1. FM Journal Club
February, 2011

2. Background 3 - 28 % of babies, No standard definition 6 wk peak
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

3. 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

4. Colic and Probiotics Just in Case Search: Journal of Family Practice
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

5. The Reference
Lactobacillus Reuteri DSM in Infantile Colic: A Randomized, Double-Blind Placebo-Controlled Trial.
Sevino et at. Pediatrics 2010; 126; e526-e533. Online August 16, 2010.

6. 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)

7. 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.

8. Were patients similar? Table 1 Page e529
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.

9. Blinding Method of blinding Patients/Clinicians/Assessors: p. e528:
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

10. How Complete Was Follow – Up? Intention to Treat?
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)

11. Was the study stopped early?No

12. 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?

13. Results: Dichotomous: Reduction in crying time by 50%(ITT) p. 529
Day
Responders
L. Reuteri (%) ITT
EER
Placebo (%)
ITT
CER
ARR
|CER – EER |
RRR
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
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 seen in the ITT analysis, in fine print.

14. 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

15. Other results No differences in Growth parameters, GI symptoms,
Adverse events:
Not powered for adverse events
Rhinitis, ezcema, fever, otalgy, GERD
“unrelated”

16. Application: Similar to my patients?
Solely breast fed
Italian
Full term, otherwise healthy
Recruited from general and outpatient practices

17. Application: All relevant outcomes considered?
Real or Surrogate: minutes of crying time?, flora?
Adverse outcomes?
Long term outcomes?

18. 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

19. 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