Transcript Document

FM Journal Club
February, 2011
Background
• 3 - 28 % of babies,
– All babies cry most in the first 3 mo
• No standard definition
– Rule of Threes, ≥ 3 hrs, ≥ 3 d/ wk, ≥ 3 wk
• 6 wk peak
•  60% by 3 mo, 90% by 4 mo
• Most treatment works in 1/3 of babies
Background
• Social phenomenon:
– “Caretakers perception of what is
excessive or prolonged (crying) and
caretakers ultimate response to the
perception defines it as a problem.” Up to
Date
Colic and Probiotics
• Just in Case
– Journal of Family Practice
• Search:
– Dynamed: No mention under colic tx
– UpToDate: 2 RCT’s, good synopsis
• 2010 Double blind, pacebo controlled RCT
• 2007 Prospective randomized, no placebo,
open, simethacone vs probiotic
– Google Scholar: 1st reference
The Reference
• Lactobacillus Reuteri DSM in Infantile
Colic: A Randomized, Double-Blind
Placebo-Controlled Trial.
– Sevino et at. Pediatrics 2010; 126; e526e533. Online August 16, 2010.
Methods
• 50 term breast fed babies, recruited
from general practice and outpatient
clinics, randomly assigned to receive
Lactobacillus reuteri or placebo and
evaluated for 21 days, for crying time
and gut flora.
• 5 drops of suspension, once a day
before the feed in the morning for 21
days. (108 colony forming units)
Were the patients randomized?
Was Allocation Concealed?
• Page e 527: Study design
– Randomized, using random digit method,
computer generated numbers. Two
treatment randomization, with random
block of varying size. The pediatrician
allocated the next available product entry
into the trial, each patient received it
directly from the department.
Were patients similar?
• Table 1
– Probiotics slightly older by 4 days
– No sig differences according to P values
• Page e529
– There were no significant differences
between the groups regarding type of
delivery, gender, age, family history or GI,
atopy, or growth or median crying time.
Blinding
• Method of blinding
– Active study product: suspension of freeze
dried L. Reuteri in sunflower oil in dark
bottle. Placebo: Identical w/o L. Reuteri.
• Patients/Clinicians/Assessors: p. e528:
– The bottles were coded and blinded by the
study statistician for both participants and
pediatricians, and code was revealed to
the investigators once recruitment, data
collection, and all … analysis complete
How Complete Was Follow –
Up? Intention to Treat?
• Follow-up
– None “lost”, 46 completed the trial
• Intention to Treat
– 4 excluded from analysis
• 1 fever
• 2 failure to complete daily forms
• 1 GERD
– The 4 treated as responders as they were
all in the placebo group. (p. 528)
Was the study stopped early?
• No
Results: Continuous Variable
• Day 21: Reduction in daily crying time
– Placebo: 35 min
– L. Reuteri: 90 min
– P = 0.022
• Days 7, 14 not statistically significant.
Noted in discussion and in Table 2. Not
in main text.
– Reporting bias?
Results: Dichotomous: Reduction
in crying time by 50%(ITT) p. 529
Day Responders
L. Reuteri
(%) ITT
EER
Responders
Placebo (%)
ITT
CER
ARR
ITT
|CER –
EER |
RRR
ITT
NNT
P
value
7
21/25 (84%)
11/25 (44%)
84%-44%
40%
40%/84%
48%
1/.4
2.5
.007
14
24/25 (96%)
16/25 (64%)
96%-64%
32%
32%/96%
33%
1/.32
3.1
0.011
21
24/25 (96%)
18/25 (72%)
96%-72%
24%
24%/96%
25%
1/.25
4
0.049
Results reported in tables and and abstract are the non ITT, and the results
in the abstract are the more dramatic P values. Not the the 0.049 seen in
the ITT analysis, in fine print.
Error
• Type II?
• Power Calculation p. 528
• 80% power to detect a difference of 50
min of crying with a dropout rate of 20%
• Type I?
– Possible with tiny sample size
Other results
• No differences in Growth parameters,
GI symptoms,
• Adverse events:
– Not powered for adverse events
– Rhinitis, ezcema, fever, otalgy, GERD
– “unrelated”
Application: Similar to my
patients?
•
•
•
•
Solely breast fed
Italian
Full term, otherwise healthy
Recruited from general and outpatient
practices
Application: All relevant
outcomes considered?
• Real or Surrogate: minutes of crying
time?, flora?
• Adverse outcomes?
• Long term outcomes?
Application: Will my patient
benefit? Risks,harms and
costs
• NNT: 4. You need to treat
approximately 4 infants for 3 weeks with
L. Reuteri, to have 1 additional infant
display a 50% reduction in crying time.
• 72% responders to placebo at 21 days
• 96% responders to L. Reuteri at d.
• Effect is decreasing over time
Application
• 90% are better at 4 months of age
• Remember in treatments studied “Most
treatments works in 1/3 of babies”
• 50 minutes less crying time may be very
important to families
• Tiny study, need replication
• Many studies can’t be replicated