Several important developments have been made in the field of management of diarrhea in children as a result of research done in India and globally. It is important to take follow-up steps to ensure that the benefits of new knowledge reach affected children in India and at the same time ensure that new products are not inappropriately used.

The Indian Academy of Pediatrics Committee For Framing Guidelines On The Management Of Diarrhea In Children (members listed in Annexure 1) convened a meeting at the All India Institute of Medical Sciences, New Delhi, to revise the guidelines for management of diarrhea in children. The focus of this review was oral rehydration solutions, zinc and probiotics in acute diarrhea, drug treatment of dysentery, and management of diarrhea in the young infant and severely malnourished subjects. The meeting was convened to achieve a consensus on these issues based on careful review of the literature and keeping in mind the requirements of treatment of individual children as well as the needs of Diarrheal Diseases National Control Program. As individual studies are often too small to yield precise estimation of effect size, the recommendations are largely based on pooled data or meta-analysis of randomized placebo controlled trials.

We summarize below the available data followed by consensus recommendations of the group.

The current standard WHO ORS has a sodium concentration of 90 mEq/L (glucose 110 mmol/L, osmolarity 311 mOsm/L), which corresponds to the stool electrolyte composition in toxin-mediated diarrhea. However, it has worked well even in young children with non-cholera diarrhea when used according to the recommended guidelines with ready access to plain water during oral rehydration.

Several considerations lead to the clinical evaluation of reduced osmolarity oral rehydration salts solutions and they have been examined by WHO(1). Initially, one main concern was the potential risk of hyper-natremia with standard WHO-ORS in children with non-cholera diarrhea. There was also the recognition that the standard WHO-ORS may provide too much sodium to edematous children. In later years, there were reports of recurrent dehydration in young infants treated with standard WHO-ORS on a weight to volume basis as replacement of ongoing stool losses that was promptly reversed when patients were kept nil orally and on intra-venous fluid regimens. Finally, laboratory experiments showed that reduced osmolarity solutions (sodium 60 mmol/L, glucose 80-120 mmol/L, osmolarity 240 mOsmol/l) promote water and sodium absorption more efficiently than the WHO-ORS.

A recently published meta-analysis of trials of reduced osmolarity ORS was reviewed(2). The meta-analysis included all randomized trials in which a reduced osmolarity ORS containing glucose, malto-dextrin or sucrose (total osmolarity 210-268 mOsmol/l) and a sodium con-centration ranging from 50 to 75 mEq/L was used . These studies were conducted mainly in developing countries and included well-nourished and malnourished children aged 1 month to 5 years with acute diarrhea of duration <7 days with dehydration. Four of the studies were done in India, two as part of large multi-center trials.

Results of the meta-analysis were as follows: (i) Use of reduced osmolarity ORS was associated with a significant 39% reduction in need for IVF; need for IVF was considered an important outcome measure as in many peripheral health facilities, where IV therapy is often unavailable, reducing the need for unscheduled IV therapy would reduce the risk of death from dehydration, (ii) 19% reduction in stool output and (iii) 29% lower incidence of vomiting (Table I). The incidence of hyponatremia (serum sodium <130 mEq/L) at 24 hours, evaluated in 3 clinical trials was greater among children given reduced osmolarity ORS. 51 children treated with reduced osmolarity ORS and 36 children treated with standard WHO ORS developed hyponatremia (OR = 1.45, 95% CI: 0.93 to 2.26). None of these children were symptomatic. This difference was not statis-tically significant but could be as much as twice that associated with standard WHO ORS.
 

Unscheduled IV

9

39% (19%, 53%)

Stool output

12

19% (12%, 26%)

Vomiting

6

29% (8%, 45%)

An analysis of all studies was conducted (1), stratifying them according to the sodium content of the reduced osmolarity ORS: (i) reduced osmolarity ORS containing less than 75 mEq/L of sodium (range 60 to 70 mEq/L), and (ii) reduced osmolarity ORS containing exactly 75 mEq/L of sodium. Table II shows the comparison of each of the two types of reduced osmolarity ORS with standard WHO ORS and not a direct comparison with each other. ORS solution with a sodium concentration of 75 mEq/L and sodium concentration of less than 75 mEq/L are both more effective than standard WHO ORS with regard to need for unscheduled IV therapy and occurrence of vomiting and that the incidence of hyponatremia, while not significantly higher than for standard WHO ORS, could be up to double its incidence. Although the effect size suggests a trend that is consistent with greater reduction in stool output in the ORS with sodium concentration of less than 75 mEq/L, the test for interaction could not differentiate between the efficacy of ORS solution with a sodium concentration of 75 mEq/L and and that of ORS solution containing sodium less than 75 mEq/L, even on unidirectional tests of significance.

Odds ratio (95% CI) for unscheduled IV therapy 
for patients given RED OSM ORS when 
compared to those given standard WHO ORS

N = 4 studies
N = 678 children


0.65 (0.41 to 1.00)

N = 4 studies
N = 1175 children


0.56 (0.39 to 0.80)

Ratio of geometric means (95%CI) for stool
output in children given RED OSM ORS when
compared to those given standard WHO ORS 

N = 8 studies 
N = 771 children
0.69 (0.49 to 0.98)

N = 4 studies
N = 1049 children
0.88 (0.71 to 1.06)

Odds ratio (95%CI) for vomiting for patients 
given RED OSM ORS when compared to those 
given standard WHO ORS

N  =3 studies
N = 270 children
0.49 (0.27 to 0.91)

N = 3 studies
N = 1031 children
0.74 (0.58 to 0.95)

Odds ratio (95%CI) for hyponatremia (<130 
mEq/L) for patients given RED OSM ORS when 
compared to those given standard WHO ORS

N = 3 studies
N = 139 children 
Not analyzed

N = 3 studies
N = 1120 children
1.45 (0.93 to 2.26)

In the pooled data (1) of all studies with cholera diarrhea in children there was a small, but statistically significant reduction, in mean serum sodium at 24 hours in patients receiving reduced osmolarity ORS (sodium 70-75 mEq/L, glucose 75-90 mmol/L, osmolarity 245-268 mOsm/L) when compared with those given standard WHO ORS [(mean difference 0.8 mEq/L, 95% CI: 0.6 to 1.0). The children receiving reduced osmolarity ORS did not have a higher risk, than those receiving standard WHO ORS, of developing hyponatremia (serum sodium <130 mEq/L) at 24 hours (RR = 1.8, 95% CI: 0.9 to 3.2), but a possible doubling of the incidence cannot be ruled out based on the confidence intervals. None of these children with hyponatremia were symptomatic. Stool output at 24-hours was not different between treatment groups in children with cholera in the multicentre study (sodium 75 mEq/L, glucose 75 mmol/L, osmolarity 245 mOsm/L). In the other two studies, however, stool output was reduced by about 30% in children with cholera who were treated with reduced osmolarity ORS.

The combined analysis of three studies(1) that compared the efficacy and safety of reduced osmolarity ORS (osmolarity 245-249 mOsm/L) to that of standard WHO ORS in adults with cholera showed a minimal, and statistically insignificant, mean reduction of 0.5 ml/kg (95% CI: –14.6 to +15.6) in stool output during the first 24 hours among patients given reduced osmolarity ORS. A small, but statistically significant reduction in mean serum sodium of 1.3 mEq/L (95% CI: 0.3 to 2.3) was observed at 24-hours in patients treated with reduced osmolarity ORS when compared to those given standard WHO ORS. None of these patients who developed hypo-natremia became symptomatic.

The WHO Meeting of Experts(1) concluded that there are programmatic and logistic advantages of using a single solution around the world for all causes of diarrhea in all ages. After reviewing the data the group of experts proposed that reduced osmolarity ORS with 75 mEq/L of sodium and 75 mmol/L of glucose is effective in adults and children with cholera and that reduced osmolarity ORS solution with 60 mEq/L of sodium does not seem to be significantly better than reduced osmolarity ORS solution containing 75 mEq/L of sodium. They concluded that safety data in patients with cholera, while limited, are reassuring.

The WHO Meeting of Experts(1) further recommended that this formulation falls within the ranges defined by the WHO’s Program for the Control of Diarrheal Diseases (CDD) in March 1992 for a safe and efficacious oral rehydration solution, which, therefore, remain unchanged. The recom-mended ranges were that the total substance concentration (including that contributed by glucose) should be within the range 200-311 mmol/L. The individual substance concentra-tion of glucose should at least equal that of sodium, but should not exceed 111 mmol/L and that of sodium should be within the range of 60-90 mmol/L. The concentrations of potassium, citrate and chloride should be with-in the range of 15-25 mmol/L, 8-12 mmol/L and 50-80 mmol/L respectively as shown below (1).

The rationale for use of specific nutrients as treatment of acute diarrhea is based on their effects on immune function or on intestinal structure or function and on the epithelial recovery process during diarrhea.

Zinc deficiency has been found to be widespread among children in developing countries, and occurs in most of Latin America, Africa, the Middle East and South Asia. Zinc has been identified to play a critical role in metallo-enzymes, polyribosomes, the cell membrane, and cellular function, leading to the belief that it also plays a central role in cellular growth and in the function of the immune system. Intestinal zinc losses during diarrhea aggravate pre-existing zinc deficiency. Convincing evidence for its clinical importance has come from recent randomized controlled trials of zinc during acute diarrhea.

The results of pooled analyses (3) of zinc treatment trials in children with acute diarrhea and the findings of subsequent studies are summarized in Table III. The main features of these trials include the randomized placebo controlled design subjects’ aged between 6 months and 3 years, and daily elemental zinc dose ranging from 10 to 30 mg per day.

Risk of continuation of diarrhea

Relative hazards

Pooled analysis (3)

1252/1194

0.85 (0.76 to 0.95)

Subsequent studies in South-East Asia

Strand et al. (4)
Bahl et al. (5)
Bhatnagar et al. (6)

442/449
404/401
132/134

0.79 (0.68 to 0.93)
0.89 (0.80 to 0.99)
0.76 (0.59 to 0.97)

Diarrhea lasting >7 days

Odds ratio

Pooled analysis

1252/1194

0.78 (0.56 to 1.09)

Subsequent studies in South-East Asia

Strand et al.
Bahl et al.
Bhatnagar et al.

442/449
404/401
132/134

0.57 (0.38 to 0.86)
0.61 (0.33 to 1.12)
0.09 (0.01 to 0.73)

Stool output

Difference in means
or Ratio of geometric means

Roy et al. (7)
Dutta et al. (8)
Bhatnagar et al.

57/54
44/36
132/134

–91 g
–900 g (–1200 to –590)
0.69 g/kg  (0.48, 0.99)

Reproduced from Reference 1

In the trials subjected to pooled analysis, zinc supplemented children had 16% faster recovery (95% CI 6% to 22%). Zinc treatment also resulted in a 20% reduction (95% CI –2% to 38%) in the odds of acute episodes lasting >7 days. The findings of the subsequent trials are consistent with the conclusions of the meta analysis. The study by Bhatnagar et al. is of interest as it was hospital based, involved cases of acute diarrhea with dehydration and measured impact on stool output. In the zinc treated children, the total stool output was reduced by 31% (95% CI 1% to 52%) than in the placebo group.

The effect of zinc did not vary significantly with age, or nutritional status assessed by anthropometry. The effects were not dependent upon the type of zinc salts: zinc sulfate, zinc acetate or zinc gluconate. The optimal dose is yet to be determined but there seems to be little gain in efficacy when the commonly used 20 mg daily dose of elemental zinc was increased to 30-40 mg daily. Majority of the studies so far were conducted in South East Asia, where zinc deficiency is common. Finally, there is relatively little data on children aged less than 6 months to allow any conclusions about efficacy in this age group.

Another study conducted in Bangladesh(9) used a cluster randomized design to evaluate the effect on mortality and morbidity of providing daily zinc for 14 days to children with diarrhea as part of the diarrhea treatment programme in the community. The inter-vention and the comparison clusters were both given ORS and advice on feeding during diarrhea. The children in the zinc cluster had a shorter duration (hazard ratio 0.76, 95%CI 0.65 to 0.90) and lower incidence of diarrhea (rate ratio 0.85, 95% CI 0.76 to 0.96) than children in the comparison group, lesser admission to hospital of children with diarrhea (rate ratio 0.76; 95% CI 0.59 to 0.98), and lower mortality due to non injury deaths, notably diarrhea or pneumonia (rate ratio 0.49; 95% CI 0.25 to 0.94) in the zinc treated cluster. The data are consistent in showing a beneficial effect of zinc in acute diarrhea.

The efficacy of 40mg elemental zinc mixed with a liter of standard WHO ORS solution was compared with ORS without zinc and with zinc syrup administered separately from ORS(5). While zinc-ORS was superior to ORS alone, it was less efficacious in reducing duration of the episode than zinc supplements given separately from the ORS solution. The data are currently too limited.

The therapeutic benefits in acute diarrhea may be attributed to effects of zinc on various components of the immune system and its direct gastrointestinal effects. Zinc deficiency is associated with lymphoid atrophy, decreased cutaneous delayed hypersensitivity responses, lower thymic hormone activity, a decreased number of antibody forming cells and impaired T killer cell activity. Zinc deficiency has also been recently shown to affect the differentiation of CD4 response towards Th1 rather than Th2 pathway. The direct intestinal effects of zinc deficiency include decreased brush border activity, enhanced secretory response to cholera toxin, and altered intestinal permeability, which is reversed by supplementation.

Probiotics are nonpathogenic micro-organisms that, when ingested exert a positive influence on the health or physiology of the host. They consist of either yeast or bacteria, predominantly Bifidobacterium and Lacto-bacillus. There is some preliminary evidence that ingestion of probiotics offers therapeutic benefit in the treatment of acute gastroenteritis in children. There are several possible mechanisms by which probiotics may exert their clinical effects. They can protect the intestine by competing with pathogens for attachment, strengthening tight junctions between enterocytes and enhancing the mucosal immune response to pathogens.

The group reviewed the available published randomized controlled studies on therapeutic benefits of probiotics in acute diarrhea. Most of the studies are small in size except for a single large multicentre trial and have been done in developed countries. None of the studies are from India. Some inferences are possible from the recently published meta-analyses.

The first meta-analysis reported details of 10 treatment studies involving hospitalized children aged 1-48 months with diarrhea less than 7 days(11). All studies were conducted in developed countries from the West except for one from Thailand. The probiotics used were Lactobacillus GG, Lactobacillus reuteri, Saccharomyces boulardii, Streptococcus thermophillus lactis, Lactobacillus acido-philus and Lactobacillus bulgaricus. Rota-virus was the cause of diarrhea in more than 75% cases in studies from Finland, 28% in Russia, 48% in Thailand and 35% in the multicentre trial. Figure 1 summarizes the pooled effect of probiotics on duration of diarrhea in 7 trials involving 679 children. Probiotics significantly reduced the duration of diarrhea compared with the placebo by 21 hours (the pooled weighted mean difference assuming the random–effect model was –20.1 (95% CI –26.1, –14.2).

The second meta-analysis included most of the studies from the first analysis and one small study from Pakistan, which enrolled only 36 subjects(12). The results were consistent with the earlier meta-analysis reporting a reduction in diarrheal duration of 0.7 days (95% CI 0.3 to 1.2) in subjects who received lactobacillus compared with those who received the placebo.

The first meta-analysis(11) further reported subgroup analysis for different probiotic strains (Fig. 1). Both LGG (pooled weighted mean difference assuming the random-effect model was –22 (95% CI –31.3, –21.8) and L. reuteri (pooled weighted mean difference assuming the random–effect model was –25.3 (95% CI–40.7 to –9.95) signi-ficantly reduced the duration of diarrhea as compared to the placebo. There was only one study with Lactobacillus acidophilus which reported a trend in the reduction of diarrheal duration but this was not statistically significant –13.6 (95% CI –28 to 0.83) . Only LGG (data not shown) showed a consistent effect on the reduction in risk of diarrhea lasting >3 days (pooled estimate RR 0.4 95% CI 3 to 9).

LGG and L. reuteri significantly reduced duration of diarrhea as compared with the placebo in 297 children with rotavirus diarrhea (weighted mean difference –24.8h (95% CI –31.8 to –17.9) while a similar effect was not seen in a small sub-group of subjects with invasive diarrhea 1.3h (95%CI –15.3 to 17.9) (Fig. 2).

Lactobacillus GG is not available in the Indian market. The other commonly available probiotics are Lactic Acid bacillus, Lacto-bacillus acidophilus and Saccharomyces boulardii.

The group recommended that based on the above studies there is presently insufficient evidence to recommend probiotics in the treatment of acute diarrhea in our settings as:

The IAP group suggested that for assessment of diarrhea in young infants (up to age 2 months) recommendations by the Integrated Manage-ment of Neonatal and Childhood Illnesses, which is an adapted version of Integrated Management of Child-hood Illnesses for India, should be followed. The following additional recommendations were made:

The issue of indiscriminate use of antibiotics as well the increasing incidence of antibiotic resistance is causing great concern. The national diarrheal disease control program currently recommends the use of cotrimoxazole as the first line drug for the management of acute bloody diarrhea.

Recent studies from India and other Asian, as well as non-Asian developing nations have shown high rates of resistance of shigella to cotrimoxazole, ampicillin, chloramphenicol and tetracyclines. Resistance rates to nalidixic acid and quinolones are still low.

The following consensus was reached on the issues of antibiotics:

Vomiting is the commonest symptom associated with acute diarrhea in children. Often vomiting is particularly distressing to the parents and therefore, antiemetics are frequently prescribed. Concerns were raised by members, on their use, in view of the serious side effects these drugs can produce. Low osmolarity ORS is expected to reduce the incidence of vomiting in children with acute gastroenteritis. Most children with vomiting can be managed with frequent small sips (5-10 ml) of ORS.

In children who are HIV positive or are immunocompromised due to other immuno-deficiency states the management of acute diarrhea varies from the management in the immunocompetent. The causative organisms of diarrhea differ and the consequences of diarrhea are more severe in these children, particularly in those with Cryptospori-diosis(13). The primary determinant of the organisms and consequences is whether the child is receiving antiretroviral therapy and its intensity. A HIV positive child with acute diarrhea must have a stool culture, stool examined for ova, cysts and atypical protozoa (includes isospora, microspora and crypto-spora on at least three occasions) and CD4 counts determined.

Children on intense retroviral therapy and CD4 counts greater than 500 can be managed like normal children with diarrhea.

We acknowledge Ministry of Health, Government of India and the WHO for providing technical support and CMS for their support for the meeting.