A Critical Appraisal of meta analysis of the article "early vs late refeeding in children with acute diarrhea"

2. Dr. Shubhra Prakash Paul
MD (Ped.) Part II
Bangladesh Institute of Child Health

3. Title
Early versus Delayed
Refeeding for Children
with Acute Diarrhoea
(Intervention Review)

4. Article Particulars
Gregorio GV, Dans
Authors
LF, Silvestre MA
Evidence-based Child
Health: a Cochrane Review
Journal
Journal
2012; 7:2: 721–757.
DOI 10.1002/ebch.1835

5. Background
 Acute diarrhea is one of the principal
causes of morbidity and mortality among
children in developing countries.
 Oral rehydration therapy and dietary
management is the cornerstone of
treatment.
 There is a lack of data and studies on
both the timing and type of feeding that
should be adopted during the course of
the illness.

6. Objective
To compare the efficacy and safety
of early and late reintroduction of
feeding in children with acute
diarrhea.

7. Methodology
Criteria for considering studies for
this review
I. Types of studies
Randomized Controlled Trial (RCT)
II. Types of participants
Children less than 10 years old with
acute diarrhea, including both
breastfed and non-breastfed

8. Methodology
III. Types of Intervention
Intervention: Early Refeeding group
Feeding was reintroduced within 12
hours from start of rehydration;
continuous breastfeeding during
rehydration was included in this group.
Control: Late Refeeding group
Feeding was reintroduced more than
12 hours after start of rehydration.

9. Methodology
IV. Types of Outcome Measure
Primary
Duration of diarrhea (hours) from
admission until cessation of diarrhoea.
Secondary
• Total stool output (ml/kg) during the
first 24 hours and 48 hours after start
of rehydration.
• Percentage weight gain 24 hours
after start of rehydration and at
resolution of diarrhea.

10. Methodology
III. Types of Outcome Measure contd.
Secondary contd.
• Unscheduled intravenous (IV) fluid
therapy.
• Cases of vomiting
Adverse events (all adverse effects including)
• Hyponatraemia (low sodium; serum
sodium level ≤130 mmol/L),
• Hypokalaemia (low potassium;
serum potassium level ≤3
mmol/L), and
• Development of persistent diarrhoea

11. Methodology
Search Method
Search Engine used
• Cochrane Infectious Diseases Group
Specialized Register (May 2011)
• CENTRAL (The Cochrane Library
2011, Issue1)
• MEDLINE (1966 to May 2011)
• EMBASE (1974 to May 2011)
• LILACS (1984 to May 1981) and
• mRCT (metaRegister of Controlled
Trial)

12. Methodology
Search Method
Search terms used
‘diarrhoea’, ‘refeeding’,
‘breastfeeding’ and ‘feeding’

13. Methodology
Search Method
Searched researcher and
organizations
• World Health Organization:
• Child Health and Nutrition Research
Initiative
• International Clinical Epidemiology
Network USAID;
• Asian Development Bank;
• World Bank
• International Centre for Diarrheal
Disease Research, Bangladesh
(ICDDR,B)

14. Data collection and analysis
Trial selection
Trials are selected by the first two
authors.
Assessment of risk of bias
Risk of bias of each trial is assessed
using six components: Sequence
generation, Allocation, Concealment,
Blinding, Incomplete outcome data,
Selective outcome reporting and other
biases.

15. Data collection and analysis
Assessment of risk of bias
(contd.)
Trials are classified into two groups high
risk of bias (trials with unclear sequence
generation or allocation or concealment
and trials where less than 90% of
randomized participants completed the
trial) and low risk of bias. Studies with
low risk of bias were included.

16. Data collection and analysis
Data extraction and management
For continuous outcomes, authors extracted
arithmetic means and standard deviations for
each treatment group and noted the number
of participants in each group. In trials with
multiple interventions (where two or more
types of feeding were used as treatment
groups), authors pooled the means and
standard deviations of the different feeding
groups across the treatment arms

17. Data collection and analysis
Data analysis
The authors
• Analysed the data using Review Manager
5 and all results were presented with a
95% confidence interval (CI).
• Combined trials that compared early
versus late feeding using meta-analysis.
• Analyzed data using an available case
approach (i.e. all patients for whom an
outcome was measured and reported are
included in the analysis).

18. Data collection and analysis
Data analysis
• Compared dichotomous data using risk
ratio. The mean difference was used to
combine continuous data summarized by
arithmetic means and standard deviation.

19. Data collection and analysis
Subgroup analysis and investigation of
heterogeneity
• The presence of statistical heterogeneity
among the interventions was evaluated by
inspecting the forest plot and by performing a
2 test for heterogeneity using a p value of
0.10 to determine statistical significance.
• Subgroup analysis is used to investigate the
effect of age , nutritional status (normal and
mild malnutrition versus moderate and severe
malnutrition),

20. Data collection and analysis
Subgroup analysis and
investigation of heterogeneity
breastfeeding (breastfed and non-breastfed
infants) and type of food reintroduced (diluted
versus full-strength milk formula, lactose-free
versus lactose containing)

21. Result
Result of the search
22 relevant trials are assessed
• 12 trials are selected
• 10 trials are excluded
 5 Trials do not satisfy the definition
of early or late refeeding used in this
review
 3 Trials were unclear about when
the refeeding started
 2 Trials were not randomized
controlled trials

22. Result
Total 1283 patients in 12 trials are included
(757 for early refeeding and 526 for late
refeeding)
Drop out
1226 patients were used in the final
analysis
Early Late refeeding
refeeding ( 502 )
(724 )

23. Result
Location
12 Trials were conducted in 16 countries
• 1 Multicentre study including 11
European countries
• Each 2 trials from UK, USA, Burma and
Israel
• Each 1 trial from Egypt, Pakistan and
Peru
Among these 12
• 10 trials conducted in hospital setting
• 2 trials enrolled patients from out patient
clinic

24. Result
Participants
All trials included children with acute diarrhea
of 14 days or less in duration.
• 6 trials ---- duration of diarrhoea 5 – 7 days
• 4 trials ---- duration of diarrhoea < 72 hours
Age
All trials included children less than five years
old.
Only two trials considered the nutritional status of the
participants.
• 6 trials ---- Age of children < 2 years of age
• 2 trials ---- Age of children 3 months to 3

25. Result
Type and timing of refeeding
Early feeding group
• Half- or full-strength cow’s milk formula - 4
trials
• Boiled rice or the child’s usual diet –3 trials
• Soy-based milk formula - 2 trials
• Breast milk or cow’s milk formula - 1 trial
• Another trial allocated patients to receive
either oral rehydration solution and
breastfeeding during the rehydration phase or
oral rehydration alone for 24 hours

26. Result
Type and timing of refeeding
Late feeding group
• Feeding after start of rehydration was
allowed either after 24 hours – 7 trials
• 48 hours – 2 trials
• 20 hours – 1 trial
• between 24 and 48 hours – 1 trial
• One trial allowed feeding only after the
diarrhea had stopped

27. Result
Duration of Follow up Trials
Until resolution of diarrhoea 6
Two weeks after hospital discharge 5
Once full strength milk formula could 1
be tolerated

28. Result
Outcome reported
Overall mean duration of diarrhea from 7
admission to resolution
The number who required unscheduled use of IV 6
fluids
Total stool output in the first 24 hours 3
Oral intake in the form of ORS, formula or rice 6
between 24 and 48 hours
Mean percentage weight gain at the 24th hour 3
after start of rehydration
Mean percentage weight gain at the resolution of 3
diarrhoea

29. Forest plot of early versus late
refeeding in the outcome of
unscheduled use of intravenous fluids
There was no significant difference in both groups in the
number of participants who needed IV fluids (RR 0.87, 95% CI
0.48 to - 1.59; 813 participants, 6 trials

30. Result
Outcome reported contd.
The number of participants with vomiting 4
The development of persistent diarrhea 4
The length of hospital stay 2
Monitored patients for development of 3
hyponatraemia or hypokalaemia

31. Result
Effects of intervention
I. Duration of diarrhea (hours) from
admission until cessation of
diarrhoea
• Shorter Duration
Early feeding group 2 trial
Late feeding group 1 trial
• Similar outcome on both group 4
trial

32. Result
Effects of intervention
II. Total stool output (ml/kg) during the
first 24 and 48 hours after start of
rehydration
After rehydration total stool output in
The first 24 hours 3 trials
48 hours 3 trials
Less stool output
24 hours (early refeeding) 1 trial
48 hours (Late refeeding) 1 trial

33. Result
Effects of intervention
III. Percentage weight gain at the 24th hour
after start of rehydration and at
resolution of diarrhea
No difference was observed in the mean
percentage weight gain at the 24th
hour after start of rehydration and at
resolution of illness
IV. Cases of vomiting
No significant difference between the
two groups in the number of patients
with episodes of vomiting (RR 1.16, 95% CI
0.72 to 1.86; 456 participants, five

34. Result
Effects of intervention
V. Adverse events: development of
persistent diarrhea
There was no significant difference in
the number of patients who developed
persistent diarrhea (RR 0.57, 95% CI
0.18 to 1.85; 522 participants, four trials)

35. Discussion
 Some physicians still recommend variable
periods of fasting during acute diarrhea to
allow ’bowel rest’ followed by gradual
reintroduction of food. The proponents of this
practice contend that early refeeding may
increase the stool output and lead to more
complications, such as unscheduled use of IV
fluids, episodes of vomiting, and persistent
diarrhea.
 Present meta-analysis did not provide
evidence that early refeeding increases
unscheduled use of IV fluids, episodes of
vomiting, and development of persistent

36. Discussion
 The results support existing practice of early
refeeding during or after start of rehydration of
patients
 The review clearly shows that early refeeding
does not adversely affect the secondary
outcome measures: stool output, weight gain
at the end of treatment (which ) likely reflects
rehydration, the unpredicted need for
intravenous fluids, onset of vomiting,
persistence of diarrhea, hyponatremia or
length of hospital stay.

37. Limitation of the study
• 7 of the 12 trials (with 1283 participants)
included in this review came from high –
income countries limiting the applicability
for low-income countries.
• Quality assurance is difficult because 8
trials were published in or before 1990,
when the methods rarely included details
about randomization, allocation,
concealment or blinding
• Heterogeneity regarding participants,
interventions and outcome measures

38. Limitation of the study
• No data were provided on the aetiology of
acute diarrhoea, but different organisms
have varying influence on a child’s
symptoms, severity of dehydration,
tolerance of food and thus rate of
recovery
• No consideration was given to use of
adjuvant treatment such as zinc,
probiotics.

39. Recommendation
Further trials with more homogenous
populations (particularly children at high
risk from recurrent diarrhea and
malnutrition with diarrhea of known
etiology) is recommended

40. Message
There is little additional risk of
unscheduled use of IV fluids, persistent
diarrhea, vomiting or longer hospital stays
for children who were re-fed early. So
there is no need to keep the bowel at rest
during the episode of acute watery
diarrhea.