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GADJAH MADA
UNIVERSITY
EBM of
Gastrointestinal diseases
What is Evidence-Based Medicine?
See a patient
Monitor the
change
Ask a question
Apply the evidence
Seek the best
evidence
Appraise that evidence
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Kekuatan Bukti Ilmiah
Ia
Ib
IIb
III
Uji pra klinik
IIa
IV
CS
CS
Meta
analisis
RCT
Non
randomized
trial
Quasi
exp
Observational
study
Expert
opinion
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Pharmacology of antidiarrhoeal: the myth
Directly increase
viscosity of stools
Delay food passage
Enough time for water
absorption in the intestine
• kaolin,
• pectin,
• bismuth subgallat
• opiate,
• anticholinergic
• Smooth muscle
depressant
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KAOLIN
Pharmacology
• composed of hydrated aluminium silicate.
• It is not absorbed when taken by mouth,
• is excreted in the stool
How they work
Claim:
• adsorbs toxins,
• alters bacterial flora and can 'coat' the intestinal lining
to produce a 'general protective effect'.
• appears to bind cholera toxin
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A study of 97 children with
acute diarrhoea
kaolin
Other Study (1970)
supportive therapy
kaolin
more 'formed' stools
no difference
• in the duration of diarrhoea,
• mean number of stools/ day,
• the clinical course of the
disease.
stool frequency or stool weight
the loss of water and salts in the
stools was not reduced.
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Adverse effects of kaolin-pectin combination
increased losses of sodium and potassium in the stool
•
•
worsen electrolyte disorders in children with severe
diarrhoea
increased fat and nitrogen losses in the stool.
Drug interactions
The effectiveness of trimethoprim, chloroquine and
pyremethamine, is reduced when they are given with kaolinpectin.
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Why kaolin does not cure diarrhoea
•
•
•
•
•
Organisms responsible for diarrhoea
Kaolin absorbs some bacterial toxins
Kaolin may partly coat intestinal wall
Kaolin is excreted in stool
Kaolin may make some stools look firmer
No correction of dehydration.
No action against germs
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Best evidence
“diarrhoea”, “diarrhea”, “rct”, “clinical trials”, “children”,
“child”, “kaolin”, “pectin”
3 Clinical trials involving 208 children
kaolin, pectin/kombinasi kaolin-pectin
Duration of diarrhoea
Average stools volume daily
OR= 0.82; 95% CI (0.64-2.74)
OR= 0.52; 95% CI (0.37-1.59)
Does not show better clinical outcome vs. placebo
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Atapulgit
To bind with glycoprotein on “mucus
lining” of gastrointestinal tract
Increases protective effects of “mucus barrier”
Claim
• to bind bacterial toxin in intestine,
• To adsorb fibrinogen & blood clotting factors,
• to form more firm stools
Shows effect as adsorbent only
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Best evidence
“diarrhoea”, “diarrhea”, “rct”, “clinical trials”,
“children”, “child”, “atapulgit”: 1970-2003
3 clinical trials involving 142 children
Length of diarrhoea & frequency/volume feces
2 studies: shorter duration
Duration of diarrhoea
Average volume of stools daily
1 study: difficult to assess (comb
OR= 0.79; 95% CI (0.411.87)
OR= 0.93; 95% CI (0.571.98)
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parameter
• Duration of diarrhoea
• Stools consistency
misleading
• Masking effect: not diarrhoea
• Dehydration remains
• Could not be detected
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Why attapulgite and smectite
adsorbents do not cure diarrhoea
• Absorb some fluid from intestinal cavity
• Organisms responsible for diarrhoea
• May make stools look firmer,
• No correction of dehydration.
• No action against germs
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activated charcoal
antidote in the emergency treatment of poisoning and
drug overdoses.
Dosage as antidiarrhoea: 1/100 dosage for treating poisoning
In combination with antacid or antimotility
1. Is not absorbed orally.
2. Adsorbent activity dependent on
a. Dosage and preparation,
b. Gastric acidity
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Activated charcoal
It adsorbs and inactivates a number of organic and inorganic
compounds by binding them in the gut
binds to and makes other drugs such as tetracycline
inactive, and affects digestive enzymes and intestinal
micronutrients
No longer recommended as antidiarrhoea
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Sulphonamides
Pharmacology
•
•
•
•
•
•
Non-absorbable
work mainly in the large intestine.
Absorption of sulphaguanidine by the body is slow and
erratic.
15 to 50 per cent is systematically absorbed and
excreted by the kidneys.
About 5 per cent of succinylsulphathiazole and
phthalylsulphathiazole is systematically absorbed.
Is mostly excreted in the stools
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Why non-absorbable sulphonamides
do not cure diarrhoea
• E. coli and cholera are mostly resistant to
sulphonamides
• Non absorbable sulphonamides cannot
penetrate intestinal wall and have limited
action upon Shigella bacteria
• Drug is mostly excreted in stool.
Diarrhoea and dehydration continue
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Loperamide
• Opioid synthetic analog,
• Poor oral absorption
• 40% oral dose will be excreted unchanged in the
stools, 10% in urine.
• Tmax: 5 hours (capsules); 2.5 hours (liquid)
• T1/2 7-12 hours
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Loperamide
Antimotility effect
•
•
•
•
• Inhibit prostaglandin stimulation in
bowel movement
Prolonged food transit in the gut
Reduce daily volume of stools
Increase viscosity and density of stools
Shorten duration of diarrhoea up to 24 hours
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Adverse effect of loperamide
•
•
•
•
•
•
•
•
•
Nausea, vomitus, drowsiness, dizziness, depression,
Blure vision, abdominal pain, headache
Nectoticans Enterocolitis,
Toxic megacolon,
Ileus paralysis,
Severe abdominal distension.
Babies death after its administration (drops).
Central Nerves Depression (at low dose, 0.1 mg/BW),
Coma (0,5 mg/kgBB).
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Risk & Benefit of antidiarrhoea
NNT = number needed to treat
NNH= number needed to harm
antidiarrhoe
NNT
NNH
Kaolin
Pectin
Atapulgit
Neomycin
Loperamida
TMP/SMX
Ciprofloxacin
Ofloxacin
12
14
9,2
10.7
5.3
7.5
13.4
11.8
5
9
3.2
5.4
2.1
3.8
4.4
3.2
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Table 1 Categories of evidence and recommendations
Evidence categories
I.
Based on well designed randomised controlled trials,
meta-analyses, or systematic reviews
II. Based on well designed cohort or case-control studies
III. Based on uncontrolled studies or consensus
Strength of recommendation categories
A.
B.
Directly based on category I evidence
Directly based on category II evidence or extrapolated
from category I evidence
C.
Directly based on category III evidence or extrapolated
from category I or II evidence
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"Antidiarrhoeal" drugs and antiemetics
• have no practical benefits for children with acute
or persistent diarrhoea.
• do not prevent dehydration or improve
nutritional status.
• Some have dangerous, and sometimes fatal,
side-effects.
• These drugs should never be given to children
below 5 years.
(Evidence level I, Recommendation A)
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Antimicrobials are reliably helpful only
• for children with bloody diarrhoea (probable
shigellosis),
• suspected cholera with severe dehydration,
(Evidence level I, Recommendation A).
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Recommendations regarding pharmacotherapy of
diarrhoeal disease in children
Evidence
Level of evidence &
recommendation
Infants and children with gastroenteritis should
not be treated with antidiarrhoeal agents
[I,A]
Most bacterial gastroenteritis does not require
or benefit from antibiotic treatment
[I,A]
Antibiotic treatment may be indicated for
salmonella gastroenteritis in the very young, in
immunocompromised patients, and in those
who are systemically ill
[III,C]
Patients with shigella dysentery should receive
antibiotic treatment
[I,A].
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Recommendations on assessment of
hydration
Evidence
Level of evidence &
recommendation
Assess risk of dehydration on the basis of
age (highest in young infants) and
frequency of watery stools and vomiting
[II,B]
Assess presence/severity of dehydration on
the basis of recent weight loss (if possible)
and clinical examination. Signs of proved
value in assessing dehydration include
“prolonged skinfold”, dry oral mucosa,
sunken eyes, and altered neurological
status
[I,A].
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Recommendations on fluid management
Evidence
Level of evidence &
recommendation
An ORS containing sodium 60 mmol/l,
glucose 90 mmol/l, potassium 20 mmol/l,
and citrate 10 mmol/l with an low
osmolality of 240 mmol/l is safe and
effective for the prevention and treatment
of dehydration in children with acute
gastroenteritis
[I,A]
In the vast majority of cases rehydration
should be carried out using ORT
[I,A]
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Recommendations on fluid management (cont’d)
Evidence
Rehydration should normally be completed
over a three to four hour period
a. “Mild” dehydration (3–5%): 30–50 ml/kg as
ORT over three to four hours
b. “Moderate” dehydration (5–10%): 50–100
ml/kg as ORT over three to four hours
c. “Severe” dehydration (10% +): 100–150
ml/kg as ORT over three to four hours
d. Reassess hydration immediately after
giving the estimated deficit
Severe dehydration with signs of shock: 20
ml/kg boluses of normal saline intravenously
Level of evidence &
recommendation
[II,B]
[III,C]
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Recommendations on fluid management (cont’d)
Evidence
Level of evidence &
recommendation
When organ perfusion is restored begin ORT.
In hypernatraemic dehydration,ORT is safer
than intravenous rehydration
[II,B]
In hypernatraemic dehydration use “slow
ORT”, aiming to complete rehydration over
12 hours, and monitor serum sodium to
avoid a rapid reduction
[III,C]
To prevent primary dehydration or recurrence
of dehydration, allow unrestricted fluids,
and in high risk cases either
(a) Alternate normal drinks (for example, milk
or water) with ORS, or
(b) give normal drinks and 10 ml/kg ORS
after each watery stool
[III,C],
[III,C].
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Recommendations on nutritional management
Evidence
Level of evidence &
recommendation
Breast feeding should continue through
rehydration and maintenance phases of
treatment
[II,C]
Formula feeds should be restarted after
completion of rehydration
[I,A]
If there is persistent diarrhoea after
reintroduction of feeds, evidence for lactose
intolerance should be sought. If the stool pH
is acid and contains more than 0.5%
reducing substances a lactose free formula
should be considered
[III,C].
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