FM Journal Club February, 2011

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

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 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

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.

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 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.

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

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)

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 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 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