Recent Trends in the Management of Acute Watery Diarrhea in Children / 37

Shinjini Bhatnagar, Nitya Wadhwa

Recent Trends in the

4 Management of Acute
Watery Diarrhea in Children

Diarrhea is responsible for 15% of the 10.5 million deaths among children less than 5 years
old in all developing countries.1 In India, diarrhea constitutes 13% of all common illnesses
in children under 3 years of age.2 The ideal recommended management of diarrhea, is use
of WHO ORS for treating dehydration and maintaining hydration, restricted antimicrobial
use and continued feeding with energy dense feeds. In the last few years extensive research
done in India and other similar settings has led to significant changes in the treatment of
acute watery diarrhea.

NEW REDUCED OSMOLARITY ORS

WHO Expert Group (2001) recommended that reduced osmolarity ORS with 75 mEq/l of
sodium and 75 mmol/l of glucose (osmolarity 245mOsm/l) should be the universal solution
for all causes of diarrhea and at all ages. These recommendations were endorsed by the
National Task Force of the Indian Academy of Pediatrics (2003, 2006) The new formulation
was approved by the Drug Controller of India and was introduced in the National DiarrheaI
Disease Control programme by the Government of India in June 2002.

COMPOSITION OF REDUCED OSMOLARITY ORS

Component Concentration (mmol/L)
Sodium 75
Chloride 65
Potassium 20
Citrate 10
Glucose 75
Osmolarity 245

Why was there a need for a new ORS formulation?

The standard WHO ORS with a sodium concentration of 90 mEq/L (glucose 110 mmol/l,
osmolarity 311 mOsm/l), was evolved based on the stool electrolyte composition in toxin-
38 / Pediatric Gastroenterology

mediated diarrhea. Over the last 30 years this ORS has worked well even in young children
with non-cholera diarrhea when used, according to the recommended guidelines, with plain
water given ad-libitum. Initially, the main concern among pediatricians with use of standard
WHO-ORS was the potential risk of hypernatremia in children with non-cholera diarrhea
and the increased incidence of recurrent dehydration in young infants that was reversed
when patients were kept fasting and on intravenous fluid regimens. Further, it was also
perceived that use of oral rehydration solution in the treatment of diarrhea reduces the
risk of diarrheal mortality through prevention and treatment of dehydration but does not
decrease diarrheal duration or stool output. It prompted care givers and physicians to prescribe
irrational antimicrobial and antidiarrheal therapy. The above concerns and results from
laboratory experiments that showed water and sodium is absorbed more efficiently from
reduced osmolarity solutions (sodium 60 mmol/l, glucose 80-120 mmol/l, osmolarity 240
mosmol/l) than the standard WHO-ORS lead to the clinical evaluation of reduced osmolarity
oral rehydration salts solutions in many large double blind randomized clinical trials.

Efficacy of the new reduced osmolarity ORS in non cholera diarrhea

Most of the evidence comes from twelve large randomized trials that evaluated reduced
osmolarity3 ORS solutions containing glucose, maltodextrin or sucrose (total osmolarity 210-
268 mosmol/l) and a sodium concentration ranging from 50 to 75 mEq/l. These studies
were conducted mainly in developing countries and included both well-nourished and
malnourished children aged 1 month to 5 years, with acute diarrhea (<7 days) and
dehydration. It is important to note that four of the studies were done in India, two as
part of large multi-center trials. The results of a meta-analysis of these trials showed that
use of reduced osmolarity ORS was associated with a significant 39%( 95 % CI 19%, 53%),
reduction in need for intravenous fluids, 19% (12%, 26%), reduction in stool output and
29% (8%, 45%) lower incidence of vomiting as compared with the standard WHO ORS,
(sodium 90 mEq/L glucose 110 mmol/l, osmolarity 311 mOsm/l). The need for intravenous
fluids is considered an important outcome measure as in many peripheral health facilities,
where IV therapy may not be available; reducing the need for unscheduled IV therapy would
reduce the risk of death from dehydration.

Efficacy of the New Reduced Osmolarity ORS in cholera diarrhea

Reduced osmolarity ORS was found to be as effective in adults with cholera (no statistically
significant differences in the stool output between groups receiving reduced osmolarity or
standard WHO ORS). Although, evaluated in a small number of children with cholera, there
was a 30% reduction in the initial 24 hour stool output with reduced osmolarity ORS4.

Is reduced osmolarity ORS safe?

The incidence of hyponatremia (serum sodium <130 mEq/l) at 24 hours among children
with non cholera diarrhea given reduced osmolarity ORS was marginally greater as compared
to the standard WHO ORS.3,4 However these differences were not statistically significant
and none of these children were symptomatic.
 Recent Trends in the Management of Acute Watery Diarrhea in Children / 39

The safety data in patients with cholera, while limited, are reassuring. In the pooled
data4 of all studies with cholera diarrhea in children there was a small reduction (mean
difference 0.8 mEq/l, 95% CI: 0.6 to 1.0) in mean serum sodium at 24 hours in patients
receiving reduced osmolarity ORS (sodium 70-75 mEq/l, glucose 75-90 mmol/l, osmolarity
245-268mOsm/l) when compared with those given standard WHO ORS. This was similar
to results seen in adults with cholera, who had a small, but statistically significant reduction
in mean serum sodium of 1.3 mEq/l (95% CI: 0.3 to 2.3) at 24-hours in those treated with
reduced osmolarity ORS (sodium 75 mEq/l, glucose 75mmol/l, with an osmolarity of 245
mOsm/l). None of these patients who developed hyponatremia became symptomatic.

Zinc in Diarrheal Diseases

Zinc deficiency is common in children from developing countries due to lack of intake of
animal foods, high dietary phytate content, which limits zinc absorption, and inadequate
food intake5. There are also increased fecal losses of zinc during diarrhea which aggravates
pre existing zinc deficiency.6,7 The initial evidence that low plasma zinc was associated with
increased severity of diarrhea came from observational studies.8,9 A large body of evidence
shows that zinc supplementation reduces morbidity from diarrhoea in high risk populations.
Convincing evidence of zinc supplementation given during a diarrheal episode on therapeutic
benefits comes from large randomized placebo controlled studies. over the last 5-6 years.10,11
Majority of the studies were conducted in South East Asia, in subjects aged between 6
months and 3 years, and the daily elemental zinc dose ranged from 10 to 30 mg per day.
The pooled analysis has shown that zinc supplemented children had 16% faster recovery
(95% CI 6% to 22%) with a 34% reduction (95% CI 17% to 48%) in the acute episodes lasting
more than 7 days. Additionally, in the zinc treated children, the total stool output was
reduced by 31% (95% CI 1% to 52%) as compared to the placebo group. This is an important
finding as stool output is the most objective marker of severity and a useful proxy indicator
for risk of dehydration, in hospitalized children with acute diarrhea and dehydration.12
The three different zinc salts evaluated zinc sulfate, zinc acetate or zinc gluconate have been
found to be equally effective. Further the significant beneficial effects on morbidity were
not restricted to children with low baseline concentrations of plasma or serum zinc. There
was little gain in efficacy when the commonly used 20mg daily dose of elemental zinc was
increased to 30-40mg daily10-13. Some studies also reported reduction in diarrhoea morbidity
in the subsequent 23 months without further supplementation.10
Effect of providing daily zinc for 14 days to children with diarrhea as part of the diarrhea
treatment programme in the community using a cluster randomized design was evaluated
in Bangladesh.14 There was a 24% shorter duration (95%CI 0.65 to 0.90) and 15% lower
incidence of diarrhea (95%CI 0.76 to 0.96) in the zinc cluster than those in the comparison
group. The zinc treated cluster had a 24% (95% CI 0.59 to 0.98) lesser rate of admission
to hospital of children with diarrhea and 51% (95% CI 0.25 to 0.94) lower mortality due
to noninjury deaths, notably diarrhea or pneumonia.
40 / Pediatric Gastroenterology

Zinc was also found to have significant therapeutic effects in persistent diarrhea by
decreasing duration of episodes, lowering stool frequency and resulting in a 42% reduction
of treatment failures or deaths.10
Therapeutic benefits of zinc administration during diarrhea are biologically plausible
because of its effects on various components of the immune system and its direct
gastrointestinal effects. Zinc affects various immune mechanisms and modulates host resistance
to several pathogens.15 Zinc deficiency is associated with lymphoid atrophy, decreased
cutaneous delayed hypersensitivity responses, lower thymic hormone activity, a decreased
number of antibody forming cells, impaired T killer cell activity and differentiation of CD4
response towards Th1 rather than Th2 pathway. Zinc is said to improve absorption of water
and electrolytes by helping in early regeneration of intestinal mucosa, and restoration of
enteric enzymes. Zinc deficiency enhances secretory response to cholera toxin, and alters
intestinal permeability, which is reversed by supplementation.

Should zinc be mixed with ORS?

Currently there are no recommendations for mixing zinc with ORS for the global or national
diarrhea control programme. Zinc (mixed with ORS) is consumed over a period of time
making it difficult to ensure a standardized zinc exposure during a diarrheal episode.

WHO, IAP and Govt of India recommendations for use of zinc as an adjunct to ORS
in the treatment of diarrhea
WHO Task Force (2001) reviewed all the evidence available and recommended that 20 mg
(once or in two divided doses) per day should be given for 10-14 days starting as early
as possible after onset of diarrhoea.11 Any of the three zinc salts e.g. sulphate, gluconate
or acetate may be recommended. These recommendations were endorsed by Indian Academy
of Pediatrics (2003 and 2006)16 and the Govt of India (2007). It is emphasized that ORS remains
the mainstay of therapy during acute diarrhea and zinc has an additional benefit in the
reduction of stool volume and duration of diarrhea as an adjunct to ORS.
There is little evidence on the efficacy of zinc during diarrhea in children less than
6 months, including young infants, and ongoing trials will allow clearer interpretation of
its role. Currently for infants 2 up to 6 months, 10 mg per day of elemental zinc is
recommended.
The present WHO and the Govt of India strategy to focus on introduction of zinc along
with reduced osmolarity ORS in the current case management of diarrhoea is an important
step in public health. The administration of zinc with oral rehydration salts for diarrhoea
in the programme settings has resulted in increased use of these salts, decreased use of
antimicrobials and antidiarrheals, and reduction in hospital admissions.17

Lack of evidence to use probiotics and antisecretory drugs in treatment of diarrhea

Probiotics
There is presently insufficient evidence16 to recommend probiotics in the treatment of acute
diarrhea in our settings as almost all the studies till now were done in developed countries.
 Recent Trends in the Management of Acute Watery Diarrhea in Children / 41

It may not be possible to extrapolate the findings of these studies to our setting where
the breastfeeding rates are high and the microbial colonization of the gut is different. The
effect of probiotics is strain related and there is paucity of data to establish the efficacy
of a single strain available in the Indian market. The earlier studies have documented a
beneficial effect on rotavirus diarrhea which was present in more than 75% of cases in studies
from the west. Rotavirus constitutes about 25% of diarrhea in hospitalized children and
15% in outpatient practice in India. The primary outcome analyzed in all the studies was
the duration of diarrhea. The more objective parameter of stool output has not been evaluated.
To recommend a particular species it will have to be first evaluated in randomized controlled
trials in Indian children. Further there is an additional need to study the doses and the
duration of therapy with different strains.
A recent meta analysis18 analyzed the preventive role of probiotics in acute diarrhea.
All 34 reported randomized placebo controlled trials were conducted in developed countries
in health care settings except one which was carried out in the community in a developing
country. The analysis concluded that while there is a role of probiotics in the prevention
of acute diarrhea there is insufficient evidence for extrapolation of these results for use
in developing countries as studies in these settings are lacking.

Antisecretory Drugs in Diarrhea

There is presently not enough evidence on either safety or efficacy of antisecretory drugs
like racecadotril for its routine use in the treatment of diarrhea.19 There is no data from
our settings. Methodology of most of the published studies is questionable in addition to
them being sponsored by a drug company. More importantly all results are not made available
after another large multicentre study evaluating efficacy and safety of the same drug.

REFERENCES
1. National Family Health Survey (NFHS-2) India, 1998-99.
2. Bhandari N, Bhan MK, Sazawal S. Mortality associated with acute watery diarrhea, dysentery and
persistent diarrhea in rural north India. Acta Paediatr 1992;S381:3-6.
3. Hahn SK, Kim YJ, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration
due to diarrhoea in children: systematic review. British Medical Journal, 2001;323:81-5.
4. Reduced osmolarity oral rehydration salts (ORS) formulation. A report from a meeting of experts
jointly organized by UNICEF and WHO. UNICEF HOUSE, New York, USA, 18 July, 2001; WHO/
FCH/CAH/0.1.22.
5. World Health Organization. Complementary Feeding of Young Children in Developing Countries:
A Review of Current Scientific Knowledge. Document ref. WHO/NUT/98.1. Geneva: World Health
Organization;1998.
6. Castillo-Duran C, Vial P, Uauy. R. Trace mineral balance during acute diarrhea in infants. J Pediatr
1988;113:452-7.
7. Ruz M, Solomons NW. Fecal zinc of endogenous zinc during oral rehydration therapy for acute
diarrhea. J Trace Elem Exp Med 1995;7:89-100.
8. Bhandari N, Bahl R, Hambidge KM, et al. Increased diarrhoeal and respiratory morbidity in association
with zinc deficiency: a preliminary report. Acta Pediatr 1996;85:146-50.
42 / Pediatric Gastroenterology

9. Bahl R, Bhandari N, Hambidge KM, et al. Plasma zinc as a predictor of diarrhoel and repiratory
morbidity in children in an urban slum setting. Am J Clin Nutr 1998;68(Suppl 41):4-7.
10. Zinc Investigators Collaborative Group: Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat
A, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing
countries; pooled analysis of randomized controlled trials. Am J Clin Nutr 2000;72:1516-22.
11. Fontaine O. Report of a meeting, New Delhi 7-8 May 2001. Effect of zinc supplementation on clinical
course of acute diarrhea. J Health Popul Nutr. 2001;19(4):338-46.
12. Bhatnagar S, Bahl R, Sharma PK, Kumar GK, Saxena SK, Bhan MK. Zinc treatment with oral rehydration
therapy reduces stool output and duration of diarrhea in hospitalized children; a randomized controlled
trial. J Pediatr Gastroenterol Nutr 2004;38:34-40.
13. Black RE. Zinc deficiency, Infectious Disease and Mortality in the Developing World. J Nutr 2003; 133(5
Suppl 1):1485S-9S.
14. Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S, Vaughan JP. Effect of zinc
supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children:
community randomized trial. BMJ 2002;325(7372):1059.
15. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection.
Am J Clin Nutr 1998;68 (suppl.2):447S-463S.
16. Bhatnagar S, Bhandari N, Mouli UC, Bhan MK. Consensus statement of IAP National Task Force: Status
report on management of acute diarrhea. Indian Pediatr 2004;41:335-348
17. Baqui AH, Black RE, EI Arifeen S, Yunus M, Zaman K, Begum N, Roess AA, Santosham M. Zinc therapy
for diarrhea increased the use of oral rehydration therapy and reduced the use of antibiotics in
Bangladeshi children. J Health Popul Nutr.2004;22(4):440-2.
18. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of
acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis.
2006 Jun;6(6):374-82.
19. Bhan MK, Bhatnagar S. Editorial: Racecadotril-Is there enough evidence to recommend it for treatment
of acute diarrhea? Indian Pediatr. 2004;41:1203-04.