Resuscitation with NS is associated with metabolic acidosis and hyperchloremia [6-12]. When children with acute diarrhea and severe dehydration were treated with NS infusion, pH decreased despite clinical improvement in dehydration, as compared to a Polyelectrolyte solution [13]. Worsening of acidosis may have profound clinical implications as pH <7.20 may be associated with multi-organ dysfunction [14]. RL may independently improve pH in such cases, as lactate gets converted to bicarbonate in vivo.

This single centre, double blind, randomized controlled trial was conducted from May 2009 to September 2010 in Pediatric emergency facilities at a tertiary-care referral teaching hospital. Ethical approval was obtained from Institute’s ethics committee. The data were monitored by an independent investigator not involved in the recruitment or management of the patients and was reviewed periodically.

Eligible children were randomly assigned to receive either RL (RL group) or NS (NS group). Random allocation sequence was computer generated (www.randomizer.org) by an independent pediatrician, not involved in patient management. RL and NS were obtained in identical-looking bottles. The bottles-set (consisting of 10 bottles each of 500 mL= 5000 mL of the study fluids) were serially numbered according to the random sequence. Their labels were replaced by the study labels containing the study name and serial number. As the subsequent eligible child got randomized, the bottles-set with next serial number was used for rehydration. This was administered by staff nurse on duty. The participants, treating physicians and assessors managing the patients were thereby, blinded to the intervention.

In addition to study fluids, all children received replacement fluids for ongoing losses (watery stools or vomit) and maintenance fluids. We used either reduced-osmolarity WHO oral rehydration solution (ORS) [5] or an intravenous solution of 0.45% saline in 5% dextrose and 2mEq/L Potassium chloride–as replacement fluids depending upon the child’s ability to drink. The volume of replacement fluids was calculated by 10 mL/kg of body weight per stool or vomit. The replacement fluids were charted every 2-hourly after assessment of ongoing losses. Children also received age appropriate mainte-nance fluids throughout the study period [5]. All children received oral zinc supplements (10-20 mg/day) [5].

Resolution of hypotension and disappearance of clinical features of severe dehydration was taken as endpoint for primary outcome. RL-group and NS-group were compared for primary and secondary outcomes. The primary outcome variable was change in pH from baseline. Pre-specified secondary outcome variables were changes in serum bicarbonate levels, base deficit, and serum electrolytes (sodium, potassium, and chloride) from baseline. We also compared the two groups for all cause mortality during hospital stay, duration of hospital stay, volume of fluids required for rehydration, and local complications at cannula site.

Statistical analysis: The sample size calculations were based on the study results of Juca, et al. [3]. To pick up a difference in pH of 0.1 with a standard deviation of 0.07, with an a error of 0.05 and power of 90%, we needed 22 children (11 in each group).

Analysis was performed according to intention-to-treat principle. For primary outcome, the two groups were compared for change in pH from baseline, by using repeated measures ANCOVA (analysis of co-variance). Similarly, changes in serum bicarbonate levels, base deficit, serum electrolytes levels from baseline were also compared by repeated measures ANCOVA. For dichotomous outcomes, we used Fisher’s Exact test to compare proportions between the two groups. Mann Whitney ‘U’ test was used for comparing fluid requirements and duration of hospital stay between the two groups. All analysis was performed with SPSS 17.0.

Thirty four children, presenting with acute diarrhea and severe dehydration, were assessed for eligibility. Twelve children were excluded (persistent diarrhea 4, severe malnutrition 3, consent denied 3, hypoglycemia 2) (Fig. 1). Twenty two children (11 in each group) were randomly allocated to either RL group or NS group.

Fig.1 Flow diagram of patients.

The baseline demographic and clinical characteristics of the study groups are presented in Table I. The two groups were not significantly different for baseline demographic characteristics, acid-base status, renal function tests, and risk of mortality at the baseline (Pediatric index of mortality-2) [19]. Vibrio cholera (eltor ogawa serotype) was the predominant etiology of diarrhea (55%). There was one protocol violation during the study period. One patient in RL-group received NS for 3 hours before being recognized. Subsequently, all fluids were as per randomization.

TABLE I Baseline Characteristics of Study Population

# Pediatric Index of Mortality 2 Score [19]; $ Stool culture was not available for 4 subjects (2 in each group); *P<0.05.

All 22 children received one cycle of rapid intravenous hydration. Four children in RL-group and six children in NS-group had signs of severe dehydration at the end of first rapid intravenous rehydration and required a second cycle of rapid intravenous hydration. No child required third cycle of rapid intravenous rehydration. We compared RL-group and NS-group for change in pH from baseline to primary end point. After adjusting for baseline serum sodium and chloride, the change in pH from baseline was not significant in RL-group (from 7.17 ± 0.11 to 7.28 ± 0.09) as compared to NS-group (7.09 ± 0.11 to 7.21 ± 0.09), (P=0.17) (Fig. 2). We also compared the two groups for the time taken to meet the primary end point, which was also not significantly different (log rank test, P= 0.40).

Fig. 2 Change in pH from the baseline.

The change in serum bicarbonate from baseline, was significantly higher in RL group than NS group (P=0.02). The change in serum potassium from baseline, was significantly lesser in RL group than NS group (P=0.03). There was no difference in change of base deficit, and serum sodium/ chloride from baseline between RL-group and NS-group (Table II).

TABLE II Effect of Rapid Intravenous Rehydration on Acid-base Status, Electrolytes and Renal Function Tests

The children in RL group required intravenous fluids for significantly shorter duration as compared to NS group (log rank test, P=0.005). Median total fluids (including intravenous and ORS) requirement was less in RL-group [310 mL/kg (IQR- 230, 365)] as compared to NS-group [530 mL/kg (IQR- 324, 750)], P=0.01. Children in RL group required less ORS solution than NS-group [median requirement-60 mL/kg (IQR- 35, 70) vs 123 mL/kg (IQR- 69, 233), respectively (P=0.01)]. Children in RL group had shorter median hospital stay [38 hours (IQR- 27, 50)] than NS group [51 hours (IQR- 36,71)] (P=0.03). There was one death in NS group during study period. Assigned cause of death was septic shock. Two children in NS group, who reached primary end point once, were found to be severely dehydrated again after 4-hours and 24-hours of enrolment, requiring intravenous fluids supplementation. Both children grew V. cholerae in stool culture. None of the children in RL group developed features of dehydration once it had been corrected.

In this double blind, randomized, single-centre trial, improvement in pH over baseline in RL-group was not significant as compared to NS-group among children with acute diarrhea and severe dehydration.

Resuscitation with NS has been shown to be associated with metabolic acidosis and hyperchloremia in animal models, healthy adult volunteers, and diseased adult subjects [6,8-11,13]. The low pH can itself potentiate cellular injury [20]. On the contrary, lactate in RL gets converted to bicarbonate ions in vivo and can improve pH, in addition to intravascular expansion. We did not find any significant difference in the change in pH over baseline among RL and NS groups. The reason for this difference in observations is the presence of severe volume depletion in children in our study. The improvement in pH in both RL-group and NS-group is likely to be due to intravascular volume expansion. In adult human volunteers and diseased adults, the pH decreased from the baseline after NS infusion but the subjects in those studies were not dehydrated [8, 11]. In the study by Juca, et al. [13]; however, the pH in NS group decreased from baseline even in dehydrated children. The children in NS-group in our study did not develop significant hyperchloremia. We observed a significantly greater decline in serum potassium values from baseline in NS-group compared to RL-group at primary end point. The difference could be attributed to the composition of the two fluids as NS does not have potassium as a constituent.

In the study by Juca, et al. [13], the primary outcomes (volume of fluids and time to hydration) were not different in two groups. In our study, the fluid requirement was significantly less in RL-group as compared to NS-group. These results should be interpreted with caution as our study aimed to pick differences in pH over baseline and was not powered to answer these outcomes. Unblinded nature of the previous study [13] and difference in the sodium and chloride concentrations of Ringer’s Lactate and polyelectrolyte solution could also have contributed for the difference. However, in animal models of hemorrhagic shock, fluid requirement was found to be significantly less in RL-group than NS-group [6]. In the current study, the duration of hospitalization in RL-group was shorter as compared to NS-group. This finding may have financial implications considering the huge burden of disease (median of 3.2 episodes of diarrhea per child-year) [18]. The faster turnover time of beds would be helpful for providing care to more children, especially in the resource-constrained setting. However, these clinical outcomes need to be proven by adequately powered studies. The statistically significant differences obtained in the current study for these outcomes could be due to chance owing to lack of power to measure these outcomes and the differences in the baseline characteristics among two groups.

We used standard WHO guidelines for the management of acute diarrhea [5]. The strengths of our study are the study design, proper blinding, and objective primary outcome. The results met the assumptions drawn during calculating the sample size [16]. However, 55% of our children had cholera. Therefore, our results are valid mainly for cholera-endemic areas. There was no child <1 year of age in the study and hence the results are not applicable to infants. We could not test for rotavirus diarrhea due to non-availability of kits. It remains to be studied whether improvement in pH translates into an impact on hard outcomes like mortality.

In children with acute diarrhea and severe dehydration receiving rapid intravenous rehydration, improvement in pH from the baseline was not significant in RL-group as compared to NS-group.

Acknowledgements: Dr Sourabh Dutta and Dr SK Sharma, India for statistical input and Dr David Grimes, Family Health International, USA for his critical comments on the manuscript.

Contributors: VM: conceived the idea, was involved in management & data collection, wrote the first draft, interpreted the data and will act as guarantor; SS designed the study, did randomization and blinding, statistically analyzed the data, and critically evaluated the manuscript; AS: helped in management and data collection; JK: supervised the biochemical analysis of samples and edited the manuscript. The final manuscript was approved by all authors.

Funding: None; Competing interests: None stated.