Constipation in childhood what is new for pediatricians and dietitians?

Constipation in childhood what is new for pediatricians and dietitians? Jan Taminiau-Marc Benninga Emma Children s Hospital / AMC, Amsterdam / The Netherlands

Approach of the child Complaints History Findings Laboratory Therapeutic options Follow up

What to ask a patient History: Is it possibly constipation? Number of defecations per week Episodes of fecal incontinence per week Retentive posturing or excessive volitional stool retention History of painful or hard bowel movements History of large diameter stools which may obstruct the toilet Presence of a large fecal mass in the rectum

History Meconium production within 48 hours after birth Obstruction: Vomiting, bilious Pain after eating Poor appetite Malnutrition, weight loss Distended abdomen, ileus, bowel sounds Hirschsprung, explosive defecation, red face, once every week

Solitary rectal ulcer Usually adolescents takes 1-2 years on laxatives to cure

Laboratory investigations On indication not as screening Hypochromic anemia correlation to intake Hypothyroidism Hypercalcemia Salt loosing nephropathy, dehydration Celiac IgA TTG Stool cultures, calprotectin, elastase Mantoux Disaccharidases in duodenal biopsy

Investigations Flat X ray abdomen dilated loops Large bowel-small bowel Transit time, small and large bowel Lactulose breath test, small bowel transit Abdominal ultrasound Sigmoidoscopy Rectal biopsy Ano-rectal manometry to show a rectal inhibitory reflex with distension (small balloon insufflation)

Constipation Transit time normal 60% of constipated children Treatment trial and error

Transit time Initial X-Ray After swallowed rings X-Ray

Diagnosis Slow transit constipation With laxatives

Cochrane review correlation of investigations to clinical symptoms of constipation Abdominal radiography Colonic transit time (CTT) Rectal ultrasound scanning (US) for rectal diameter No correlation of clinical symptoms of constipation to fecal loading on Abdominal radiography, CTT or Rectal US Berger J Ped 2012

Rome IV diagnostic Criteria for Functional Constipation Children older than 4 years Must include 2 or more of the following occurring at least once per week for a minimum of 1 month with insufficient criteria for a diagnosis of irritable bowel syndrome: 2 or fewer defecations in the toilet per week At least 1 episode of fecal incontinence per week History of retentive posturing or excessive volitional stool retention History of painful or hard bowel movements Presence of a large fecal mass in the rectum History of large diameter stools that can obstruct the toilet

Rome IV Diagnostic Criteria for Functional Constipation Infants and toddlers up to the age of 4 Must include 1 month of at least 2 of the following: 2 or fewer defecations per week History of excessive stool retention History of painful or hard bowel movements History of large-diameter stools Presence of a large fecal mass in the rectum In toilet-trained children, the following additional criteria may be used: At least 1 episode/week of incontinence after the acquisition of toileting skills

Rome IV Diagnostic Criteria for Infant Dyschezia Must include in an infant <9 months of age: 1. At least 10 minutes of straining and crying before successful or unsuccessful passage of soft stools 2. No other health problems Infant with defecation discomfort: Uncomfortable defecation in infants is not identical to constipation Therapy: Dietary measures, cow s milk issue, soluble fiber

Rome IV diagnostic Criteria for Non-retentive Fecal Incontinence At least a 1-month history of the following symptoms in a child with a developmental age older than 4 years: 1. Defecation into places inappropriate to the sociocultural context 2. No evidence of fecal retention 3. After appropriate medical evaluation, the fecal incontinence cannot be explained by another medical condition

Treatment of children with functional non-retentive faecal incontinence (soiling) Explanation and support for the child and parents Non - accusatory approach Toilet training program with a rewarding system Biofeedback training no or only a minor role If necessary referral to a mental health professional is recommended

Average prevalence for children is 12 % 0-10% >10-20% >20-30% >30-40% Mugie SM, et al. Best Pract & Res Clin Gastroenterol 2011

0-10% Calabar Prevalence in schools >10-20% >20-30% >30-40% Mugie SM, et al. Best Pract & Res Clin Gastroenterol 2011

Age specific prevalence of functional constipation among adolescent Nigerians

Prevalence of constipation according to gender in Nigeria

CFC represents a significant burden on the health care system... Reported in two years in USA 1,7 (1.1%) million constipated children More outpatient visits and Emergency Dep visits More days of school missed Children with constipation: $3,374/year Children without: $1,096/year Total extra burden of childhood constipation 4 billion dollar/year in the US Liem O, et al. J Pediatr 2009

What keeps children constipated?

Behavior Mechanisms of Constipation Abuse Nerves, muscles, ICCs + Stress Food Genetics Sensation

Fibers Cow s milk Probiotics

Prevalence of constipation in pre-school children Underconsumption of plant foods? 368 children, 3-5 yrs (kindergarten) 28,8% constipation (Rome II criteria)! Median dietary fiber intake of constipated children was significantly lower than non-constipated children: 3.4 g/d vs. 3.8 g/d, p = 0.044 (weight ± 17 kg) Corresponding to 40% reference dietary fiber intake No difference in fluid intake Lee WT et al. J Pediatr Child Health 2007

Wheat Bran and Stool Weight: A Dose / Response 90 75 Increase in stool weight over baseline (g) 60 45 30 p<0.01 n-6 15 0 0 5 10 15 20 25 30 Wheat fiber (g) Stephen et al. Br J Nutr. 1986

Effect of Glucomannan 2.5 gr/d in the treatment of childhood constipation Median number / week 14 12 10 8 6 4 2 p = NS * * n=80 3-16 yr Baseline 4 weeks later 0 Defecation Gluc Defecation Placebo Chmielewska A, et al. Clin Nutr 2011

Success % Glucomannan vs placebo Rate of success 80 P=NS 70 60 50 40 30 20 10 0 56% 58% Gluco Placebo 95% CI 38%-72% 95% CI 41%-74% Chmielewska A, et al. Clin Nutr 2011

AFPFF 18 gr vs PEG 3350 + E 0.5 gr/kg as treatment for childhood constipation 70 60 50 AFPFF PEG 3350 NS Improvement Rate Def freq/w from 2-4 40 30 20 10 0 N = 100 6.5 ± 2.7 yrs Enrolment 2 weeks 4 weeks 8 weeks AFPFF (Acacia fiberpsyllium fiber-fructose) Quitadamo P, et al. J Pediatr 2012

RCT: plums(prunes) vs. psyllium(6gram) for Constipation in adults The laxative effects of plums a combination: sorbitol (14.7g 100g) dietary fiber (6g 100g) polyphenols (184 mg 100g) exact mechanism has not been established plums softer stools less staining Attalauri et al. Aliment Pharmacol Ther 2011

Effectiveness of using a behavioral intervention to improve dietary fiber intake in children with constipation No significant benefit was demonstrated in terms of a reduction in laxative use or increased stool frequency associated with additional fiber intake!!!!! CG 10 grams IG 14 grams Sullivan PB, et al. J Hum Nutr Diet, 2011

Have to eat 30 grams of fiber 1.5 kilogram of fruits daily

IBS children Healthy children Haemophilus parainfluenzae Ruminococcus Alistipes Prominent in IBS Saulnier DM, et al. Gastroenterology 2011

Constipation Rationale for the use of probiotics Differences in the intestinal microbiota in healthy and constipated subjects bifidobacteria non-pathogenic E coli, bacteroides total number of microorganisms Improved transit time Several studies involving B. animalis DN 173 010 Zoppi G, et al. Acta Paediatr 1998 Salminen S, et al. Scand J Gastro 1997 Picard C, et et al. Aliment Pharmacol Ther 2005

Functional constipation in children Bifidum bacterium lactis DN 173010 Functional constipation (Rome III criteria) Aged 3 to 16 y N=159 N=79 B lactis DN-173 010 1.2x10 10 CFU Orally BID, for 3 weeks N=80 Placebo Orally, for 3 weeks N=74 ITT analysis N=74 ITT analysis Tabbers MM et al. Pediatrics 2011

Primary outcome The change in stool frequency from baseline to after 3 wk of product consumption Probiotic group n = 74 Control group n = 74 MD 0.3 (95% CI -1.45 to 0.51) P=0.35 Tabbers MM et al. Pediatrics 2011

Secondary outcome Success rate 3 BM per wk and <1 fecal incontinence episodes in 2 wk 40% 30% 38% 24% Probiotic group n = 74 20% 10% Control group n = 74 0 RR 1.6 (95% CI 0.97 to 2.7) P=0.06 Tabbers MM et al. Pediatrics 2011

Functional constipation in children B lactis DN 173010 In constipated children, the fermented dairy product containing B lactis DN-173 010 did increase stool frequency, but this increase was comparable in the control group Insufficient evidence to recommend fermented dairy products containing B lactis strain DN-173 010 in this category of patients Tabbers et al. Pediatrics 2011.

Probiotics for functional constipation RCTs in children - summary Reference Probiotic Constipation N Effect Banaszkiewicz & Szajewska 2005 Bu et al. 2007 Coccorullo et al. 2010 LGG L casei rhamnosus Lcr35 <3 BM per wk for at least 12 wk <3 BM per wk for >2 mo 60 NS 27 (?) L reuteri DSM 17938 Rome III criteria 44 Tabbers et al. 2011 B lactis DN 173010 Rome III criteria 160 NS Guerra et al. 2011 B longum Rome III criteria 59 Total 350

A vicious circle of learned behavior Large hard stools stools Large / hard Pain Pain Stool Stoolwithholding behavior withholding behavior Van Dijk M, et al. Pediatrics 2009

Biofeedback training in the treatment of childhood constipation: a RCT 80 NS 60 40 33% 32% 52% 47% 59% 50% 57% 48% 20 0 6 weeks 6 months 1 year 1.5 year CT (N = 94) CT + BF (n = 98) Van der Plas RN, et al. Lancet 1996

Behavioral therapy for childhood constipation: a randomized, controlled trial Defecation frequency per week Baseline Posttreatment Follow-up CT 2.2 7.5 6.3 BT 2.2 5.5 5.7 * *p=.025 Fecal incontinence frequency per week Baseline Posttreatment Follow-up CT 15.6 1.6 2.8 BT 15.5 1.8 3.4 NS Success (%) Posttreatment Follow-up CT 62.9 63.3 BT 57.2 53.6 NS

Behavioral therapy for childhood constipation: a randomized, controlled trial Behavioral therapy with laxatives has no advantage over CT in treating childhood constipation Behavioral therapy was focused on removing fear for defecation, aggressive behavior more related However, when behavior problems are present, behavioral therapy or referral to mental health services should be considered, might shorten treatment period Van Dijk M, et al. Pediatrics 2008

Pediatric constipation: current treatment strategies New drugs Pelvic floor surgery Colectomy or Stoma (inc. anterograde irrigation) % patients Diagnosis (exclusion of organic pathology) Lifestyle modifications Diet, fluid, exercise Oral and / or rectal laxatives Nurse-led Bowel retraining +/- biofeedback Transabdominal electrical stimulation Sacral nerve stimulation time

4 STEPS Education / demystification / toilet training Disimpaction Maintenance Follow-up NASPGHAN guidelines, JPGN, 2006

Baseline characteristics Enema PEG p-value Number 46 44 Male 29 31 Age in years 7.9±2.9 7.2±2.6 Defecation/wk 1.9±1.9 1.5±1.2 0.46 Symptom duration (years) 5.2±3.3 4.7±2.8 0.29 Daytime fecal incontinence/wk 15.7±13.1 16.6±12.4 0.13 Night time fecal incontinence 28% 34% 0.70 Abdominal pain 48% 64% 0.37 Watery stools 4% 9% 0.18 Bekkali et al, J Pediatr 2009

Results 6 days daily enemas or 6 days 1.5 gr PEG daily Enemas n=46 PEG n=44 Drop-outs n=5 Successful disimpaction n=37 80% Successful disimpaction n=30 68% Drop-outs n=5 *chi 2 statistics p=0.28 (ITT) Bekkali et al, J Pediatr 2009

Defecation Defecation frequency/ wk (±SE) ns Intake * ns Disimpaction Enema PEG

Fecal incontinence / wk Fecal incontinence * ns * Enema PEG Intake Disimpaction

Adverse events % 70 ns 60 50 40 30 20 10 Enema PEG Abdominal pain

Adverse events % 90 80 70 60 50 40 30 20 10 ns Enema PEG Anxiety

One Enema followed by oral Clean out versus oral clean out Miller KM, et al. Ped Emer Care 2012

Enema versus oral Clean out P = 0.05 49% vs 28%; no stools since ED discharge in the enema arm Miller KM, et al. Ped Emer Care 2012

Enema versus oral Clean out 54% of children in the enema arm were reported as somewhat upset or very upset by the therapy No children in the oral cleanout arm were upset (P < 0.05) The majority of all families (95%) reported their ED visit was very helpful. Miller KM, et al. Ped Emer Care 2012

2011

Stool Frequency per Week Cochrane Database Syst Rev 2011

Lactulose versus PEG Polyethylene glycol is better than lactulose in outcomes of: Stool frequency per week Form of stool Relief of abdominal pain Need for additional medication Polyethylene Glycol should be used in preference to Lactulose in the treatment of Chronic Constipation Cochrane Database Syst Rev 2011

Percentage Long term Follow-up and constipation 100 80 60 40 20 No succes lax+ No succes lax- Succes lax+ Succes lax- 0 0,5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time of follow-up (years) Bongers et al. Pediatrics 2010

One year treatment of childhood constipation PEG 3350 with electrolytes vs PEG 4000 A double blind RCT N = 97 (age 6 16 years) Children defecation freq < 3/wk + at least one other Rome III criterion 12 month-treatment Bekkali N et al DDW 2012;A1398

Percentage One year treatment of childhood constipation PEG 3350 with electrolytes vs PEG 4000 A double blind RCT 80 60 40 20 0 NS Success percentage at 12 months PEG 3350 PEG 4000 Bekkali N et al DDW 2012;A1398

Percentage Enemas versus oral laxatives for one year in children with chronic constipation: RCT 80 NS E 60 40 20 CT 0 3 6 9 12 Months Bongers M et al. Clin Gastroenterol Hepatol. 2009

Long-term effects of transabdominal electrical stimulation in treating children with slow-transit constipation 39 patients with STC (12-18 yrs) 9-V battery-operated interferential stimulating machine 2 electrodes on the anterior adominal wall and 2 electrodes placed on the back between T9 and L2 on either side Physiotherapists administered 1 to 2 months of TES to 39 children (20 minutes, 3 times a week) 15 continued to self-administer TES (30 minutes daily for more than 2 months) Ismail et al. J Pediatr Surg 2009 Leong et al. J Pediatr Surg 2011

Long-term effects of transabdominal electrical stimulation in treating children with slow-transit constipation Leong et al. J Pediatr Surg 2011

Long-term effects of transabdominal electrical stimulation in treating children with slow-transit constipation 73% of patients perceived improvement, lasting more than 2 years in 33% and less than 6 months in 25% to 33% Perception of urge initiated defecations improved 80% from nil Leong et al. J Pediatr Surg 2011

Sacral nerve stimulation Introduced as therapy in urology Indications: overactive bladder symptoms urgency incontinence urinary retention fecal incontinence pelvic floor dysfunction constipation

Sacral Neuromodulation Therapy: A Promising Treatment for Adolescents With Refractory Functional Constipation Patients fulfilled Rome III criteria for functional constipation Not responding to intensive conservative treatment (oral and/or rectal laxatives, or colonic lavage, and behavioral approaches) No urge to defecate, no spontaneous defecation 30 girls, median age of 15.2 years (range, 10 18) Median therapy duration at time of inclusion was 7 years (range, 1 17 years)

Sacral Neuromodulation Therapy: A Promising Treatment for Adolescents With Refractory Functional Constipation A tined lead is inserted through needle Needle removed 1 4 weeks testing period with external device Permanent neuromodulator Van Wunnik et al Dis Colon Rect 2012

Defecation frequency per week Follow-up (months)

Abdominal pain Follow-up (months

Sacral Neuromodulation Therapy: Conclusion SNM seems to be an effective short-term treatment in adolescents with chronic functional constipation refractory to intensive conservative treatment Improvement of defecation frequency, urge to defecate and reduction of severe abdominal pain Sustained effects up to 2 years However longer term follow up is warranted Van Wunnik et al Dis Colon Rect 2012

120 sensor fiber optic catheter

Mid ascending colon Colonic respons to sacral nerve stimulation in constipation SNS Splenic flexure sigmoid colon 60min Dinning et al. Br J Surg 2012

NEW DRUGS in the pipeline

New and emerging drugs for constipation Ileal bile acid A3309 Stimulates propulsive motility Phase IIb transporter inhibitor and fluid secretion

Efficacy in chronic constipation: 3 SCBM/week % subjects with an average of 3 SCBM per week over 12 weeks (normalisation) 35% 30% 28.9*** 28.9*** 25% 23.6*** 24.7*** 23.6*** 23.9** 23.5** 20% 19.5** 15% 10% 11.3 9.6 12.1 13.0 5% 0% n=236 n=214 n=190 Pooled data INT -6 USA -13 USA -11 Placebo PRU 2 mg PRU 4 mg **p<0.01 vs. placebo ***p<0.001 vs. placebo Camilleri et al. N Engl J Med 2008 Tack et al. Gut 2009 E Quigley et al. Aliment Pharmacol Ther 2009

Prucalopride in children with constipation 37 subjects (24M/13F) ages 4 to 12 years enrolled In case of impaction, a clean-out was completed before entry 0.01 to 0.03 mg/kg/day PRU oral solution Treatment for 8 weeks Evaluation of Efficacy, Safety and Tolerability Winter H. et al. DDW 2009;A

Prucalopride in children with constipation PRU at doses of 0.01 to 0.03 mg/kg/day for 8 weeks in children aged 4 to 12 years with functional constipation appears to be Safe Efficacious Children who were passing < 3 BM/week had a rapid response to PRU and passed an average of 1 BM/day within one week of starting therapy Well tolerated Most frequently reported AEs: headache (24%), abdominal pain (22%), upper respiratory tract infection (19%) Most AEs were:mild and moderate in severity often associated with the highest dose of PRU Winter H. et al. DDW 2009;A

Common osmotic laxatives in children Laxative Dosage Side Effects Lactulose 1-3 ml/kg 1 or 2 times daily Flatulence, abdominal pain Lactitol 5-40 gr 1 or 2 times daily Flatulence, abdominal pain Magnesium oxide 500-2000 mgr/day Hypermagnesaemia due to concurrent renal failure Milk of magnesia >6 months: 1-3 ml/kg/day (divide into 1-2 doses) See previous PEG 3350-4000 maintenance 0.26-0.84 gr/kg/day Loose stools, bad taste (PEG+additional electrolytes) PEG 3350 disimpaction 1-1.5 gr/kg/day See previous Mineral oil (liquid paraffin) >12 months: 1-3 ml/kg/day Bad taste, anal leakage, aspiration pneumonia < 12 months

Stimulant laxatives Stimulant laxatives Bisacodyl Senna Sodium picosulfate Dosages 3-10 y: 5 mg /day > 10 y: 5-10 mg /day 2-6 y: 2.5-5 mg once or twice/day 6-12 y: 7.5-10 mg /day > 12 y: 15-20 mg /day 1 month-4 y: 2.5-10 mg once/day 4-18 y: 2.5-20 mg once/day

Enemas Rectal laxatives/enemas Bisacodyl Sodium docusate Sodium phosphate Dosages 2-10 y: 5 mg once /day > 10 y: 5-10 mg once /day < 6 y: 60 ml > 6 y: 120 ml 1-18 y: 2.5 ml/kg, max. 133 ml/dose NaCl Mineral oil neonate < 1 kg: 5ml, > 1kg: 10 ml > 1 y: 6 ml/kg once or twice/day 2-11 y: 30-60 ml once/day > 11 y: 60-150 ml once/day

Percentage Long term Follow-up and constipation 100 80 60 40 20 No succes lax+ No succes lax- Succes lax+ Succes lax- 0 0,5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time of follow-up (years) Bongers et al. Pediatrics 2010

Conclusions The role of fibre remains uncertain The role of the microbiome should be explored Probiotics are not recommended Stool withholding behaviour important in young children PEG is the first choice as maintenance Enemas have no role as maintenance treatment TES and SNS are promising New drugs such as prucalopride, linaclotide and lubiprostone are promising in adults but should be tested in children with constipation

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