Treatments for intractable constipation in childhood.

BACKGROUND: Constipation that is prolonged and does not resolve with conventional therapeutic measures is called intractable constipation. The treatment of intractable constipation is challenging, involving pharmacological or non-pharmacological therapies, as well as surgical approaches. Unresolved constipation can negatively impact quality of life, with additional implications for health systems. Consequently, there is an urgent need to identify treatments that are efficacious and safe. OBJECTIVES: To evaluate the efficacy and safety of treatments used for intractable constipation in children. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers up to 23 June 2023. We also searched reference lists of included studies for relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any pharmacological, non-pharmacological, or surgical treatment to placebo or another active comparator, in participants aged between 0 and 18 years with functional constipation who had not responded to conventional medical therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were symptom resolution, frequency of defecation, treatment success, and adverse events; secondary outcomes were stool consistency, painful defecation, quality of life, faecal incontinence frequency, abdominal pain, hospital admission for disimpaction, and school absence. We used GRADE to assess the certainty of evidence for each primary outcome. MAIN RESULTS: This review included 10 RCTs with 1278 children who had intractable constipation. We assessed one study as at low risk of bias across all domains. There were serious concerns about risk of bias in six studies. One study compared the injection of 160 units botulinum toxin A (n = 44) to unspecified oral stool softeners (n = 44). We are very uncertain whether botulinum toxin A injection improves treatment success (risk ratio (RR) 37.00, 95% confidence interval (CI) 5.31 to 257.94; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Frequency of defecation was reported only for the botulinum toxin A injection group (mean interval of 2.6 days). The study reported no data for the other primary outcomes. One study compared erythromycin estolate (n = 6) to placebo (n = 8). The only primary outcome reported was adverse events, which were 0 in both groups. The evidence is of very low certainty due to concerns with risk of bias and serious imprecision. One study compared 12 or 24 µg oral lubiprostone (n = 404) twice a day to placebo (n = 202) over 12 weeks. There may be little to no difference in treatment success (RR 1.29, 95% CI 0.87 to 1.92; low certainty evidence). We also found that lubiprostone probably results in little to no difference in adverse events (RR 1.05, 95% CI 0.91 to 1.21; moderate certainty evidence). The study reported no data for the other primary outcomes. One study compared three-weekly rectal sodium dioctyl sulfosuccinate and sorbitol enemas (n = 51) to 0.5 g/kg/day polyethylene glycol laxatives (n = 51) over a 52-week period. We are very uncertain whether rectal sodium dioctyl sulfosuccinate and sorbitol enemas improve treatment success (RR 1.33, 95% CI 0.83 to 2.14; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Results of defecation frequency per week was reported only as modelled means using a linear mixed model. The study reported no data for the other primary outcomes. One study compared biofeedback therapy (n = 12) to no intervention (n = 12). We are very uncertain whether biofeedback therapy improves symptom resolution (RR 2.50, 95% CI 1.08 to 5.79; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). The study reported no data for the other primary outcomes. One study compared 20 minutes of intrarectal electromotive botulinum toxin A using 2800 Hz frequency and botulinum toxin A dose 10 international units/kg (n = 30) to 10 international units/kg botulinum toxin A injection (n = 30). We are very uncertain whether intrarectal electromotive botulinum toxin A improves symptom resolution (RR 0.96, 95% CI 0.76 to 1.22; very low certainty evidence) or if it increases the frequency of defecation (mean difference (MD) 0.00, 95% CI -1.87 to 1.87; very low certainty evidence). We are also very uncertain whether intrarectal electromotive botulinum toxin A has an improved safety profile (RR 0.20, 95% CI 0.01 to 4.00; very low certainty evidence). The evidence for these results is of very low certainty due to serious concerns with risk of bias and imprecision. The study did not report data on treatment success. One study compared the injection of 60 units botulinum toxin A (n = 21) to myectomy of the internal anal sphincter (n = 21). We are very uncertain whether botulinum toxin A injection improves treatment success (RR 1.00, 95% CI 0.75 to 1.34; very low certainty evidence). No adverse events were recorded. The study reported no data for the other primary outcomes. One study compared 0.04 mg/kg oral prucalopride (n = 107) once daily to placebo (n = 108) over eight weeks. Oral prucalopride probably results in little or no difference in defecation frequency (MD 0.50, 95% CI -0.06 to 1.06; moderate certainty evidence); treatment success (RR 0.96, 95% CI 0.53 to 1.72; moderate certainty evidence); and adverse events (RR 1.15, 95% CI 0.94 to 1.39; moderate certainty evidence). The study did not report data on symptom resolution. One study compared transcutaneous electrical stimulation to sham stimulation, and another study compared dietitian-prescribed Mediterranean diet with written instructions versus written instructions. These studies did not report any of our predefined primary outcomes. AUTHORS' CONCLUSIONS: We identified low to moderate certainty evidence that oral lubiprostone may result in little to no difference in treatment success and adverse events compared to placebo. Based on moderate certainty evidence, there is probably little or no difference between oral prucalopride and placebo in defecation frequency, treatment success, or adverse events. For all other comparisons, the certainty of the evidence for our predefined primary outcomes is very low due to serious concerns with study limitations and imprecision. Consequently, no robust conclusions could be drawn.

Pediatric neurogenic bowel dysfunction: ICCS review document.

INTRODUCTION: The International Children's Continence Society (ICCS) aims to improve the quality of life in children with lower urinary tract dysfunction. A substantial portion of children also have problems with bowel dysfunction. There is a lack of evidence-based information on managing neurogenic bowel dysfunction (NBD) in children. OBJECTIVE/METHODS: The ICCS aimed to provide an up-to-date, selective, non-systematic review of NBD's definitions, assessment, and treatment. RESULTS: Specific definitions and terminology are defined within the document. Recommendations and considerations for physical assessment, history taking, and diagnostic studies are made. Management updates, both surgical and non-surgical, are provided as well as recommendations for follow-up and monitoring of individuals with NBD. CONCLUSION: This review of the current literature will help guide NBD management and research to improve NBD care.

Fecal amine metabolite analysis before onset of severe necrotizing enterocolitis in preterm infants: a prospective case-control study.

Infants developing necrotizing enterocolitis (NEC) have a different metabolomic profile compared to controls. The potential of specific metabolomics, i.e. amino acids and amino alcohols (AAA), as early diagnostic biomarkers for NEC is largely unexplored. In this multicenter prospective case-control study, longitudinally collected fecal samples from preterm infants (born <30 weeks of gestation) from 1-3 days before diagnosis of severe NEC (Bell's stage IIIA/IIIB), were analyzed by targeted high-performance liquid chromatography (HPLC). Control samples were collected from gestational and postnatal age-matched infants. Thirty-one NEC cases (15 NEC IIIA;16 NEC IIIB) with 1:1 matched controls were included. Preclinical samples of infants with NEC were characterized by five increased essential amino acids-isoleucine, leucine, methionine, phenylalanine and valine. Lysine and ethanolamine ratios were lower prior to NEC, compared to control samples. A multivariate model was rendered based on isoleucine, lysine, ethanolamine, tryptophan and ornithine, modestly discriminating cases from controls (AUC 0.67; p < 0.001). Targeted HPLC pointed to several specific AAA alterations in samples collected 1-3 days before NEC onset, compared to controls. Whether this reflects metabolic alterations and has a role in early biomarker development for NEC, has yet to be elucidated.

An ESPGHAN Position Paper on the Use of Low-FODMAP Diet in Pediatric Gastroenterology.

Excluding oligo-, di-, monosaccharides and polyols (FODMAPs) from the diet is increasingly being used to treat children with gastrointestinal complaints. The aim of this position paper is to review the available evidence on the safety and efficacy of its use in children and provide expert guidance regarding practical aspects in case its use is considered . Members of the Gastroenterology Committee, the Nutrition Committee and the Allied Health Professionals Committee of the European Society for Pediatric Gastroenterology Hepatology and Nutrition contributed to this position paper. Clinical questions regarding initiation, introduction, duration, weaning, monitoring, professional guidance, safety and risks of the diet are addressed. A systematic literature search was performed from 2005 to May 2021 using PubMed, MEDLINE and Cochrane Database of Systematic Reviews. In the absence of evidence, recommendations reflect the expert opinion of the authors. The systematic literature search revealed that the low-FODMAP diet has not been comprehensively studied in children. Indications and contraindications of the use of the diet in different pediatric gastroenterological conditions are discussed and practical recommendations are formulated. There is scarce evidence to support the use of a low-FODMAP diet in children with Irritable Bowel Syndrome and no evidence to recommend its use in other gastrointestinal diseases and complaints in children. Awareness of how and when to use the diet is crucial, as a restrictive diet may impact nutritional adequacy and/or promote distorted eating in vulnerable subjects. The present article provides practical safety tips to be applied when the low-FODMAP diet is considered in children.

Bowel Lengthening Procedures in Children with Short Bowel Syndrome: A Systematic Review.

INTRODUCTION: The aims of the study are to systematically assess and critically appraise the evidence concerning two surgical techniques to lengthen the bowel in children with short bowel syndrome (SBS), namely, the longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP), and to identify patient characteristics associated with a favorable outcome. MATERIALS AND METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception till December 2019. No language restriction was used. RESULTS: In all, 2,390 articles were found, of which 40 were included, discussing 782 patients. The median age of the patients at the primary bowel lengthening procedure was 16 months (range: 1-84 months). Meta-analysis could not be performed due to the incomparability of the groups, due to heterogeneous definitions and outcome reporting. After STEP, 46% of patients weaned off parenteral nutrition (PN) versus 52% after LILT. Mortality was 7% for STEP and 26% for LILT. Patient characteristics predictive for success (weaning or survival) were discussed in nine studies showing differing results. Quality of reporting was considered poor to fair. CONCLUSION: LILT and STEP are both valuable treatment strategies used in the management of pediatric SBS. However, currently it is not possible to advise surgeons on accurate patient selection and to predict the result of either intervention. Homogenous, prospective, outcome reporting is necessary, for which an international network is needed.

A Collaborative Effort to Advance Drug Development in Pediatric Constipation and Irritable Bowel Syndrome.

ABSTRACT: Pediatric functional gastrointestinal disorders including irritable bowel syndrome with constipation and functional constipation are common conditions in childhood, but no drugs are U.S. Food and Drug Administration (FDA) approved for chronic use in pediatric patients with these disorders. Despite efforts to better standardize the diagnosis of these conditions in children (including recent modifications to the Rome criteria), conducting pediatric clinical trials to support drug approval remains a challenge. In March 2018, FDA, in collaboration with the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, American Gastroenterological Association, and American College of Gastroenterology, convened a public workshop to discuss the challenges and opportunities in conducting pediatric clinical trials in functional gastrointestinal conditions. The workshop assembled gastroenterologists, psychologists, patients, patient advocates, regulators, and industry representatives to discuss trial design and conduct including alternative designs, eligibility criteria, instruments for patient- and observer-reported outcomes, and optimal primary endpoints to support regulatory approval. This report summarizes the workshop, key challenges and knowledge gaps identified, and outlines areas where further research efforts are needed to overcome barriers to developing drugs to treat these conditions.

Simultaneous assessment of colon motility in children with functional constipation by cine-MRI and colonic manometry: a feasibility study.

BACKGROUND: Colonic manometry is the current reference standard for assessing colonic neuromuscular function in children with intractable functional constipation (FC). Recently, cine magnetic resonance imaging (cine-MRI) has been proposed as a non-invasive alternative. We compared colonic motility patterns on cine-MRI with those obtained by manometry in children, by stimulating high-amplitude propagating contractions (HAPCs) with bisacodyl under manometric control while simultaneously acquiring cine-MRI. METHODS: After Institutional Review Board approval, adolescents with FC scheduled to undergo colonic manometry were included. A water-perfused 8-lumen catheter was used for colonic manometry recordings. After an intraluminal bisacodyl infusion, cine-MRI sequences of the descending colon were acquired for about 30 min simultaneously with colonic manometry. Manometry recordings were analysed for HAPCs. MRI images were processed with spatiotemporal motility MRI techniques. The anonymised motility results of both techniques were visually compared for the identification of HAPCs in the descending colon. RESULTS: Data regarding six patients (three males) were analysed (median age 14 years, range 12-17). After bisacodyl infusion, three patients showed a total of eleven HAPCs with colonic manometry. Corresponding cine-MRI recorded high colonic activity during two of these HAPCs, minimal activity during seven HAPCs, while two HAPCs were not recorded. In two of three patients with absent HAPCs on manometry, colonic activity was recorded with cine-MRI. CONCLUSIONS: Simultaneous acquisition of colonic cine-MRI and manometry in children with FC is feasible. Their motility results did not completely overlap in the identification of HAPCs. Research is needed to unravel the role of cine-MRI in this setting.

The influence of prenatal and intrapartum antibiotics on intestinal microbiota colonisation in infants: A systematic review.

OBJECTIVES: The intestinal microbiota develops in early infancy and is essential for health status early and later in life. In this review we focus on the effect of prenatal and intrapartum maternally administered antibiotics on the infant intestinal microbiota. METHODS: A systematic literature search was conducted in PubMed and EMBASE. All studies reporting effect on diversity or microbiota profiles were included. RESULTS: A total of 4.030 records were encountered. A total of 24 articles were included in the final analysis. Infants from mothers exposed to antibiotics during delivery showed a decreased microbial diversity compared to non-exposed infants. The microbiota of infants exposed to antibiotics was characterised by a decreased abundance of Bacteriodetes and Bifidobacteria, with a concurrent increase of Proteobacteria. These effects were most pronounced in term vaginally born infants. CONCLUSION: Maternal administration of antibiotics seems to have profound effects on the infant gut microbiota colonisation. Interpretation of microbiota aberrations in specific populations, such as preterm and caesarean born infants, is complicated by multiple confounding factors and by lack of high quality studies and high heterogeneity in study design. Further research is needed to investigate the potential short- and long-term clinical consequences of these microbial alterations.

A Systematic Review and Meta-analysis of Paediatric Inflammatory Bowel Disease Incidence and Prevalence Across Europe.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] is often one of the most devastating and debilitating chronic gastrointestinal disorders in children and adolescents. The main objectives here were to systematically review the incidence and prevalence of paediatric IBD across all 51 European states. METHODS: We undertook a systematic review and meta-analysis based on PubMed, CINAHL, the Cochrane Library, searches of reference lists, grey literature and websites, covering the period from 1970 to 2018. RESULTS: Incidence rates for both paediatric Crohn's disease [CD] and ulcerative colitis [UC] were higher in northern Europe than in other European regions. There have been large increases in the incidence of both paediatric CD and UC over the last 50 years, which appear widespread across Europe. The largest increases for CD have been reported from Sweden, Wales, England, the Czech Republic, Denmark and Hungary, and for UC from the Czech Republic, Ireland, Sweden and Hungary. Incidence rates for paediatric CD have increased up to 9 or 10 per 100 000 population in parts of Europe, including Scandinavia, while rates for paediatric UC are often slightly lower than for CD. Prevalence reported for CD ranged from 8.2 per 100 000 to approximately 60 and, for UC, from 8.3 to approximately 30. CONCLUSIONS: The incidence of paediatric IBD continues to increase throughout Europe. There is stronger evidence of a north-south than an east-west gradient in incidence across Europe. Further prospective studies are needed, preferably multinational and based on IBD registries, using standardized definitions, methodology and timescales.

Reporting on outcome measures in pediatric chronic intestinal failure: A systematic review.

BACKGROUND & AIMS: Chronic intestinal failure (IF) in children is a rare and heterogeneous disease requiring treatment with parenteral nutrition. A uniform definition for chronic IF and standardized outcome measures to compare therapeutic trials in these children are lacking. Therefore, the aim of this study is to systematically assess how definitions and outcome measures are defined in therapeutic trials of children with chronic IF. METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception till August 2018. No language restriction was used. RESULTS: A total of 1766 articles was found of which 70 studies fulfilled our inclusion criteria. 54 studies (76%) did not report any definition of IF. Of the 16 studies (23%) which reported a definition of IF, 7 different definitions were found. The two most frequently used definitions were: (1) the inability to absorb adequate nutrients to maintain body weight or normal growth and development (n = 5), and (2) the dependence upon parenteral nutrition to maintain minimal energy requirements for growth and development (n = 5). A total of 117 different outcomes were reported. The three most reported outcome measures were: mortality (n = 27), liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl trans peptidase) (n = 27), and growth (n = 23). Quality of reporting was considered fair to poor in most studies. CONCLUSION: There is a lack of reported definitions in studies concerning pediatric IF. Heterogeneity exists in outcome reporting in research concerning pediatric chronic IF. Therefore, we recommend the development of a core outcome set.

Controversies in the Management of Functional Constipation in Children.

PURPOSE OF REVIEW: Functional constipation (FC) in children is a common health problem with reported worldwide prevalence rates up to 32.2%. The majority of children with constipation respond to oral laxative treatment. After 5 years of intensive treatment, however, approximately 50% of children remain symptomatic. To discuss the evidence for new treatments in these children, including pre- and probiotics, pelvic physiotherapy, prucalopride, sacral nerve stimulation, and surgery, and to highlight the controversies surrounding them. RECENT FINDINGS: Pre- and probiotics and prucalopride are not effective in the treatment of childhood constipation. Pelvic physiotherapy and sacral nerve stimulation are promising treatment options but larger trials are needed. Surgery for pediatric constipation is the treatment of last resort. Large, well-designed placebo-controlled trials with proper outcome measures, as suggested by the Rome foundation pediatric subcommittee on clinical trials, are necessary to provide more insight regarding the efficacy of new treatments in childhood constipation.

Variability of core microbiota in newly diagnosed treatment-naïve paediatric inflammatory bowel disease patients.

BACKGROUND & AIMS: Intestinal microbiota is considered to play a crucial role in the aetiology of inflammatory bowel disease (IBD). We aimed to describe faecal microbiota composition and dynamics in a large cohort of children with de novo (naïve) IBD, in comparison to healthy paediatric controls (HC). METHODS: In this prospective study, performed at two tertiary centres, faecal samples from newly diagnosed, treatment-naïve paediatric IBD patients were collected prior to bowel cleansing for colonoscopy (t0) and 1, 3 and 6 weeks and 3 months after initiation of therapy. The microbial profiles of Crohn's disease (CD) and Ulcerative colitis (UC) patients were compared with HC and linked to therapeutic response. Microbiota composition was analysed by IS-pro technology. RESULTS: Microbial profiles of 104 new IBD-patients (63 CD, 41 UC, median age 14.0 years) were compared to 61 HC (median 7.8 years). IBD was mainly characterised by decreased abundance of Alistipes finegoldii and Alistipes putredinis, which characterize a healthy state microbial core. The classifier including these core species as predictors achieved an AUC of the ROC curve of .87. Core bacteria tended to regain abundance during treatment, but did not reach healthy levels. CONCLUSION: Faecal microbiota profiles of children with de novo CD and UC can be discriminated from HC with high accuracy, mainly driven by a decreased abundance of species shaping the microbial core in the healthy state. Paediatric IBD can therefore be characterized by decreased abundance of certain bacterial species reflecting the healthy state rather than by the introduction of pathogens.

Motility of the left colon in children and adolescents with functional constpation; a retrospective comparison between solid-state and water-perfused colonic manometry.

BACKGROUND: Using water-perfused (WP) high-resolution manometry, we recently demonstrated that children with functional constipation (FC) lacked the postprandial increase in distal colonic cyclic motor patterns that was observed in healthy adults. Our aim was to determine if similar results could be detected using a solid-state (SS) manometry catheter. METHODS: We performed a retrospective analysis of 19 children with FC (median age 11.1 years, 58% male) who underwent colonic manometry with a SS catheter (36 sensors, 3 cm apart). Data were compared with previously published data using a WP catheter (36 sensors, 1.5 cm apart) recorded from 18 children with FC (median age 15 years; 28% male). KEY RESULTS: The cyclic motor patterns recorded by the SS catheter did not differ from those previously recorded by the WP catheter. There was no detected increase in this activity in response to the meal in either group. Long-single motor patterns were recorded in most patients (n = 16, 84%) with the SS catheter. The number of these events did not differ from the WP recordings. In the SS data, HAPCs were observed in 4 children prior to the meal, in 5 after the meal. This did not differ significantly from the WP data. CONCLUSIONS & INFERENCES: These data recorded by SS manometry did not differ from WP manometry data. Regardless of the catheter used, both studies revealed an abnormal colonic response to a meal, indicating a pathology which is not related to the catheter used to record these data.

Prevalence of functional gastrointestinal disorders among adolescents in Buenos Aires, Argentina. / Prevalencia de los trastornos funcionales digestivos entre los adolescentes de Buenos Aires, Argentina.

INTRODUCTION AND AIMS: The prevalence of functional gastrointestinal disorders (FGIDs) in Argentinean children and adolescents has not yet been studied. Our aim was to determine the prevalence of FGIDs among children and adolescents in Argentina using the Rome III diagnostic criteria. MATERIALS AND METHODS: A total of 483 children, 12-18 years of age, from 3 private schools and 3 public schools, were included in the study. Each child completed the Spanish version of the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III), which is an age-appropriate and previously validated instrument for diagnosing FGIDs according to the Rome III criteria. Sociodemographic data (age, sex, type of school, family structure and size, family history of gastrointestinal disorders) and data on stressful life events were also obtained. RESULTS: The mean age of the population studied was 15 years (standard deviation 1.74, range 12-18, 52.8% boys). Of the respondents, 229 children (47.4%) attended private school and 254 children (52.6%) attended public school. In total, 82 children (17.0%) were diagnosed with an FGID, according to the Rome III criteria. Abdominal migraine (16.4%) was the most common diagnosis, followed by irritable bowel syndrome (7.0%), functional constipation (6.4%), and aerophagia (5.6%). Girls suffered significantly more from FGIDs than boys (22.4 vs. 12.2%, P=.0032). Children attending private school had significantly more FGIDs than children in public schools (20.5 vs. 13.8%, P=.0499). CONCLUSION: FGIDs are common among Argentinean children and adolescents.

Sacral neuromodulation versus personalized conservative treatment in patients with idiopathic slow-transit constipation: study protocol of the No.2-trial, a multicenter open-label randomized controlled trial and cost-effectiveness analysis.

PURPOSE: The evidence regarding the (cost-)effectiveness of sacral neuromodulation (SNM) in patients with therapy-resistant idiopathic slow-transit constipation is of suboptimal quality. The Dutch Ministry of Health, Welfare and Sports has granted conditional reimbursement for SNM treatment. The objective is to assess the effectiveness, cost-effectiveness, and budget impact of SNM compared to personalized conservative treatment (PCT) in patients with idiopathic slow-transit constipation refractory to conservative treatment. METHODS: This study is an open-label, multicenter randomized controlled trial. Patients aged 14 to 80 with slow-transit constipation, a defecation frequency (DF) < 3 per week and meeting at least one other Rome-IV criterion, are eligible. Patients with obstructed outlet, irritable bowel syndrome, bowel pathology, or rectal prolapse are excluded. Patients are randomized to SNM or PCT. The primary outcome is success at 6 months (DF ≥ 3 a week), requiring a sample size of 64 (α = 0.05, ß = 0.80, 30% difference in success). Secondary outcomes are straining, sense of incomplete evacuation, constipation severity, fatigue, constipation specific and generic quality of life, and costs at 6 months. Long-term costs and effectiveness will be estimated by a decision analytic model. The time frame is 57 months, starting October 2016. SNM treatment costs are funded by the Dutch conditional reimbursement program, research costs by Medtronic. CONCLUSIONS: The results of this trial will be used to make a final decision regarding reimbursement of SNM from the Dutch Health Care Package in this patient group. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov , identifier NCT02961582, on 12 October 2016.

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.

Sacral nerve stimulation for constipation and fecal incontinence in children: Long-term outcomes, patient benefit, and parent satisfaction.

OBJECTIVE: To evaluate the long-term efficacy of sacral nerve stimulation (SNS) in children with constipation and describe patient benefit and parent satisfaction. METHODS: Using a prospective patient registry, we identified patients <21 years old with constipation treated with SNS for >2 years. We compared symptoms, medical treatment, PedsQL Gastrointestinal Symptom Scale (GSS), Fecal Incontinence Quality of Life Scale (FIQL), and Fecal Incontinence Severity Index (FISI) before SNS and at follow-up. We contacted parents to administer the Glasgow Children's Benefit Inventory (GCBI) and a parent satisfaction questionnaire. KEY RESULTS: We included 25 children (52% male, median age 10 years): 16 had functional constipation, six anorectal malformation, two tethered spinal cord, and one Hirschsprung's disease. Defecation frequency did not change after SNS but patients reporting fecal incontinence decreased from 72% to 20% (P<.01) and urinary incontinence decreased from 56% to 28% (P=.04). Patients using laxatives decreased from 64% to 44% (ns) and patients using antegrade enemas decreased from 48% to 20% (P=.03). GSS, most FIQL domains, and FISI were improved at follow-up. Six (24%) patients had complications requiring further surgery. Of the 16 parents contacted, 15 (94%) parents indicated positive health-related benefit and all would recommend SNS to other families. CONCLUSIONS & INFERENCES: Sacral nerve stimulation is a promising and durable treatment for children with refractory constipation, and appears particularly effective in decreasing fecal incontinence. Although a quarter of patients experienced complications requiring additional surgery, nearly all parents reported health-related benefit. Future studies to identify predictors of treatment response and complications are needed.

Long-term outcome of intractable constipation treated by sacral neuromodulation: a comparison between children and adults.

AIM: Sacral neuromodulation (SNM) is a minimally invasive therapy for functional constipation (FC) and is most often used to treat adults. Recent studies suggest that SNM may also beneficial in children. However, comparative data regarding preferred age of SNM for FC are lacking. Therefore, long-term results of SNM for FC were compared between children and adults. METHOD: All patients treated with SNM for FC between 2004 and 2015 were evaluated. Outcomes of children (age 10-18 years) were compared with those for adults (≥ 18 years). The primary end-point was a defaecation frequency of three or more times per week, which is consistent with the ROME-III criteria. Secondary outcomes were quality of life (QoL; SF-36) and the Cleveland Clinic Constipation Score. RESULTS: One hundred and eighty patients (45 children, 135 adults) were eligible for SNM. The mean age was 15.8 (children) and 41.4 years (adults). One hundred and twenty-six patients received permanent SNM (38 children, 88 adults). Mean follow-up was 47 months in both groups. Defaecation frequency increased in both groups after SNM compared with baseline. Defaecation frequency in adults was higher than in children. The increased defaecation frequency was maintained during the entire follow-up period in both groups. QoL of children was impaired compared with the Dutch population with regard to bodily pain, general health and vitality. Adults had worse QoL with regard to physical functioning, bodily pain, general health, vitality and social functioning compared with the Dutch population. QoL of children did not differ from adults. CONCLUSION: Sacral neuromodulation (SNM) should be considered in children (< 18 years) with FC. However, the indication of SNM for FC remains debatable considering the limited improvements and high costs.

Brain processing of rectal sensation in adolescents with functional defecation disorders and healthy controls.

BACKGROUND: Decreased sensation of urge to defecate is often reported by children with functional constipation (FC) and functional nonretentive fecal incontinence (FNRFI). The aim of this cross-sectional study was to evaluate cerebral activity in response to rectal distension in adolescents with FC and FNRFI compared with healthy controls (HCs). METHODS: We included 15 adolescents with FC, 10 adolescents with FNRFI, and 15 young adult HCs. Rectal barostat was performed prior to functional magnetic resonance imaging (fMRI) to determine individual pressure thresholds for urge sensation. Subjects received 2 sessions of 5 × 30 seconds of barostat stimulation during the acquisition of blood oxygenation level-dependent fMRI. Functional magnetic resonance imaging signal differences were analyzed using SPM8 in Matlab. KEY RESULTS: Functional constipation and FNRFI patients had higher thresholds for urgency than HCs (P < .001). During rectal distension, FC patients showed activation in the anterior cingulate cortex, dorsolateral prefrontal cortex, inferior parietal lobule, and putamen. No activations were observed in controls and FNRFI patients. Functional nonretentive fecal incontinence patients showed deactivation in the hippocampus, parahippocampal gyrus, fusiform gyrus (FFG), lingual gyrus, posterior parietal cortex, and precentral gyrus. In HCs, deactivated areas were detected in the hippocampus, amygdala, FFG, insula, thalamus, precuneus, and primary somatosensory cortex. In contrast, no regions with significant deactivation were detected in FC patients. CONCLUSIONS & INFERENCES: Children with FC differ from children with FNRFI and HCs with respect to patterns of cerebral activation and deactivation during rectal distension. Functional nonretentive fecal incontinence patients seem to resemble HCs when it comes to brain processing of rectal distension.