Knmp congres 4okt-1500u-marc benninga

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Knmp congres 4okt-1500u-marc benninga

  1. 1. Obstipatie en laxeermiddelen onder de loep Marc Benninga, kinderarts maag-darm-leverziekten Emmakinderziekenhuis/AMC, Amsterdam
  2. 2. Objectives• What is constipation• Pathophysiology• Treatment
  3. 3. Functional ConstipationAt least a 2 month history of at least two of the following 6 criteria:1) 2 or fewer defecations/wk, developmental age of at least 4 yrs;2) At least one episode of fecal incontinence/wk;3) Retentive posturing or excessive volitional stool retention;4) History of painful or hard bowel movements;5) History of large diameter stools which may obstruct the toilet;6) Presence of a large fecal mass in the rectum Rasquin et al. Gastroenterology 2006
  4. 4. Prevalence of constipation
  5. 5. 0-10%>10-20%>20-30%>30-40% Mugie et al. Best Pract & Res Clin Gastroenterol 2011
  6. 6. Childhood functional constipation is a common disease….• Occurs in 0.3-8% of the pediatric population and in 5-10% of school age children• Represents 3% of visits to pediatricians and 25% of visits to pediatric gastroenterologists• Age: 40% of children with constipation develop symptoms during the first year of life• Gender boys > girls
  7. 7. Childhood functional constipation represents a significant burden on the health care system• 1.7 (1.1%) million constipated children• More outpatients visits and ED visits• More days of school missed• Children with constipation: $ 3074 / yr• Children without: $ 1096 / yr Total extra burden of childhood constipation 4 billion dollar/yr in the US!!! Liem et al. J Pediatr 2009
  8. 8. Symptoms of Functional Constipation (%) Defecation frequency < 3/wk 34 Fecal incontinence 69 Retentive posturing 58 Painful defecation 69 Large diameter stools 62 Presence of a large fecal mass 41 Boccia et al. J Pediatr 2007
  9. 9. Fecal incontinence Organic (10%) Functional (90%)• Neurologic damage• Anal sphincter anomalies• functional constipation 80% • non-retentive fecal incontinence 20% JPGN 2005
  10. 10. behavior colon rectum sphincter food
  11. 11. Withholding behavior Fissure Painful defecationHard stools Fear Withholding Life events???: • Divorce • Death • Sexual abuse
  12. 12. Treatment• Education / demystification / toilet training• Disimpaction• Maintenance• Follow-up NASPGHAN JPGN 2006
  13. 13. Chronic constipation: Medical and surgical management Colectomy or Stoma (inc. Pelvic floor anterograde surgery irrigation) Nurse-led% patients Bowel Sacral nerve retraining stimulation Oral +/- and / or biofeedback Lifestyle rectal modifications laxatives Diet, fluid, Diagnosis exercise (exclusion of organic pathology) time
  14. 14. Arch Dis Child. 2009;94:117-31
  15. 15. Effect of Glucomannan in the treatment of childhood constipation 14 14 12 12 n=80 10 10 Baseline 8 8Median number 4 weeks later / week 6 p = NS 6 4 4 2 2 * * 0 0 Defecation Defecation Gluc Placebo Chmielewska A, et al. Clin Nutr 2011
  16. 16. Rate of success P=NS 80 70 60Success % 50 40 95% CI 38%-72% 30 95% CI 41%-74% 20 56% 58% 10 0 Gluco Placebo Chmielewska A, et al. Clin Nutr 2011
  17. 17. RCT: plums(prunes) vs. psyllium for constipation The laxative effects a combination: • sorbitol (14.7 g ⁄ 100 g) • dietary fibre (6 g ⁄ 100 • polyphenols (184 mg⁄ 100 g) • exact mechanism has not been established Attalauri et al. Aliment Pharmacol Ther 2011
  18. 18. BackgroundProbiotics & effects on constipation symptoms:• Enhance peristalsis of the colon and consequently decrease colonic transit time• Soften stools by stimulating water and electrolyte secretion Moro et al. JPGN 2002, Picard. Aliment Pharmacol Ther 2005, Bouvier M. Bioscience and microflora 2001, Marteau et al. Aliment Pharmacol Ther 2002
  19. 19. Methods (1)• Double-blind, placebo-controlled randomised multicentre, two nation (the Netherlands and Poland) trial• 160 children, age 3-16 years, with a defecation frequency < 3/weekAND Fulfilling ≥ 1 of the other Rome-III criteria: fecal incontinence > 1/week, large amount of stools which clog the toilet, painful defecation, withholding behavior, abdominal or rectal fecal impaction
  20. 20. Primary outcome The stool frequency change from baseline to 3 weeks of product consumption 2.9 in probiotic group vs 2.6 in placebo, P=0.35 7Defecation / week 6 5 Baseline 4 3 weeks 3 2 1 0 Probiotics Placebo
  21. 21. Rate of success P=0.06 40 35 30 RR 1.61, 95% CI 0.98Success % 25 20 to 2.69 15 24% 38% Number needed to 10 5 treat of 7 0 Placebo Probiotics Tabbers et al. Pediatrics 2011
  22. 22. `Until more data are available, we believe the use of probiotics for the treatment of constipation condition should be considered investigational` 2010
  23. 23. Baseline characteristics Enema PEG p-valueNumber 46 44Male 29 31Age in years 7.9±2.9 7.2±2.6Defecation/wk 1.9±1.9 1.5±1.2 0.46Symptom duration (years) 5.2±3.3 4.7±2.8 0.29Daytime fecal incontinence/wk 15.7±13.1 16.6±12.4 0.13Night time fecal incontinence 28% 34% 0.70Abdominal pain 48% 64% 0.37Watery stools 4% 9% 0.18 Bekkali et al, J Pediatr 2009
  24. 24. Results Enemas PEG n=46 n=44Drop-outs Successful disimpaction Successful disimpaction Drop-outs n=5 n=37 n=30 n=5 80% 68%*chi2 statistics p=0.28 (ITT)
  25. 25. Defecation * EnemaDefecation frequency/ ns ns PEGwk (±SE) Intake Disimpaction
  26. 26. Fecal incontinence *Fecal incontinence / wk Enema ns * PEG Intake Disimpaction
  27. 27. Adverse events 70 60 ns% Enema 50 40 PEG 30 20 10 Abdominal pain
  28. 28. Adverse events 90 ns 80 70 Enema 60% 50 PEG 40 30 20 10 Anxiety
  29. 29. Maintenance therapy
  30. 30. PEG and childhood constipationAuthors Journal Year Pts DrugsPashankar J Pediatr 2001 24 PEGLoening JPGN 2002 49 PEG vs MoMGremse Clin Ped 2002 37 PEG vs lactulosePashankar APAM 2003 83 PEGPashankar Clin Ped 2003 73 PEGMichail JPGN 2004 28 PEGLoening JPGN 2004 74 PEGVoskuijl Gut 2004 90 PEG vs lactuloseDupont JPGN 2005/2006 96 PEG vs lactuloseRendelli APT 2006 76 PEG vs lactuloseLoening Pediatr 2006 79 PEG vs MOMThomson JPGN 2007 47 PEG vs placebo!Nurko J Pediatr 2008 103 Peg vs placebo
  31. 31. Motility center
  32. 32. Effect of PEG 3350 With Electrolytes vs Lactulose 14 *p<0.05 Baseline 12 n=91 8 weeks later 10 Median 8number / 6 week 4 * * * * 2 0 Def Def FI FI PEG 3350 Lactulose PEG 3350 Lactulose Voskuijl WP, et al. Gut 2004; 53:1590
  33. 33. Side effects after 8 weeks % patients with side effects 80 * p<0.05 60 Transipeg 40 * * * Lactulose 20 * 0 Abdominal Straining Pain Bad taste pain No difference: diarrhea, stool consistency, nausea, bloating, flatulence difference: diarrhea, stool consistency,
  34. 34. PEG 3350 for constipation in children younger than 18 months old75 Infants 0 – 17 months• Initial 0,9 g/kg/day (0,26-2,14)• Maintenance 0.8 g/kg/day (0,26-1,26)• Duration of therapy (3 wks – 21 months)• Relieve of constipation 97,6% ?????? Loening-Baucke et al. JPGN 2004
  35. 35. Effective dose PEG 4000 per age group Age category Dosage Range 6 – 12 months 4g (2.5-5g) 13 m – 3 years 6g (4-7,4g) 4 – 7 years 12g (7-16g) 8 – 15 years 16g (16-24g) 0.5 g/kg! Dupont et al. JPGN 2006
  36. 36. Efficacy per age group after 3 months of treatmentAge category Efficacy6 – 12 months 100% (15/15)13 m – 3 years 90% (27/30)4 – 7 years 93% (26/28)8 – 15 years 91% (21/23) Dupont et al. JPGN 2006
  37. 37. PEG 4000 versus Lactulose Safety in children Laboratory results: - HCO3-- , Na+, K+, Cl-- 3 + + - Creatinin, Osmolality, Albumin, Total protein, Iron, Vita a Folates, Vitdd - Hb, Ht No changes after 3 or 12 months of therapy Pashankar et al. Arch Pediatr Adolesc Med 2003, Dupont et al. JPGN 2005
  38. 38. Safety of high-dose PEG+E case report 33 month child ingested 160mg/kg iron Whole bowel lavage with PEG+E performed over 5 days Total volume administered: 44.3 litres No clinical adverse events and no electrolyte abnormalities detected Child made full recovery Kaczorowski JM et al. Ann Emerg Med 1996
  39. 39. PEG intestinal lavage and aspiration in a7-year old boy with severe constipation • Vomiting results in migration of the ng-tube • Recheck ng-position Wong et al. Arch Dis Child 2002 Liangthanasarn et al. JPGN 2003
  40. 40. Adults Bisacodyl Children Price KJ Elliot TM Cochrane Database Syst Rev 2001;3, What is the Role of Stimulant Laxatives in the Management of Childhood Constipation and Soiling? SELECTION CRITERIA: All identified randomised controlled trials (RCTs) which compare the administering of stimulant laxatives to children with either placebo or alternative treatment. DATA COLLECTION AND ANALYSIS: No trials were found that met the selection criteria.
  41. 41. Protocol• Randomization stratified by age and gender• 1 year: 1) conventional treatment (CT): - education - 0.5 – 1.5 g/kg polyethylene glycol - behavioral modification 2) Additional treatment with rectal enemas: - 3/week first 3 months; reduced by 1 enema/week every 3 months
  42. 42. Intake Characteristics CT (n=50) ATE (n=50)Boys % 66 64Age at baseline, y 11.0 10.5medianDuration of symptoms, y 7.0 6.5medianDef. freq / week 1.0 1.5medianFI freq / week 7.0 7.5median
  43. 43. Defecation frequency NS 25 P= <.001* P= <.001*times per week 20 15 10 5 0 baseline one year baseline one year CT ATE
  44. 44. Fecal incontinence NS P= <.001* P= <.001* 45times per week 40 35 30 25 20 15 10 5 0 baseline one year baseline one year CT ATE
  45. 45. Success during one year 80 NS ATE 60 CTPercentage 40 20 0 3 6 9 12 Months
  46. 46. Conclusions• No additional effect of rectal enemas in treatment of functional constipation• Rectal enemas have no role in maintenance therapy• Development of new treatment compounds for childhood constipation is needed
  47. 47. Side effects of enemas• Related to water and electrolyte disturbances resulting from: − Hyperphosphataemia − Hypocalcaemia − Hypernatraemia − Metabolic acidosis• Absorptive effect of enema components and to their inadequate elimination in patients with co- morbidities Mendoza J et al. Aliment Pharmacol Ther 2007
  48. 48. Problem???
  49. 49. Are constipation drugs effective and safe to be used in children?: a review of the literature• Lack of large well-designed placebo controlled trials in childhood constipation• Any interpretation with regards to the evidence for the effectiveness or safety of laxatives used in children is difficult• Serious side effects of laxatives in children are rarely reported; however, evidence for the safety of short- and long-term use of laxatives in children with constipation is limited Van Wering et al. Expert Opin Drug Saf 2011
  50. 50. NEW DRUGS in the pipeline!
  51. 51. 5-HT4 RECEPTOR AGONISTS Selectivity of agonists Receptor binding profile at therapeutic concentrationsClass Drug 5-HT4 5-HT3 5-HT2 5-HT1 D2 hERG Cisapride + + + + Renzapride + +Benzamide Clebopride + + + Mosapride + + Naronapride + Tegaserod + + +Carbazimide Velusetrag +Benzofurane Prucalopride +
  52. 52. Pooled data: Response maintained over the 12 week treatment period50%45% placebo pru 2mg pru 4mg40%35%30%25%20%15%10%5%0% run-in Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 % subjects with ≥3 SCMB/week
  53. 53. PRUCALOPRIDE Safety and tolerability: adverse events Most common drug-related adverse events 30 Placebo (n=661) Prucalopride 2 mg (n=659) Prucalopride 4 mg (n=657)0 25 20Patients (%) 15 10 5 0 e e l l a a in na in na a a ch ch oe oe se se pa mi pa mi da da rrh rrh au au do do ea ea ia ia N N Ab Ab D D H H Events during treatment period Events excluding Day 1 Tack et al. Gastroenterology 2008
  54. 54. Efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipationGoldberg M et al. Aliment Pharmacol Ther 2010
  55. 55. The Role of Chloride Channels in Intestinal Transport• Lubiprostone is a bicyclic functional fatty acid• Selectively activates chloride channel-2 (CIC-2) – Enhance intestinal fluid secretion – Facilitate increased motility• FDA approved in January 2006 Lubiprostone
  56. 56. Effects of Lubiprostone on Number of Spontaneous Bowel Movements 7 p = 0.0001 p = 0.0017 p = 0.0002 p = 0.0002 6 5 24 µg lubiprostone BID Bowel 4movements per week 3 Placebo 2 1 n = 242 Intent-to-treat population 0 Baseline Week 1 Week 2 Week 3 Week 4 Johanson et al. Am J Gastroenterol 2008
  57. 57. Long-Term Safety and Effectiveness of Lubiprostone, in Patients with Chronic Idiopathic Constipation Parkman et al. Dig Dis Sci 2011
  58. 58. Linaclotide
  59. 59. Two Randomized Trials of Linaclotide for Chronic Constipation Primary end point: N = 1276 >3 CSBMs per week Lembo et al. New Eng J Med 2011
  60. 60. Adverse effects of Linaclotidein patients with Chronic Constipation Lembo et al. New Eng J Med 2011
  61. 61. Long-term follow-up offunctional constipation
  62. 62. Primary care physicians• After 2 months of treatment 40% remains symptomatic• Primary care physicians tend to undertreat• Colonic evacuation with laxatives were more likely to respond Borowitz et al. Pediatrics 2005
  63. 63. Clinical outcome at follow up N = 47, median age 3,5 months 100Cumulative success percentage (%) 80 60 *= p 0.002 40 20 < 3 months symptoms 0 > 3 months symptoms 0 6 12 18 24 30 36 Time until first success (months) Vanden Berg et al. J Pediatr 2006
  64. 64. Results Outcome with and without laxatives 190 190 188 187 183 188 186 174 165 154 137 126 115 76 24 1 Number included 3 2 3 3 6 0 0 5 3 3 3 2 1 0 0 0 Number missing 100 80 No succes lax+ No succes lax-Percentage 60 Succes lax+ Succes lax- 40 20 0 0,5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time of follow-up (years)
  65. 65. Summary and Conclusions• Constipation is a common entity in childhood constipation• Early and long-lasting treatment with oral laxatives is necessary in the majority of children with constipation• Serious side effects of oral and rectal laxatives are rarely reported

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