Christophe Faure

Evaluation and Treatment of Functional Constipation in Infants and Children: Evidence-Based Recommendations From ESPGHAN and NASPGHAN

Background: Constipation is a pediatric problem commonly encountered by many health care workers in primary, secondary, and tertiary care. To assist medical care providers in the evaluation and management of children with functional constipation, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition were charged with the task of developing a uniform document of evidence-based guidelines. Methods: Nine clinical questions addressing diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to October 2011 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. For therapeutic questions, quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Grading the quality of evidence for the other questions was performed according to the classification system of the Oxford Centre for Evidence-Based Medicine. During 3 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation. Results: This evidence-based guideline provides recommendations for the evaluation and treatment of children with functional constipation to standardize and improve their quality of care. In addition, 2 algorithms were developed, one for the infants <6 months of age and the other for older infants and children. Conclusions: This document is intended to be used in daily practice and as a basis for further clinical research. Large well-designed clinical trials are necessary with regard to diagnostic evaluation and treatment.

Bone Morphogenetic Protein-2 and -4 Limit the Number of Enteric Neurons But Promote Development of a TrkC-Expressing Neurotrophin-3-Dependent Subset

The hypothesis that BMPs (bone morphogenetic proteins), which act early in gut morphogenesis, also regulate specification and differentiation in the developing enteric nervous system (ENS) was tested. Expression of BMP-2 and BMP-4, BMPR-IA (BMP receptor subunit), BMPR-IB, and BMPR-II, and the BMP antagonists, noggin, gremlin, chordin, and follistatin was found when neurons first appear in the primordial bowel at embryonic day 12 (E12). Agonists, receptors, and antagonists were detected in separated populations of neural crest- and noncrest-derived cells. When applied to immunopurified E12 ENS precursors, BMP-2 and BMP-4 induced nuclear translocation of phosphorylated Smad-1 (Sma and Mad-related protein). The number of neurons developing from these cells was increased by low concentrations and decreased by high concentrations of BMP-2 or BMP-4. BMPs induced the precocious appearance of TrkC-expressing neurons and their dependence on neurotrophin-3 for survival. BMP-4 interacted with glial cell line-derived neurotrophic factor (GDNF) to enhance neuronal development but limited GDNF-driven expansion of the precursor pool. BMPs also promoted development of smooth muscle from mesenchymal cells immunopurified at E12. To determine the physiological significance of these observations, the BMP antagonist noggin was overexpressed in the developing ENS of transgenic mice under the control of the neuron-specific enolase promoter. Neuronal numbers in both enteric plexuses and smooth muscle were increased throughout the postnatal small intestine. These increases were already apparent by E18. In contrast, TrkC-expressing neurons decreased in both plexuses of postnatal noggin-overexpressing animals, again an effect detectable at E18. BMP-2 and/or BMP-4 thus limit the size of the ENS but promote the development of specific subsets of enteric neurons, including those that express TrkC.

Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients.

BACKGROUND & AIMS In adults, irritable bowel syndrome (IBS) and functional dyspepsia (FD) are chronic conditions that often start during childhood. We investigated mucosal serotonin (5-HT) signaling in children with the idea that data from subjects with a shorter history may improve our understanding of underlying pathophysiological mechanisms. METHODS Ninety-eight children undergoing gastroscopy or colonoscopy were studied prospectively. Biopsy specimens were evaluated for inflammation, enterochromaffin cell numbers, 5-HT content, and messenger RNA (mRNA) levels for the synthetic enzyme, tryptophan hydroxylase 1, and the serotonin transporter (SERT) were assessed by quantitative real-time reverse-transcription polymerase chain reaction. RESULTS Data from 12 children with IBS and 17 with FD were compared with age-matched controls (12 with rectal biopsies and 12 with gastric biopsies) and with subjects with organic disorders. In patients with FD, a small number of immune cells were observed in the gastric mucosa in half of the patients, but no abnormalities with respect to the 5-HT pathway were identified. In patients with IBS, no differences were detected between patients and controls regarding intraepithelial lymphocytes and CD3+ cells in the lamina propria although all patients showed at least a slight inflammatory infiltrate. In the IBS samples, higher 5-HT content (P < .01) and lower SERT mRNA (P < .05) were detected as compared with controls. Severe inflammation in the colonic mucosa had a high impact on 5-HT signaling with a significant decrease in enterochromaffin cells (P < .01) and 5-HT content (P < .01) and a high SERT mRNA expression (P < .01). CONCLUSIONS These results confirm the role of 5-HT signaling in IBS in children and argue against such a role in FD.

A critical appraisal of current management practices for infant regurgitation--recommendations of a working party.

Regurgitation is a common manifestation in infants below the age of 1 year and a frequent reason of counselling of general practitioners and paediatricians. Current management starts with postural and dietary measures, followed by antacids and prokinetics. Recent issues such as an increased risk of sudden infant death in the prone sleeping position and persistent occult gastro-oesophageal reflux in a subset of infants receiving milk thickeners or thickened “anti-regurgitation formula” challenge the established approach. Therefore, the clinical practices for management of infant regurgitation have been critically evaluated with respect to their efficacy, safety and practical implications. The updated recommendations reached by the working party on the management of infant regurgitation contain five phases: (1A) parental reassurance; (1B) milk-thick ening agents; (2) prokinetics; (3) positional therapy as an adjuvant therapy; (4A) H2-blockers; (4B) proton pump inhibitors; (5) surgery.

Pharmacokinetics of Proton Pump Inhibitors in Children

The use of proton pump inhibitors (PPIs) has become widespread in children and infants for the management of paediatric acid-related disease. Pharmacokinetic profiles of only omeprazole and lansoprazole have been well characterised in children over 2 years of age with acid-related diseases. Few data have been recently published regarding the pharmacokinetics of pantoprazole in children, and none are available for rabeprazole or esomeprazole. The metabolism of PPI enantiomers has never been studied in the paediatric population.A one-compartment model best describes the pharmacokinetic behaviour of omeprazole, lansoprazole and pantoprazole in children, with important interindividual variability for each pharmacokinetic parameter. Like adults, PPIs are rapidly absorbed in children following oral administration; the mean time to reach maximum plasma concentration varies from 1 to 3 hours. Since these agents are acid labile, their oral formulations consist of capsules containing enteric-coated granules. No liquid formulation is available for any of the PPIs. Thus, for those patients unable to swallow capsules, extemporaneous liquid preparations for omeprazole and lansoprazole have been reported; however, neither the absolute nor the relative bioavailabilities of these oral formulations have been studied in children. Intravenous formulations are available for omeprazole (in Europe), lansoprazole and pantoprazole.PPIs are rapidly metabolised in children, with short elimination half-lives of around 1 hour, similar to that reported for adults. All PPIs are extensively metabolised by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine. Similar to that seen in adults, the absolute bioavailability of omeprazole increases with repeated dosing in children; this phenomenon is thought to be due to a combination of decreased first-pass elimination and reduced systemic clearance. The apparent clearance (CL/F) of omeprazole, lansoprazole and pantoprazole appears to be faster for children than for adults. A higher metabolic capacity in children as well as differences in the extent of PPI bioavailability are most likely responsible for this finding. This may partly account for the need in children for variable and sometimes considerably greater doses of PPIs, on a per kilogram basis, than for adults to achieve similar plasma concentrations. Furthermore, no studies have been able to demonstrate a statistically significant correlation between age and pharmacokinetic parameters among children. Despite the small number of very young infants studied, there is some evidence for reduced PPI metabolism in newborns. The limited paediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolisers having 6- to 10-fold higher area under the concentration-time curve values compared with extensive metabolisers.Finally, because a pharmacokinetic/pharmacodynamic relationship exists for PPIs, the significant interindividual variability in their disposition may partly explain the wide range of therapeutic doses used in children. Further studies are needed to better define the pharmacokinetics of PPIs in children <2 years of age.

Ultrasonographic assessment of inflammatory bowel disease in children: Comparison with ileocolonoscopy

OBJECTIVES To determine the feasibility and value of transabdominal ultrasonography of the terminal ileum and colon of children with inflammatory bowel disease (IBD) and to compare the findings with those of ileocolonoscopy. STUDY DESIGN Thirty-eight patients ranging in age from 4 to 18 years who underwent ileocolonoscopy for management of IBD or for diagnosis were studied prospectively. Twenty-one patients had Crohn disease, nine had ulcerative colitis, and eight served as control subjects. Transabdominal ultrasonography was performed on the day before ileocolonoscopy. Ultrasonographic findings were compared with the results of ileocolonoscopy, used as the reference method. RESULTS Peristalsis was recorded in all segments of the control subjects; the thickness of the terminal ileum was always less than 2.5 mm, and that of the large bowel, 2 mm or less. In the two patient subgroups, the thickness range of affected ileal and colonic segments was similar, but values were significantly different from those of the control subjects (chi-square test, p <0.0001). The overall sensitivity of the method was 88%, and the specificity, 93%. CONCLUSION Transabdominal ultrasonography should prove to be a useful clinical and investigational technique, although further studies are needed to assess its value in the treatment of children with IBD.

Esophageal Impedance Monitoring for Gastroesophageal Reflux

Dual pH-multichannel intraluminal impedance (pH-MII) is a sensitive tool for evaluating overall gastroesophageal reflux disease, and particularly for permitting detection of nonacid reflux events. pH-MII technology is especially useful in the postprandial period or at other times when gastric contents are nonacidic. pH-MII was recently recognized by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as being superior to pH monitoring alone for evaluation of the temporal relation between symptoms and gastroesophageal reflux. In children, pH-MII is useful to correlate symptoms with reflux (particularly nonacid reflux), to quantify reflux during tube feedings and the postprandial period, and to assess efficacy of antireflux therapy. This clinical review is simply an evidence-based overview addressing the indications, limitations, and recommended protocol for the clinical use of pH-MII in children.

Risk Factors for Short- and Long-Term Morbidity in Children with Esophageal Atresia

OBJECTIVE To describe short- (first year of age) and long-term (after 1 year of age) outcome in patients with esophageal atresia and identify early predictive factors of morbidity in the first month of life. STUDY DESIGN Charts of children with esophageal atresia born January 1990 to May 2005 were reviewed. A complicated evolution was defined as the occurrence of at least 1 complication: severe gastroesophageal reflux, esophageal stricture requiring dilatations, recurrent fistula needing surgery, need for gavage feeding for >or=3 months, severe tracheomalacia, chronic respiratory disease, and death. RESULTS A total of 134 patients were included. Forty-nine percent of patients had a complicated evolution before 1 year of age, and 54% had a complicated evolution after 1 year. With bivariate analysis, predictive variables of a complicated evolution were demonstrated, including twin birth, preoperative tracheal intubation, birth weight <2500 g, long gap atresia, anastomotic leak, postoperative tracheal intubation >or=5 days, and inability to be fed orally by the end of the first month. After 1 year of age, the complicated evolution was only associated with long gap atresia and inability to be fed orally in the first month. A hospital stay >or=30 days was associated with a risk of a complicated evolution at 1 year and after 1 year of age (odds ratio, 9.3 [95% CI, 4.1-20.8] and 3.5 [95% CI, 1.6-7.6], respectively). CONCLUSION Early factors are predictive of morbidity in children with esophageal atresia.

Current concepts and issues in the management of regurgitation of infants: A reappraisal

Regurgitation in infants is a common problem. Recent issues, such as the increased risk of sudden infant death in the prone sleeping position, the finding of persisting occult gastro‐oesophageal reflux with feed thickeners, and the increasing awareness of the cost‐benefit ratio of medications may challenge the currently recommended management approach. A round table was organized to elaborate on the impact of (i) the pro supine sleeping campaigns in relation to sudden infant death and (ii) advancement in medical treatment on therapeutic strategies in regurgitating infants. The participants were opinion leaders from Europe and North America (Belgium, Canada, France, UK, Italy, Switzerland and The Netherlands). The importance of parental reassurance is stressed. As a consequence of the supine sleeping campaigns aiming to decrease the incidence of sudden infant death syndrome, the “prone elevated sleeping position” is no longer advised as a first‐line therapeutic approach, although it is still recommended in “complicated reflux”. It is emphasized that milk thickeners are an adequate therapeutic tool for regurgitation, but not in reflux disease. According to the literature, the efficacy of (alginate‐) antacids, although very popular in some countries, is questionable. These recommendations will be of interest to first‐line paediatricians, since about 40% of their patients, according to the literature, present because of regurgitation.

Functional Gastrointestinal Disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Functional gastrointestinal disorders are defined as conditions in which a variable combination of chronic or recurrent gastrointestinal symptoms are present in the absence of known structural or biochemical abnormalities. There is no apparent organic disease or objective evidence of a pathologic condition. In clinical practice, most children with chronic gastrointestinal complaints have functional disorders. Despite their common occurrence, we know very little about the pathophysiology of most of these conditions. A diagnosis of a functional disorder is largely based on a patient’s report of symptoms. Whereas adults can offer accurate histories, this is not necessarily the case in children, especially those who are young. Moreover, parents often play a large role in reporting their child’s symptoms as well as in making the decision about whether to seek health care. Often the child–parent unit must be evaluated when addressing functional disorders. Considerable effort has been spent in defining pediatric functional gastrointestinal disorders. A multinational team of senior clinicians suggested working definitions (1). A recent monograph has described the spectrum of these disorders (2). It has been observed that some pediatric functional gastrointestinal disorders accompany normal development (e.g., infant regurgitation), or may be triggered by behavioral responses to age-appropriate activities (functional fecal retention during toilet training). It was also suggested that some children could inherit a temperament characterized by a predilection to gastrointestinal reactivity to stress, thereby constituting a genetic susceptibility to functional gastrointestinal disorders. At the same time it is recognized that environmental factors (parental health care seeking, stress, culture, geographic location) might play a role in the pathogenesis of functional gastrointestinal disorders. In the biopsychosocial model of clinical practice, symptoms represent the end result of autonomic nervous system reactivity and recovery, environmental stressors, and the child’s ability to cope. They are also influenced by parental responses and coping. In this report, we address functional gastrointestinal disorders associated with vomiting, abdominal pain, and disordered defecation. We have not considered infant regurgitation, which is discussed in another Working Group report.