3. Functional Constipation
At 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
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. 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. 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
18. Effect of Glucomannan in the treatment
of childhood constipation
14
14
12
12
n=80
10
10
Baseline
8
8
Median 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
19. Rate of success
P=NS
80
70
60
Success %
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
21. 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
22. Background
Probiotics & 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
25. 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/week
AND
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
26. 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
7
Defecation / week
6
5 Baseline
4 3 weeks
3
2
1
0
Probiotics Placebo
27. Rate of success
P=0.06
40
35
30
RR 1.61, 95% CI 0.98
Success %
25
20 to 2.69
15
24% 38% Number needed to
10
5
treat of 7
0
Placebo Probiotics
Tabbers et al. Pediatrics 2011
28. `Until more data are available, we
believe the use of probiotics for
the treatment of constipation
condition should be considered
investigational`
2010
30. 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
40. Effect of PEG 3350 With Electrolytes vs Lactulose
14
*p<0.05 Baseline
12
n=91 8 weeks later
10
Median 8
number / 6
week 4 * * * *
2
0
Def Def FI FI
PEG 3350 Lactulose PEG 3350 Lactulose
Voskuijl WP, et al. Gut 2004; 53:1590
42. 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,
43. PEG 3350 for constipation in children
younger than 18 months old
75 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
44. 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
45. Efficacy per age group
after 3 months of treatment
Age category Efficacy
6 – 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
46. 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
47. 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
48. PEG intestinal lavage and aspiration in a
7-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
49. 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.
51. 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
52. Intake Characteristics
CT (n=50) ATE (n=50)
Boys % 66 64
Age at baseline, y 11.0 10.5
median
Duration of symptoms, y 7.0 6.5
median
Def. freq / week 1.0 1.5
median
FI freq / week 7.0 7.5
median
53. Defecation frequency
NS
25 P= <.001* P= <.001*
times per week
20
15
10
5
0
baseline one year baseline one year
CT ATE
54. Fecal incontinence
NS
P= <.001* P= <.001*
45
times per week
40
35
30
25
20
15
10
5
0
baseline one year baseline one year
CT ATE
55. Success during one year
80 NS ATE
60 CT
Percentage
40
20
0
3 6 9 12
Months
56. 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
57. 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
59. 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
64. 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
20
Patients
(%)
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
65. Efficacy and tolerability of velusetrag, a selective 5-HT4 agonist
with high intrinsic activity, in chronic idiopathic constipation
Goldberg M et al. Aliment Pharmacol Ther 2010
66. 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
67. 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 4
movements
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
68. Long-Term Safety and Effectiveness of Lubiprostone, in Patients
with Chronic Idiopathic Constipation
Parkman et al. Dig Dis Sci 2011
73. 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
74. Clinical outcome at follow up
N = 47, median age 3,5 months
100
Cumulative 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
75. 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)
76. 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