Recommendations for pharmacological clinical trials in children with functional constipation: The Rome foundation pediatric subcommittee on clinical trials.

BACKGROUND: Evidence for the efficacy of commonly used drugs in the treatment of childhood functional constipation (FC) is scarce, studies are often of low quality and study designs are heterogeneous. Thus, recommendations for the design of clinical trials in childhood FC are needed. PURPOSE: Members of the Rome Foundation and a member of the Pediatric Committee of the European Medicines Agency formed a committee to create recommendations for the design of clinical trials in children with FC. KEY RECOMMENDATIONS: This committee recommends conducting randomized, double-blind, placebo-controlled, parallel-group clinical trials to assess the efficacy of new drugs for the treatment of childhood FC. Pediatric study participants should be included based on fulfilling the Rome IV criteria for FC. A treatment free run-in period for baseline assessment is recommended. The trial duration should be at least 8 weeks. Treatment success is defined as no longer meeting the Rome IV criteria for FC. Stool consistency should be reported based on the Bristol Stool Scale. Endpoints of drug efficacy need to be tailored to the developmental age of the patient population.

Recommendations for pharmacological clinical trials in children with irritable bowel syndrome: the Rome foundation pediatric subcommittee on clinical trials.

BACKGROUND: There is little published evidence of efficacy for the most commonly used treatments. Thus, there is an urgent need to conduct clinical trials on existing and novel therapies. PURPOSE: In order to address these issues the Rome Foundation and members of the Pediatric Committee of the European Medicines Agency formed a subcommittee on clinical trials to develop guidelines for the design of clinical trials in children with irritable bowel syndrome (IBS). The following recommendations are based on evidence from published data when available and expert opinion. KEY RECOMMENDATIONS: The subcommittee recommends randomized, double-blind, placebo-controlled, parallel-group, clinical trials to assess the efficacy of new drugs. The combined endpoints for abdominal pain are a decrease in intensity of at least 30% compared with baseline and to meet or exceed the Reliable Change Index (RCI) for the sample. Stool consistency is measured with the Bristol Stool Scale Form (BSFS). The subcommittee recommends as entry criteria for abdominal pain a weekly average of worst abdominal pain in past 24 h of at least 3.0 on a 0-10 point scale or at least 30 mm in 100 mm Visual Analog Scale. For stool endpoints the committee recommends an average stool consistency lower than 3 in the BSFS during the run-in period for clinical trials on IBS-C and an average stool consistency greater than 5 in the BSFS during the run-in period for clinical trials on IBS-D. Changes in stool consistency are the primary endpoints for both IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C).

The role of rectal chloride secretion in childhood constipation.

BACKGROUND: Disturbance in fluid secretion, driven by chloride secretion, might play a role in constipation. However, disturbed chloride secretion in those patients has yet to be evaluated. Therefore, the aim of this study was to compare chloride secretion in rectal biopsies of children with functional constipation (FC) to those without constipation. METHODS: To measure changes in short circuit current (I(sc) in µA cm(-2)) reflecting chloride secretion, intestinal biopsies from children with constipation, to either exclude or diagnose Hirschsprung's disease, and from children without constipation (controls) undergoing colonoscopy for screening of familial adenomatous polyposis, juvenile polyps or inflammatory bowel disease (IBD), were compared and studied in Ussing chambers. Following electrogenic sodium absorption blockade by amiloride, chloride secretory responses to calcium-linked (histamine, carbachol) and cAMP-linked (IBMX/forskolin) secretagogues were assessed. KEY RESULTS: Ninety-six patients (46 FC) participated; nine FC patients (n = 1 congenital syndrome and n = 8 technical problems) and 13 controls (n = 6 IBD; n = 7 technical problems) were excluded. No significant difference was found in mean (±SE) basal chloride currents between children with FC and controls (9.6 ± 1.1 vs 9.2 ± 0.8; P = 0.75, respectively). Responses to calcium-linked chloride secretagogues (histamine and carbachol) were significantly higher in controls (33.0 ± 3.0 vs 24.5 ± 2.3; P = 0.03 and 33.6 ± 3.4 vs 26.4 ± 2.7; P = 0.05 following histamine and carbachol, respectively). CONCLUSIONS & INFERENCES: Calcium-linked chloride secretion is disturbed in children with FC. Whether this defect occurs at the level of histamine receptors, components of receptor-linked signal transduction pathways or basolateral Ca(2+) -sensitive K(+) channels enhancing the electrical driving force for apical chloride secretion, remains to be explored.

Is endoscopic retrograde cholangiopancreatography valuable and safe in children of all ages?

OBJECTIVE: To evaluate indications, findings, therapies, safety, and technical success of endoscopic retrograde cholangiopancreatography (ERCP) in children of the Emma Children's Hospital Academic Medical Centre in Amsterdam, the Netherlands. DESIGN: Descriptive. Retrospective analysis by medical records. PATIENTS AND METHODS: Information was obtained by chart review of patients between 0 and 18 years who underwent ERCP from 1995 to 2005 in our center. The following data were analyzed: indications, findings, therapies, safety, and technical success. Success was defined as obtaining accurate diagnostic information or succeeding in endoscopic therapy. RESULTS: Sixty-one children (age 3 days to 16.9 years, mean age 7.0 years) underwent a total of 99 ERCPs. Of those patients, 51% (31/61) were younger than 1 year, 84% had biliary indications, and 16% had pancreatic indications for the performance of ERCP. The complication rate was 4% (4/99) and included substantial pancreatitis and mild irritated pancreas. No complications occurred in children younger than 1 year. CONCLUSIONS: ERCP is a safe and valuable procedure for children of all ages with suspicion of pancreaticobiliary diseases. Indications for ERCP are different for children and adults. A laparotomy could be prevented in 12% of children with suspicion of biliary atresia. Further research is required to determine the role of MRCP versus ERCP.

[Better medicines for children: European measures]. / Betere geneesmiddelen voor kinderen: Europese maatregelen.

The Paediatric Regulation has been in force in the EU since 1 July 2007. This has changed the procedure for obtaining marketing authorisation of medicines in Europe so that new medications can be adapted safely for use in children. Additional provisions have been made for the use of authorised and generic medications in children. Research is being stimulated through subsidies and the extension of exclusive distribution rights for manufacturers. Other initiatives are aimed at making existing data on the use of medications in children accessible. Many of these tasks are the responsibility of a special European paediatric committee, which also assesses proposals for research on medication use in children.

Review article: The clinical importance of growth in children with inflammatory bowel disease: is it important to the gastroenterologist?

BACKGROUND: Growth in children with inflammatory bowel disease is often compromised. AIM: To explore the origins of growth retardation in paediatric inflammatory bowel disease and to consider management strategies. METHODS: Relevant literature was identified and reviewed. RESULTS: A combination of the following factors results in growth retardation: insufficient food intake, malabsorption, increased catabolism, disease activity, disease extension, complications of disease and the side-effects of treatment. CONCLUSIONS: Failure of normal growth in a child with inflammatory bowel disease is an indicator of insufficient and unsuccessful therapy. The major causative factor is chronic anorexia because of chronic catabolic illness. Growth resumes to normal after effective control of the disease and nutritional intake. Regular follow-up of growth in these children is mandatory, and the measurement of both height and weight is an ideal indication of effective treatment. Failure of sustained growth in a child or adolescent with inflammatory bowel disease is a warning to consider a change of clinical strategy.

Long-term results of boerema anterior gastropexy in children.

OBJECTIVES: To analyze the long-term results of Boerema anterior gastropexy using the Visick grading system in a university teaching hospital. METHODS: Retrospective review of 247 children with severe or complicated gastroesophageal reflux disease (GERD). Patients who underwent primary gastropexy between 1990 and 2001 were divided in 3 groups: (A) neurologic impaired patients (n = 83); (B) esophageal atresia patients (n = 36); and (C) patients without underlying disease (n = 128). The median length of follow-up after gastropexy was 7 years and 8 months (range, 1.5-13 years). Follow-up was carried out using a standardized questionnaire and was obtained by telephone. Postoperative recurrence of symptoms during follow-up was considered as failure of the operation. RESULTS: Postoperative complications occurred in 20 patients (24%) in group A, in 13 patients (36%) in group B and in 23 patients (18%) in group C. Thirty-three patients died during the follow-up period, 5 of whom during the postoperative period. Six children could not be traced; thus, 208 were available for long-term follow-up. Postoperative failures occurred in 12 patients (23%) in group A, in 11 patients (31%) in group B and in 17 patients in group C (14%). Reoperation for recurrence of symptoms due to GERD was performed in 6 patients in group A, in 7 patients in group B and in 2 patients in group C. The final outcome at the time of interview was successful in 81% of group A, in 88% of group B and in 91% of group C. CONCLUSIONS: In the long term, Boerema anterior gastropexy is an effective operation for complicated GERD in children without underlying disease as well as in neurologically impaired children and patients with esophageal atresia.

[Video-capsule endoscopy in children with unexplained symptoms of the small intestine]. / Videocapsule-endoscopie bij kinderen met onbegrepen aandoeningen van de dunne darm.

Video-capsule endoscopy was used in 4 children with unexplained symptoms of the small intestine. Each patient swallowed a capsule of 11 by 27 mm, which contained a camera that takes 2 images per second (in children aged less than 8 years, the capsule was placed in the duodenum under sedation). In a 3-year-old girl with rectal bleeding following partial resection of the colon and small intestine, ulcers were seen proximal to the ileorectal anastomosis. In a 14-year-old boy with Crohn's disease and an abnormal growth curve, multiple stenoses of the small intestine were seen. In an 8-year-old boy with rectal bleeding, a solitary polypoid mass was seen that, upon operation, appeared to be the result of a partially invaginated Meckel's diverticulum. In a 17-year-old boy with weight loss, rectal bleeding and colitis, abnormalities were seen that were consistent with Crohn's disease. Patients were treated based on the endoscopic results and subsequently recovered. Video-capsule endoscopy is non-invasive and painless and provides better images of the small intestine than a standard endoscopic and radiological examination.

Assessment of the rectoanal inhibitory reflex in preterm infants with delayed meconium passage.

BACKGROUND: There is an inverse relationship between gestational age, birth weight and the time of first neonatal bowel movement. The authors hypothesized that delayed passage of meconium might result from a delayed maturation of the recto-anal inhibitory reflex (RAIR) in premature infants. OBJECTIVE: To evaluate whether the RAIR is absent in very preterm infants 28-32 weeks postmenstrual age with delayed meconium production. STUDY DESIGN: Anorectal manometry was performed in 10 preterm infants (seven male) with delayed meconium production (no meconium in the first 48 hours). Median postmenstrual age was 30 weeks (28-31 weeks). Birth weight ranged from 780 to 1930 g (median, 1395 g). A micromanometric assembly (outer diameter, 2.0 mm) was used which incorporated a 1.5-cm-long sleeve sensor for measurement of resting anal sphincter pressure and relaxation. Four side-holes recorded anal and rectal pressures. Rectal distension was performed with direct air insufflation to elicit the RAIR. RESULTS: The time from birth to passage of meconium ranged from 48 to 105 hours (median, 82 hours). The mean anal sphincter pressure, rectal pressure, and anal sphincter oscillation frequency were 22.0 +/- 5.0 mm Hg, 6.9 +/- 2.0 mm Hg, and 9.8 +/- 1.9/min, respectively. A normal RAIR was elicited in all infants. CONCLUSION: Anorectal manometry recordings in premature infants with delayed passage of meconium showed normal anorectal pressures and a normal RAIR, suggesting that delayed meconium passage is not related to the absence of a RAIR.

Prognosis of constipation: clinical factors and colonic transit time.

BACKGROUND: Measurement of colonic transit time (CTT) is sometimes used in the evaluation of patients with chronic constipation. AIM: To investigate the relation between symptoms and CTT, and to assess the importance of symptoms and CTT in predicting outcome. METHODS: Between 1995 and 2000, 169 consecutive patients (median age 8.4 years, 65% boys) fulfilling the criteria for constipation were enrolled. During the intervention and follow up period, all kept a diary to record symptoms. CTT was measured at entry to the study. RESULTS: At entry, defecation frequency was lower in girls than in boys, while the frequency of encopresis episodes was higher in boys. CTT values were significantly higher in those with a low defecation frequency (< or =1/week) and a high frequency of encopresis (> or =2/day). However, 50% had CTT values within the normal range. Successful outcome occurred more often in those with a rectal impaction. CTT results <100 hours were not predictive of outcome. However, those with CTT >100 hours were less likely to have had a successful outcome. CONCLUSION: The presence of a rectal impaction at presentation is associated with a better outcome at one year. A CTT >100 hours is associated with a poor outcome at one year.

The incidence of pediatric inflammatory bowel disease in the Netherlands: 1999-2001.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) seems to be rising. Incidence studies could provide more insight into geographical differences and thereby lead to the identification of etiological factors. The aim of this study was to prospectively assess the incidence of pediatric IBD in the Netherlands from 1999 to 2001, using both an active physician case-reporting registry and a nationwide pathology database. METHODS: All pediatricians in the Netherlands were sent monthly identification cards to be returned if they had diagnosed a new case of IBD in a pediatric patient. Follow-up questionnaires were sent to physicians reporting new cases of IBD. The pathology database contains reports from all cytologic and histologic diagnoses made in the Netherlands. Two independent raters searched the database for new IBD cases. Cases identified from the pathology database were labeled as "probable IBD" and "possible IBD." Cases were cross-checked across databases on the basis of gender, date of birth, date of biopsy, and place of residence. Age-specific incidence rates were calculated for the Dutch population for the year 2000. RESULTS: Five hundred forty-six probable cases of IBD were identified; 217 cases were labeled as possible. The incidence rate was 5.2 new cases per 100000 children (<18 years) per year. An increase in incidence with age was observed. Only 24% of the cases were ascertained through the clinical registry. CONCLUSION: The incidence of IBD cases in the Netherlands is comparable with that reported in other European countries. Epidemiological studies using case reporting by physicians may be underestimates of true incidence rates.

Severity of enterocolitis is predicted by IL-8 in paediatric oncology patients.

Enterocolitis in oncology patients remains an important complication, but there is a lack of insight into its likely severity from microbial, pathological and inflammatory aspects. Paediatric oncology patients admitted with neutropenic fever, who developed abdominal pain and diarrhoea, were monitored by the takers of rectal biopsies, cultures, and inflammatory marker measurements. Twenty-five patients were included (mean age 7.1 years). 8 patients (32%) needed intensive care treatment, 3 (12%) patients died. Gram-positive bacteraemia was diagnosed in 4 patients (16%). Most patients had negative blood and stool cultures. Predictors of a severe clinical course of the enterocolitis were an increased serum interleukin-8 (IL-8) (>1000 pg/ml) level and an increased serum C-reactive protein level (CRP) (>150 mg/l) level, both measured on the first day of clinical illness. Relative risks (RR) for admission to an Intensive Care Unit (ICU) were 11.3 (95% Confidence Interval (CI) 1.6-77.9) for elevated IL-8 levels and 6.4 (95% (CI) 0.92-45.1) for increased CRP levels. Rectal biopsies and pathology could not predict outcome (P=0.22). IL-8 analysis at the onset of enterocolitis symptoms can identify high-risk patients, which might be used clinically to design future intervention trials.

Colonic transit times and behaviour profiles in children with defecation disorders.

AIMS: To evaluate children referred for defecation disorders using the child behavioural checklist (CBCL). METHODS: A total of 215 patients were divided into three groups: 135 (5-14 years of age) with paediatric constipation (PC), 56 (5-17 years) with functional non-retentive faecal soiling (FNRFS), and 24 (5-16 years) with recurrent abdominal pain (RAP). Behavioural scores were correlated with colonic transit time (CTT) and anorectal function parameters (manometry and EMG). RESULTS: No significant differences in the mean CBCL scores were found among the three patient groups. However, children with PC and FNRFS had significantly more behavioural problems than the Dutch normative sample, while children with RAP had scores within the normal range. No significant differences were found between CTT in the patient groups, with respect to the CBCL. Similarly, no significant difference existed between children able or unable to relax their pelvic floor muscles during defecation attempts and their behaviour profiles. CONCLUSION: There seems to be no relation between colonic/anorectal function and specific behavioural profiles. On the other hand, children with defecation disorders show more behavioural problems than do controls.

Maturation of the rectoanal inhibitory reflex in very premature infants.

OBJECTIVE: To characterize anal sphincter function in very premature infants < or =30 weeks' postmenstrual age (PMA) and to evaluate the time of maturation of the rectoanal inhibitory reflex (RAIR) by using a sleeve catheter. STUDY DESIGN: Anorectal manometry was performed in 16 healthy neonates (nine girls) with a mean PMA of 29 weeks (range, 27-30 weeks) and a birth weight of 640 to 1590 g (median, 1220 g) with a micromanometric assembly (outer diameter, 2.0 mm). The assembly incorporated a 1.5-cm-long sleeve sensor for measurement of resting anal sphincter pressures and relaxation, and four side holes recorded anal and rectal pressures. Rectal distention was performed with direct air insufflation to elicit the RAIR. RESULTS: The mean anal sphincter pressure, rectal pressure, and anal sphincter oscillation frequency were 24.5+/-11.4 mm Hg, 6.5+/-4.8 mm Hg, and 11.1+/-2.3/min, respectively. A normal RAIR could be elicited in 13 (81%) infants studied. In two infants, the RAIR could not be elicited because of a low anal sphincter pressure of only 5 mm Hg. In the other child, no RAIR was seen despite the repeated insufflation of at least 5 mL of air. CONCLUSION: The majority (81%) of premature infants older than 26 weeks' PMA have normal anorectal pressures and a normal RAIR.

[Functional childhood gastrointestinal disorders. I. Chronic abdominal pain]. / Functionele gastro-intestinale ziektebeelden op de kinderleeftijd. I. Chronische buikpijn.

Chronic abdominal pain occurs in 17% of children aged 0-14 years with a peak of 33% at the age of 7 years. According to the Rome II criteria abdominal pain disorders can be classified as functional dyspepsia, irritable bowel syndrome, functional abdominal pain, abdominal migraine, and aerophagia. This new classification will hopefully lead to a more careful diagnosis of functional abdominal pain syndromes and to better treatment strategies. A thorough history taking and physical examination are the cornerstone of diagnostic workup in children with chronic abdominal pain. An extensive explanation and reassurance are the basis of an adequate treatment and in the majority of cases this is successful.

[Functional childhood gastrointestinal disorders. II. Constipation and solitary encopresis: physiology and pathophysiology]. / Functionele gastro-intestinale ziektebeelden op de kinderleeftijd. II. Obstipatie en solitaire encopresis; fysiologie en pathofysiologie.

The childhood prevalences of constipation and encopresis are 0.3-8% and 1-3% respectively. Following a recent stricter definition and classification, constipation and solitary encopresis are now recognised to be two separate entities. Constipation is characterised by infrequent defecation, often in combination with involuntary loss of faeces. Solitary encopresis most often occurs once a day after school hours. When there is no defecation, the frequency of encopresis increases, the abdominal pain becomes more severe and the appetite becomes less, until a large quantity of faeces is produced (often once per week). The physiology of the defecation and continence mechanism is complex and has only been unravelled in part. The multiple physiological mechanisms involved have a complementary and compensatory effect on each other. This makes it difficult to determine the underlying pathophysiological mechanisms of these functional disorders.

[Functional childhood gastrointestinal disorders. III. Constipation and solitary encopresis; diagnostic work-up and therapy]. / Functionele gastro-intestinale ziektebeelden op de kinderleeftijd. III. Obstipatie en solitaire encopresis; diagnostiek en therapie.

A detailed medical history in combination with a thorough physical examination, including rectal examination, form the cornerstone in the diagnostic work-up for children with functional defecation disorders. Additional investigations are often not informative and have only minor diagnostic or therapeutic implications. Medical therapy in children with functional constipation and solitary encopresis is primarily based on clinical experience. In both patient groups, the role of education, the use of diary cards and toilet training is important. In some patients behaviour interventions are important. Oral laxatives are the basis of treatment of children with functional constipation, whereas they are contra-indicated in children with solitary encopresis. In both groups, biofeedback training appears to be of little additional benefit. Long-term follow-up of children with functional defecation disorders shows that complaints continue far beyond puberty in many children.