We read with interest the results of the randomized trial on Ringer’s lactate (RL) vs normal saline in children with acute diarrhea and severe dehydration [1]. The study authors had used a rigorous methodology to address a pertinent question, and found no difference in the outcomes between the two groups. We wish to highlight a few methodological issues, which, if addressed, could have further improved the quality of the study:

The authors mention that the primary outcome variable was ‘change in pH from baseline’. However, they possibly used the difference in post-intervention pH between the groups and not the magnitude of ‘change from baseline’ for calculating the sample size. There is no mention of the mean or SD of the change in pH from baseline in the study from which the authors estimated the sample size. The sample size could have been very different if the standard deviation of this outcome was large (or small!) from the one used in the sample size calculation.

At least four different approaches can be employed to analyze a continuous outcome that is measured at two time points (i.e. baseline and after treatment) in a RCT: post-treatment, change between baseline and post-treatment, percentage change between baseline and post-treatment, and analysis of covariance (ANCOVA) with baseline value as a covariate [2]. The authors chose to use a slightly different approach using the change from baseline as the outcome but used ANCOVA to adjust for a few covariates other than the baseline pH. Compared to the change from baseline analysis, ANCOVA with baseline as the covariate has higher statistical power, particularly if correlation coefficient between baseline and follow-up values is <0.8 [2,3]. More importantly, the latter analysis has the advantage of being unaffected by baseline differences between the groups (it adjusts each patient’s follow up score for his/her baseline score) [3]. In contrast, the change from baseline analysis takes the pretest difference too seriously and might produce biased results in the presence of imbalance in baseline scores between the two groups [4]. Though not statistically significant, the baseline pH was higher in the RL group [1].

Instead of providing only the P value, the authors should have provided the results of the ‘ANCOVA’ model in a more detailed way - Vickers, et al. [3] have provided an excellent model for depicting the results of the analysis using ANCOVA model (albeit, with baseline as covariate). The unadjusted and adjusted mean difference of change from baseline along with 95% CI would have given the readers some idea about the precision of the results and the magnitude of confounding caused by the two covariates.

The term ‘repeated measures’ usually implies that the analysis involved an interaction term, i.e. ‘group*time’ in the model. It is not clear if the P value mentioned in the study refers to the P value of this interaction term.

The authors adjusted only for baseline serum sodium and chloride - the two factors found to be significant on bivariate analysis - in the ANCOVA model. Many researchers have effectively demonstrated the inappropriateness of this approach, i.e. adjustment for only ‘significant’ variables [5]. Moreover, the clinical relevance of adjusting for serum chloride when baseline serum pH had already been accounted for in the change from baseline analysis is not clear. The better approach would be to use pre-specified ANCOVA where a few a priori selected important baseline variables are used as covariates [6]. An important variable that had to be adjusted was the time interval between the baseline and the time to achieve primary end point, as the latter was not fixed in the two groups. Not including it in the model because of lack of significant result is not valid as the insignificant result is more likely be due to lack of power rather than due to true absence of difference between the groups.

1. Mahajan V, Sajan SS, Sharma A, Kaur J. Ringers lactate vs normal saline for children with acute diarrhea and severe dehydration- A double blind randomized controlled trial. Indian Pediatr. 2012;49:963-8.

2. Vickers AJ. The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study. BMC Med Res Methodol. 2001;1:6.

3. Vickers AJ, Altman DG. Statistics notes: Analysing controlled trials with baseline and follow up measurements. BMJ. 2001;323:1123-4.

4. Van Breukelen GJ. ANCOVA versus change from baseline: more power in randomized studies, more bias in nonrandomized studies [corrected]. J Clin Epidemiol. 2006;59:920-5.

5. Begg CB. Suspended judgment. Significance tests of covariate imbalance in clinical trials. Control Clin Trials. 1990;11:223-5.