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.

Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux.

BACKGROUND: The use of over-the-counter antacids has increased in children under the age of 12 years, and has been followed by an apparent increase in the use of over-the-counter histamine-2 receptor antagonists. However, the pharmacokinetic and pharmacodynamic effects of over-the-counter histamine-2 receptor antagonists in the paediatric population are largely unknown. AIM: To evaluate the pharmacokinetics and pharmacodynamics of a single dose of the over-the-counter histamine-2 receptor antagonist, ranitidine, 75 mg, in children with symptoms of gastro-oesophageal reflux disease. METHODS: Children aged between 4 and 11 years with symptoms of heartburn suspected to be due to gastro-oesophageal reflux disease were recruited at six clinical centres. Following a single dose of either oral ranitidine, 75 mg (n=19), or placebo (n=10), recording of intragastric pH and serial blood sampling were carried out for 6 h. RESULTS: The estimated pharmacokinetic parameters of ranitidine, 75 mg, were as follows: the median Cmax value of 477 ng/mL occurred within a median of 2.5 h after dosing, and the median half-life was 2.0 h. The intragastric pH began to rise approximately 30 min after dosing with ranitidine to a peak of pH; 4. The pH in the ranitidine group remained higher than that in the placebo group throughout the 6-h evaluation period. Adverse events were generally mild. CONCLUSIONS: Ranitidine, 75 mg, significantly increased the intragastric pH in children aged 4-11 years. The pharmacokinetic and pharmacodynamic profiles were similar to those in adults. Ranitidine, 75 mg, appears to be effective for the control of intragastric acidity for 5-6 h in children aged 4-11 years.

An overview of reflux-associated disorders in infants: apnea, laryngospasm, and aspiration.

Problematic airway responses in infants are common. Reflux-induced apnea affects nearly 1% of infants and involves airway closure or laryngospasm. Recurrent or chronic stridor, caused by dynamic or structural airway abnormalities, occurs in up to 1 in 100 babies. It can be difficult to distinguish microaspiration, which may represent inadequate airway protection mechanisms, from reflexive responses to esophageal refluxate, which may represent overeffective airway protection mechanisms. The diagnosis of gastroesophageal reflux (GER) in babies can be facilitated by a careful history in conjunction with esophageal pH probe monitoring, laryngoscopic evaluation, bronchoalveolar lavage, or nuclear medicine scintigraphy. Conservative lifestyle measures for treating supraesophageal manifestations of infantile GER include prone positioning and thickened feedings. Prokinetic and acid-suppressing therapies are widely used, but their efficacy is incompletely established, and none is currently approved by the US Food and Drug Administration for this purpose. Fundoplication is not indicated if nonsurgical management can prevent serious problems during the child's maturation phase when many of these manifestations spontaneously resolve. Much remains to be learned about the developmental aspects of these supraesophageal manifestations of GER. This information not only will provide a greater understanding of developmental pathophysiology, but also will improve the clinical care of large numbers of infants.

(99m)Tc antigranulocyte monoclonal antibody imaging for the detection and assessment of inflammatory bowel disease newly diagnosed by colonoscopy in children.

OBJECTIVE: This prospective study evaluated a (99m)Tc antigranulocyte monoclonal antibody Fab' imaging agent (Sulesomab) in children with inflammatory bowel disease (IBD) newly diagnosed by colonoscopy. MATERIALS AND METHODS: Ten children (4 boys, 6 girls; mean age 14 years) with newly diagnosed Crohn's disease (n = 6) or ulcerative colitis (n = 4) were studied. Colonoscopy was performed in all of these patients. Within 24 h after colonoscopy, they underwent scintigraphy with (99m)Tc-Sulesomab. Abdominal/pelvic images were acquired at 30 min (planar) and 2-4 h (planar and SPECT) after injection of Sulesomab. Eighty bowel segments were evaluated semi-quantitatively by the investigators, using these three sets of images. The Pediatric Disease Activity (PDA) was correlated with the erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, albumin, Kirschner's score, the Sulesomab bowel segment with maximum uptake, and the sum of Sulesomab score in each segment. RESULTS: The median PDA score was 26 (range 12.5-40). Three children had normal ESR and six normal WBC counts. All patients had at least one positive mucosal biopsy for IBD. While using the Kirschner's scale, the maximal severity of colonoscopy findings was graded as none (n = 2), mild (n = 4), moderate (n = 3), or severe (n = 1). Of the 59 segments evaluated with endoscopy, 35 were found to be endoscopically abnormal. The planar images identified 17 of these abnormal segments and the SPECT images 20. Nine of these ten children had abnormal bowel uptake by scintigraphy. Thus, the sensitivity of Sulesomab per patient was 90 % and per bowel segment 57 %. The correlation coefficient between the scintigraphic score for the segment with the Sulesomab maximum activity and the PDA was 0.3 (P = 0.41). CONCLUSION: In pediatric IBD assessment, planar imaging with Sulesomab did not prove very sensitive in detecting inflammation in each bowel segment. However, SPECT detected the presence of inflammation in the majority of patients. A trial comparing (99m)Tc-HmPAO-WBC with Sulesomab in a large number of patients is required.

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.

Management of supraesophageal complications of gastroesophageal reflux disease in infants and children.

Therapy of supraesophageal manifestations of gastroesophageal reflux disease (GERD) in infants and children nearly always includes "lifestyle modifications" (conservative or nonpharmacologic therapy). Depending on the severity of the GERD manifestation, pharmacotherapy is often added. Although data to support the practice are not abundant, it is rational to begin with prokinetic pharmacotherapy and to add acid suppression if pathologic effects of acid contact with the esophagus or airway are suspected. Pathologic effects of acid produce most forms of supraesophageal GERD; the exception is infantile regurgitation, the most common example of supraesophageal GERD, which is often unaccompanied by either esophagitis or evidence of acid entry into the airway. Currently, fundoplication is rarely required for pediatric GERD, but the supraesophageal complications of GERD are more common indications for this surgery than the esophageal complications in children. Other management options for supraesophageal symptoms in children include delivery of nutrients by tube feeding slowly and continuously into the stomach or, better, small intestine. Short-term or trial tube feeding uses a transnasal tube, for example, for nasojejunal feeding; longer-term tube feeding is simplified by a gastrostomy, which can be placed relatively noninvasively using endoscopy or fluoroscopy.

Update on gastroesophageal reflux and respiratory disease in children.

Pediatric respiratory diseases have been linked to gastroesophageal reflux disease (GERD), but evidence regarding the association and its potential mechanisms continues to accumulate, and important aspects remain to be determined. Evidence for the association in two common pediatric respiratory disorders - infantile apnea and asthma in older children - and difficult clinical issues associated with the diagnosis and treatment of these two disorders are reviewed. The provocative embryological and physiological connections between the upper gastrointestinal tract and the respiratory tract, and recent understanding of the compensatory anatomy and physiology that protect the normal individual from respiratory manifestations of GERD are also explored. Dysfunctions of these protections likely underlie the pathophysiology of these disorders.

Gastroesophageal reflux disease in children.

In the pediatric population, gastroesophageal reflux most often presents in infancy as effortless regurgitation, but pathologic GERD is accompanied by signs of malnutrition, respiratory diseases, and esophagitis or its complications. Because of the distinctive pathophysiology predisposing infants to GERD, the diagnostic approach must begin with a thorough history that determines the extent of further diagnostic tests and the course of management. Empiric therapy assumes importance in infants with GERD because of the limited differential diagnoses in consideration. Conservative therapy is of utmost importance because of the unique provocative factors in the pathophysiology of infantile GERD. Prokinetic pharmacotherapy takes precedence over acid suppression because of the more important role of motility factors compared with acid secretion in infantile GERD.

Common pediatric esophageal disorders.

Esophageal disorders in children can result in significant morbidity. The most common esophageal disorder seen in children is gastroesophageal reflux. Other common disorders affecting the esophagus include peptic esophageal strictures, esophageal atresia with or without tracheoesophageal fistula, caustic and foreign body ingestions, achalasia, and cricopharyngeal achalasia. We discuss what is currently known about these common pediatric esophageal disorders with regard to pathophysiology, clinical presentation, and diagnostic and treatment strategies.

Retrospective analysis of alternate-day prednisone maintenance therapy for Crohn's disease.

We reviewed the medical records of 98 children with Crohn's disease followed at Children's Hospital of Pittsburgh from 1983 to 1993 to evaluate the merits of alternate-day prednisone (AD) maintenance therapy once initial remission was achieved. Of the 98 children, 35 had adequate data recorded for eligibility to the study. Of these, 11 were in the AD group and 24 were in a group whose maintenance regimen did not include prednisone (NO). The dependent variables were frequency of flares and linear growth over time. AD therapy reduced mean symptomatic flares (0.23 +/- 0.1 vs 0.69 +/- 0.14 flares/patient/year; p = 0.04) over a 2-year follow-up period but did not delay significantly the onset of a flare after remission was achieved (16.5 +/- 3.4, vs 13.4 +/- 1.8 months; p = 0.4). Site of disease involvement had no impact on frequency of flares. Fewer patients in the AD group experienced flares, but this finding did not achieve statistical significance (4/11, 36%, vs 17/24, 71%; p = 0.07). Linear growth, measured in height percentile and growth velocity (cm/year), was not significantly reduced by the second year of either therapy. This small retrospective study suggests that AD prednisone therapy may be effective in reducing symptomatic flares in Crohn's patients without a resultant inhibition of linear growth.

Endoscopies in pediatric small intestinal transplant recipients: five years experience.

OBJECTIVE: Intestinal transplantation has become an option as a treatment for permanent intestinal failure. Endoscopy is an essential tool in assessing the intestinal allograft after intestinal transplantation. The aim of this study was to analyze our experience using endoscopy in intestinal transplant recipients. METHODS: This was a retrospective review of endoscopic and histological reports in 41 children who received an intestinal transplant between 1990 and 1995 at Children's Hospital of Pittsburgh. RESULTS: A total of 1273 endoscopies was performed of which 760 were ileoscopies via allograft ileostomy, 273 were upper endoscopies, and 240 were colonoscopies. One hundred four rejection episodes were documented histologically in 32 patients, 6 days to >4 yr after transplantation. Most episodes were mild and easily treated with increased immunosuppression; however, severe rejection with mucosal exfoliation was seen in nine patients. Rejection sometimes involved only part of the allograft. Endoscopic appearance alone without biopsies was sensitive enough to diagnose only 63% of the rejection episodes. Epstein-Barr and cytomegalovirus infections occurred in 11 and eight patients, respectively, and involved both native bowel and allograft in some. Complications of endoscopy were few: one perforation, three episodes of bleeding, and three episodes of transient respiratory compromise. CONCLUSIONS: Endoscopy is an essential tool in the postoperative assessment of intestinal transplant recipients. Frequent surveillance ileoscopies with biopsies should be performed after transplantation. If patients clinically deteriorate with fever, diarrhea, bacteremia, or gastrointestinal bleeding and a clear cause is not elucidated by ileoscopy, an upper endoscopy with biopsies is indicated.

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.