalent in the GERD than in the normal infants (Chi-square P < .05), and odds ratios were above 3 for nearly 20 items. The positive and negative predictive values for the 25-point I-GERQ score were 1.00 and .94-.98, respectively. Environmental smoke exposure did not quite reach significance as a provocative factor for GERD. Although normal infants have a high prevalence of symptoms suggesting GERD, a simple questionnaire-based score is a valid diagnostic test with high positive and negative predictive values.

Quantitative computer-assisted image analysis of suction biopsy in pediatric gastroesophageal reflux.

Gastroesophageal reflux is a disorder with well-characterized histopathological features in the adult, but the incidence and pathogenesis of epithelial injury in children are poorly understood. Esophageal suction biopsies from 80 infants exhibiting symptoms of reflux were studied by computer-assisted image analysis and the results compared to routine histological scoring. The histological features evaluated were the number of intraepithelial lymphocytes and eosinophils, papillary height, interpapillary basal cell height, and a novel measure "integrated basal cell height." We quantitatively evaluated these histological criteria by computer-assisted image analysis and compared these results to four subjective grades of esophagitis: low, mild, moderate and high. In this report we now describe this quantitative histopathologic method for the evaluation of pediatric esophageal biopsies. Utilizing this method we demonstrate that both inter- and intra-observer variability were sufficiently low to stratify the mucosal changes reliably into at least four categories. The reliability of this objective analytic technique will permit studies into the disease progression and regression in pediatric reflux esophagitis.

Reliability and validity of an infant gastroesophageal reflux questionnaire.

To improve history-taking of infants with suspected gastroesophageal reflux, we developed an Infant Gastroesophageal Reflux Questionnaire consisting of 161 items covering demographics, symptoms (regurgitation, weight deficit, respiratory difficulties, fussiness, apnea, and pain or bleeding of esophagitis), and possible causes (feeding volume and frequency, allergy, infection, colic, central nervous system abnormalities, positioning, and smoke exposure). The questionnaire was completed by primary caretakers of 69 infants aged 1 to 58 weeks suspected of having reflux. Median time to complete the questionnaire was 20 minutes. The median internal consistency of 29 pairs of redundant questions was 0.94. Median test-retest consistency of 110 items for nine respondents was 0.88. Median interobserver consistency, evaluated for 129 items in 35 questionnaires also filled out by secondary caretakers, was 0.85. The median accuracy of four externally validated items was 1.00. This questionnaire can aid pediatricians in making decisions regarding diagnoses and treatment in this common but complex disorder.

Thickened feedings as a cause of increased coughing when used as therapy for gastroesophageal reflux in infants.

To determine whether thickening of infant formula feedings with rice cereal increases coughing, we studied 25 infants from birth to 6 months of age, referred for evaluation of gastroesophageal reflux. Coughing was blindly quantified after each of a pair of isocaloric meals (one thickened and one unthickened). Coughing was more frequent after thickened feedings than after unthickened feedings.