Indian Pediatrics 2003; 40:463-476 

Current Concepts in Management of Acute Diarrhea

Correspondence to: Dr. Maharaj K. Bhan, Professor, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110 029, India. Email:[email protected]

An improved management of diarrheal illness in children is a major accomplishment that can be attributed to development and dissemination of oral rehydration salt solution and of a broader concept of oral rehydration therapy, appropriate treatment of dysentery, improved dietary treatment of childhood diarrhea and steadily declining rates of severe malnutrition(1). The limitations of the current management approach based on oral rehydration are that it does not achieve all the desired goals of therapy. Diarrhea still conti-nues to be a major cause of hospitalization and deaths in under 5 year old children and has severe economic consequences.

There is a strongly felt need among physicians and caretakers of children for additional modalities of treatment that would reduce the duration and severity of the illness, treatment failure rates and need for intra-venous fluids. Some of these newer thera-peutic modalities currently under evaluation include new generation oral rehydration solu-tions, probiotics, micronutrients and alternate feeding regimens. This review summarizes established treatment and describes the current status of the newer therapeutic modalities.

Fluid and Electrolyte Replacement

Assessment of a Child with Diarrhea for Hydration Status

The WHO-ORS is effective in correcting dehydration in all but a small proportion of cases of some dehydration within 3 to 6 hours. Intravenous fluids are required in treatment failures associated with high frequency of stools, uncontrolled vomiting or poor oral intake due to associated infection.

There are however, concerns that the formulation designed originally for the treatment of cholera is not optimal for prevention of dehydration for severely malnourished children and young infants. Research to improve the safety and efficacy of WHO oral rehydration solution has continued over the years and some of the important findings are reviewed later in this chapter.

Newer Oral Rehydration Formulations

The sodium concentration of 90 mEq/L in the current WHO oral rehydration solution corresponds to the stool electrolyte composi-tion in toxin-mediated diarrheas. This solution has nevertheless worked well even in young children with non cholera diarrhea both in developing and developed countries when used according to recommended guidelines with ready access to plain water during oral rehydration. This solution enjoys wide acceptance among physicians and families worldwide.

Several developments have lead to the clinical evaluation of oral rehydration solutions with a reduced osmolarity. Initially, the main concern was the potential risk of hypernatremia with WHO-ORS(2,3). There was also the recognition that the WHO-ORS may provide too much sodium to edematous children(4). It has been pointed out that at a rate of 100 ml/kg/day, the WHO solution can provide as much as 9 mEq/kg/day of sodium, whereas edematous children especially if they have anemia can develop heart failure on diets that provide 6 mEq/kg/day of sodium(5,6). In later years, there were reports of recurrent dehydration in young infants treated with WHO-ORS on a weight to volume basis as replacement of ongoing stool losses that was promptly reversed on nil orally intravenous fluid regimens(7,8). It was postulated that in some infants, glucose malabsorption may be relatively severe and oral fluid replacement in response to stool output simply leads to a vicious cycle with recurrent dehydration. Finally, reduced osmolarity solutions were reported to promote water and sodium absorption more efficiently than the WHO-ORS(6).

A number of oral rehydration solutions with osmolarity ranging from 210 to 268 mosmol/L and sodium ranging from 50 to 75 mEq/L have been assessed for efficacy in randomized controlled trials in adults with cholera and in children with cholera and non cholera diarrhea(9-21). The findings of these studies are summarized in Tables I and II (WHO-ORS, 2001). The study children had acute diarrhea (duration <7 days) with dehydration, they were aged 3 months to 5 years and included malnourished and well-nourished subjects. In a combined analysis of these studies in non cholera diarrhea, stool output was reduced by 20%, incidence of vomiting by about 30% and unscheduled intravenous fluid therapy by 39% in children treated with reduced osmolarity (210 to 268 mosmol/L) as compared to those treated with WHO-ORS(19).

TABLE- I

Results of Meta-analysis Comparing Reduced Osmolarity ORS with Standard ORS in Children 
with Diarrhea.

Outcome	Number of studies	Odds ratio (95% CI)
Unscheduled IV	9	0.61 (0.47, 0.81)
Stool output	12	0.81 (0.74, 0.88)*
Vomiting	6	0.71 (0.55, 0.92)
Hyponatremia	3	1.45 (0.93, 2.26)

* Ratio of geometric means
Adapted from Hahn et al.(19).

 

When low osmolarity solutions with sodium <75 mEq/L and those with sodium ³75 mEq/L were independently compared with standard WHO-ORS in the treatment of acute diarrhea with dehydration, there was a distinct trend towards greater efficacy of the former, particularly in terms of stool output and vomiting (Table II). The number of subjects was however not sufficient to ensure adequate study power for a firm conclusion on this issue.

TABLE II

Results of Meta-analysis of all Randomized Controlled Trials Comparing Reduced Osmolarity 
ORS with Standard ORS in Children With Diarrhea.

Outcome	Reduced Osmolarity ORS <75 mEq/L sodium OR (95% CI)	Standard ORS ³75 mEq/L sodium OR (95% CI)
Unscheduled IV	0.65 (0.41, 1.00)	0.56 (0.39, 0.80)
Stool output	0.69 (0.49, 0.98)*	0.88 (0.71, 1.06)*
Vomiting	0.49 (0.27, 0.91)	0.74 (0.58, 0.95)
Hyponatremia	No event reported	1.45 (0.93, 2.26)

*Ratio of geometric means.
Adapted from Hahn et al.(19)

A recent review of these findings by a WHO-task force has lead to the recommendation of a reduced osmolarity ORS containing 75 mEq/L sodium and 75 mmol/L glucose (total osmolarity 245 mosmol/L) as the preferred universal solution for prevention and treatment of diarrheal dehydration to replace the current WHO-ORS, irrespective of age, etiology or disease severity (Table III). The recommendation was based on several considerations: (i) improved efficacy in non cholera diarrhea in infants and children; (ii) comparable efficacy in adults with cholera with only a marginally elevated risk of asymptomatic hyponatremia; and (iii) the programmatic advantages of preserving a single formulation for treatment and prevention of all types of diarrheas. While it is likely that a more appropriate solution for non cholera diarrhea is one with even lower osmolarity, the risks of hyponatremia when such a solution is used in cholera may be greater and perhaps unacceptable. The WHO has also recommended a range that includes all acceptable ORS formulations including the standard ORS(21).

TABLE III

Composition of Current and Recommended Oral Rehydration Salt Solutions

Composition	Glucose (mmol/L)	Na+ (mmol/L)	K+ (mmol/L)	Cl- (mmol/L)	Citrate (mmol/L)	Magnesium (mmol/L)	Zinc (mmol/L)	Copper (mmol/L)
Standard WHO-ORS (20,21)	111	90	20	80	10
Reduced osmolarity WHO-ORS(21)	75	75	20	65
ESPGAN recommendation (3)	60	60	20	70	3
ReSoMal for severely Mal- nourished Children (28)	125	45	40	70	7	3	300	45

 

The findings of studies of clinical trials of amino acid fortified ORS, of rice and other cereal-based oral rehydration solutions in acute diarrhea and dehydration have been previously reviewed(22-27). Rice based ORS is clearly superior to WHO-ORS in efficacy in adults with cholera but the two solutions were found to be similar in efficacy in non cholera diarrhea based on the most updated meta analysis(25). Oral solutions fortified with amino acids such as L-alanine, glycine, glutamine or with di-peptides were similarly more efficacious in adult cholera but not in non cholera diarrhea in children, presumably due to the high osmolarity of these fortified solutions.

Special Considerations in Treating Dehydration in the Severely Malnourished

The high sodium content of the WHO-ORS may lead to fluid and electrolyte distur-bances in the child with severe malnutrition especially in those with edema. Dehydration tends to be over diagnosed and its severity over estimated in severely malnourished children. The WHO has therefore, recommended that the intravenous route not be used for rehydration of severely malnourished children except in cases of shock(4,28).

Severely malnourished children have low total body potassium content, which is asso-ciated with increased mortality. Such children benefit from potassium supplements(5). Potassium concentration of the standard WHO-ORS may be too low to adequately replace stool losses during diarrhea. Diluting ORS to reduce sodium leads to further reduction in potassium. A new formulation with sodium concentration of 45 mEq/L and potassium of 40 mEq/L, which also provides buffered magnesium, zinc and copper (ReSoMal), is recommended by WHO for use in severely malnourished children (Table III, 28). ReSoMal is not commercially available in many developing countries but can be prepared in a hospital formulary.

In south and south east Asia and other regions where grossly edematous forms of malnutrition are infrequent, the reduced osmolarity ORS now recommended by the WHO (osmolarity 245 mmol/L) is likely to be as well tolerated as a solution with electrolyte contents similar to ReSoMal if it were administered at a slower rate than is recommended for well-nourished children and with added potassium (3-4 mEq/kg/day) and magnesium (0.4-0.6 mmol/kg/day). This view is based on recent studies in this region as well as extensive experience in diarrhea treat- ment units. In Bangladesh, rice-based oral rehydration solution with sodium 90 mmol/L when used for treatment of dehydration in severely malnourished children was not associated with heart failure(29). Vitamins and micronutrients particularly vitamin A, zinc (2mg/kg/day), copper (0.3 mg/kg/day) and folic acid (5 mg on day 1, then 1 mg/day) are also recommended. Advantage of this reduced osmolarity ORS formulation for general use including malnutrition is that a single formulation would be promoted for all ages, irrespective of etiology or nutritional status. Further, in routine use it is difficult to prepare complex formulations like ReSoMal in health care facilities.

Further research is required to standardize assessment and treatment of dehydration in malnourished children.

Resistant Starch as an Adjuvant to Oral Rehydration Solution

Short chain fatty acids promote water and electrolyte absorption in the colon. Starch is fermented in the colon by anaerobic bacteria resulting in production of short chain fatty acids, acetate, propionate and butyrate.

Ramakrishna and colleagues studied a glucose based oral rehydration solution modified by the addition of an amylase resistant starch that is poorly digested in the small intestine of adults with cholera(30). Starch that is resistant to amylase in the small intestine is found in small quantities in many cereals and is a good substrate for colonic fermentation. High amylase maize starch, obtained from a specific variety of corn is rich in resistant starch, and when eaten uncooked, 50-70% of the starch is not digested in the small intestine(30). The researchers antici-pated that the indigestible starch would reach the colon without being absorbed in the small intestine and be metabolized there by colonic bacteria into short chain fatty acids. The use of resistant starch may provide another absorp-tion mechanism in the colon in addition to glucose mediated absorption in the small intestine. This may be particularly important in cholera, as in addition to intestinal secretion, there is decreased absorption of fluid from the large intestine, a phenomenon that can be reversed by short chain fatty acids.

In the adult cholera trial, treatment with resistant starch reduced the amount of diarrhea and shortened the duration of illness. Data in non cholera diarrhea in children are lacking. The physiologic principle demonstrated by these studies is important. The practical implications will become apparent when more clinical evaluation is carried out. In the trial by Ramakrishna et al., antibiotics were withheld for one day, which is not the usual practice(30). Timely effective antibiotics reduce the volume of stool and duration of diarrhea by about 50%. Further, the effects achieved with resistant starch are already available through rice-based and other cereal-based oral solutions, which are routinely used for treatment of adult cholera in countries such as Bangladesh. It appears that the clinical effects of rice based solutions appear earlier than with resistant starch, probably reflecting the site of action as small intestine rather than only colon for the former. The real test would be to compare efficacy of rice-based ORS and resistant starch based standard ORS to assess whether the new product is a practical advance in therapy.

Anti-Microbial Therapy

Almost 90% of diarrheal illnesses have been placed in the category of simple diarrhea manifested by watery diarrhea, low grade fever, mild malaise, abdominal cramps, nausea and occasional vomiting. In developing country children, enterotoxigenic E. coli and rotavirus are the two predominant positive organisms while viral agents account for most of such illnesses in industrialized countries.

On this basis, it has been rightly recommended that such episodes not be treated with antibiotics. Among bacterial infections, the value of antibiotics can be extremely high (Shigella and V. cholerae), questionable (Campylobacter) or none at all (Salmonella)(31).

Choice of antibiotics in dysentery is based on local sensitivity patterns of Shigella iso-lates. Although trimethoprimsulfamethoxa-zole is the recommended first line drug, resistance is common in many parts of the world and this drug is being replaced by nalidixic acid or norfloxacin or ciprofloxacin or newer quinolones. Recent studies show that short term therapy with ofloxacin and cefixime are nearly as efficacious as 5 days of therapy with the same agent against shigellosis(32-34). This should reduce costs and improve compliance.

Antibiotics significantly reduce the duration of diarrhea, the total diarrheal stool volume and the duration of excretion of vibrios. Tetracycline is the most superior oral antibiotic in cholera and is the recommended treatment of choice where strains are sensitive to this drug. The course of therapy is short and therefore, the accumulation of tetracycline in the teeth is not a significant concern in children. Other efficacious drugs in cholera include doxycycline, erythromycin, cotri-moxazole and chloramphenicol(35).

Antimicrobial therapy is indicated for clearly established Giardia lamblia diarrhea. The drugs that appear highly effective include metronidazole, furazolidone, tinidazole, quinacrine and nitazoxenide(31,36,37). Metronidazole is effective against Entamoeba histoloytica trophozoites. If a patient continues to be an asymptomatic passer of amebic cysts after successful treatment of acute illness drugs such as diloxanide furoate may be required.

It is not commonly appreciated that amebiasis is a very infrequent cause of acute dysentery in young children. Further, recent studies show that infection with non-invasive E. dispar is more common than E. histolytica so that it may be worthwhile to differentiate the two by readily applicable ELISA tests before considering therapy.

Protozoal agents such as Cryptosporidium, microsporidia and Isospora belli are common causes of diarrhea in immunocompromised individuals. Among microsporidia, human infection has been reported for Entero-cytozoon bieneusi, Encephalitozoon cuniculi and Septata intestinalis. Multiple stool examinations may be required to detect these protozoal agents. Isospora is amenable to treat-ment with antibiotics specifically sulphona-mides and pyrimethamine. In microspori-diasis, metronidazole and albendazole appear encouraging.

Since, majority of acute infections with these protozoa is self limited; most treatment trials have been done in chronic infections in patients with AIDS. Many agents were used to treat isosporiasis but a 10 day course of trimethoprim-sulfamethoxazole treats the protozoa in immunologically normal subjects and in patients with AIDS. Pyrimethamine-sulfadoxine/sulfadiazine though used less frequently has also been found to give a prompt response. Pyrimethamine used alone is effective in patients with sulfonamide allergies. Macrolide antibiotics have marginal efficacy in treating isosporiasis(38, 39). Trimethoprim-sulfamethoxazole has also been reported to effectively treat cyclospora infections. Little information on clinical experience in therapy of human micro-sporidiasis is available. Descriptive case series suggest that microsporidium S. intestinalis infection can be cured with albendazole. No therapy has proved to be beneficial for E. bieneusi although there is some evidence that albendazole may improve the clinical status without eradicating the protozoa from the stools or the small bowel(40).

There is abundance of anecdotal data regarding the use of numerous agents for cryptosporidiosis, however most of them have proved to be ineffective(41-43). Spiramycin, chloroquin, trimethroprim-sulfamethoxazole, and metronidazole failed to show a beneficial effect. Ornithine decarboxylase inhibitor, alfa-difluoremethylornithine has shown modest efficacy but its usefulness is limited by the bone marrow and gastrointestinal toxicity. Equivocal reports have been obtained with the use of hyper immune bovine colostrum. Both uncontrolled case series and a randomized controlled trial indicate that paramomycin may be effective in treating chronic intestinal cryptosporidiosis(44). The response rate varies from 30-70% and is associated with decreased intensity of infection and improved intestinal function and morphology. Newer semi-synthetic macrolide antibiotics such as clarithromycin and azithromycin have shown promise in small therapeutic trials but larger studies are required(45-46). In a recent study clarithromycin and rifabutin were highly protective against development of cryptospori-diosis in immune suppressed HIV infected persons(46). There is some preliminary evi-dence of benefits of treatment of cryptospori-diosis with nitazoxanide, a 5-nithrothiazole compound also found to be effective against a broad range of parasites, almost all anaerobic obligate and facultative bacteria and some aerobic bacteria(47). There have been some reports of resolution of cryptosporidial diarrhea with the use of zidovudine in HIV infected patients. Recently, combination anti-retroviral therapy which includes at least one HIV-1 protease inhibitor has been used for improving immunity to E. bieneusi and C. parvum in a small number of HIV-1 infected patients. The treatment resulted in complete immediate microbiological, clinical and histological responses but failed to eradicate the infection as evidenced by a rapid relapse rate(48). Another case report has documented effective treatment and successful eradication of Cryptosporidium with indinavir, a protease inhibitor, in an HIV infected person.

Micronutrients in the Treatment of Acute Diarrhea

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(49). The zinc depleting effects of diarrhea are most distinctly seen in adults receiving parenteral nutrition: intravenous zinc required to achieve positive zinc balance averaged 13 mg in patients with ongoing diarrheal fluid losses compared with 2.5 mg in patients without such losses(49-50). Although the theoretical basis for a potential role of zinc in treatment of acute diarrhea has been postulated for quite some time, convincing evidence for its clinical importance has come from recent randomized controlled trials of zinc supplementation (51-55).

The results of pooled analyses of zinc treatment trials in children with acute diarrhea and the findings of three subsequent studies are summarized in Table IV. The main features of these trials include the randomized placebo controlled design, subjects’ age between 6 months and 3 years, and daily elemental zinc dose ranging from 10 to 30 mg per day (55).

TABLE IV

Results of Pooled-analysis and New Unpublished Randomized Controlled Trials in 
Children with Acute Diarrhea Comparing Impact of Zinc with that of Placebo.

Study	Number of subjects	Effect size (95% CI)
Risk of continuation of diarrhea Relative hazards
Pooled analysis	1252/1194	0.85 (0.76 to 0.95)
Bhatnagar et al. (56)	132/134	0.77 (0.59 to 0.99)
Strand et al. (57)	442/449	0.79 (0.68 to 0.93)
Bahl et al. (58)	404/401	0.89 (0.80 to 0.99)
Diarrhea lasting >7 days Odds Ratio
Pooled analysis	1252/1194	0.78 (0.56 to 1.09)
Strand et al. (57)	442/449	0.57 (0.68 to 0.86)
Bahl et al. (58)	404/401	0.61 (0.33 to 1.12)
Stool output Difference in means or Ratio of Geometric means
Roy et al. (52)	57/54	–91 g
Dutta et al. (18)	44/36	–900 g (–1200 to –590)
Bhatnagar et al. (56)	132/134	0.73 (0.52 to 1.02)

In the trials subjected to meta 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 analyses concluded that zinc supplementation given along with appropriate fluids and food during acute diarrhea reduces the duration of the illness and its severity (55).

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 28% (95% CI-3% to 50%) than in the placebo group(56). In another Indian study by Bahl et al., the efficacy of 40 mg elemental zinc mixed with a liter of standard ORS solution was compared with ORS without zinc and with zinc syrup administered separately from ORS. 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(58).

Several other observations from these trials are noteworthy(59). 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(59). Majority of the studies so far were conducted in south Asia, where zinc deficiency is common. Finally, there are relatively few data on children aged less than 6 months to allow any conclusions about efficacy in this age group.

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 defi- ciency 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(49). Zinc deficiency has also been recently shown to affect the differentiation of CD4 response towards Th1 rather than Th2 pathway(60). 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(49,52).

It is time now time to debate potential use of zinc as treatment of acute diarrhea in child health programs. It must be first established that its promotion will not affect ORS use in a cost competition. Indeed there may be ways in which zinc can be made available with ORS packets in a way that actually increases ORS use. This was recently observed in Bangladesh (A. Baqui; personal communication). There is also a possibility that promotion of zinc as treatment of acute diarrhea may decrease antibiotic use during diarrhea which would be a major gain. This need to be demonstrated through appropriately designed studies.

Finally, a recent study from Bangladesh has found that introduction of zinc as treatment of acute diarrhea in a Primary Health Care Program resulted in decreased diarrhea related mortality. Zinc treatment during acute diarrhea was given for 2 weeks, often extending it beyond the recovery of the enrollment episode (A. Baqui, personal communication). This needs to be confirmed in programmatically tailored studies in India.

The results of trials with vitamin A treatment in acute diarrhea are summarized in Table V. The trials were all randomized placebo controlled, the subjects were aged 6 months to 5 years and a dose of vitamin A was administered (100,000 between 6 and 12 months and 200,000 IU to children over one year of age). Overall, the results indicate that vitamin A has no impact on overall diarrhea duration or stool frequency, but there is a significant reduction in episodes that become persistent, i.e., last 14 or more days. It thus appears that while the effects of treatment with zinc become apparent early in illness, effects of vitamin A large dose takes many days to manifest, possibly reflecting differences in the way they affect the gastrointestinal tract during acute infection(61-65).

TABLE V

Randomized Controlled Trials Evaluating the Effect of Vitamin A Administered During 
Acute Diarrhea on Episode Outcome.

Study	Number of subjects	Results
Henning et al.(62)	41/42	No effect on mean duration. No effect on severity.
Bhandari et al.(64)	451/444	No effect on mean duration. Marked effect on risk of persistence of diarrhea >14 days, Rate ratio 0.3 (95% CI 0.1 to 0.92).
Faruque et al.(65)	341/340	No effect on mean duration. Possibility of an effect on risk of persistence of diarrhea >14 days, Rate ratio 0.66 (95% CI 0.24 to 1.85).
Hossain et al.(63)	42/41	Effect on pro-portion of children clinically not cured by day 5, Risk ratio 0.68 (95% CI 0.5 to 0.93)

It is still not known whether other micronutrients or combinations of micro-nutrients have greater effects during acute diarrhea than that achieved with zinc alone. Bahl et al recently compared efficacy of a combination of micronutrients including zinc, vitamin A, folic acid, B12 Vitamin D, selenium and manganese in children with acute diarrhea with zinc alone (58). This study showed that zinc alone was as efficacious as these multiple micronutrients in reducing the severity of acute diarrhea but the authors recognized that with the available end study power, only large differences in diarrheal duration and stool frequency could have been detected.

In summary, there is convincing evidence that zinc treatment leads to a modest reduction in duration and severity of acute diarrhea but the role of other micronutrients needs more evaluation.

Probiotics in the Treatment of Acute Diarrhea

Probiotics have been used for long in the treatment of acute diarrhea although their efficacy has been frequently questioned.

The rationale for their use in acute diarrhea is based on one or more of several of their postulated effects. These include competition for nutrients with pathogenic microorganisms, inhibition of adhesion of pathogens to intestinal epithelial cells, production of antimicrobial substances, modification of toxins or toxin receptors and enhanced immune responses to pathogens(66-76). A systematic review of randomized, placebo controlled trials of probiotics in the treatment of acute diarrhea was recently carried out by Szajewska and Mrukowicz (Table VI)(70). In these trials, acute diarrhea was defined as passage of more than 3 loose or watery stools per 24 hours in infants and children. The use of probiotics as compared to placebo was associated with a significant reduction in the duration of diarrhea when compared to placebo: the pooled, weighted mean difference was –20.1 hours (95% CI, –26.1 to –14.2). Four of the 10 trials used Lactobacillus GG, two each Lactobacillus renteri and Lacto-bacillus acidophilus LB, another trial used Saccharomyces boulardii and another S. thermophilus with L. acidophilus and L. bulgaricus.

TABLE VI

Results of Meta-analysis Randomized Controlled Trials in Children with Acute Diarrhea 
Comparing Probiotics with Placebo.

Outocme	Number of Studies	Odds ratio or Difference in means (95% CI)
Diarrhea lasting >3 days	8	0.40 (0.28,0.57)
Diarrhea lasting >3 days (Studies with Lactobacillus GG only)	3	0.38(0.19,0.77)
Duration of diarrhea (hours)	8	-20.1(-26.1, to -14.2)
Duration of rotavirus diarrhea (hours)	5	-24.8(--31.8 to -17.9)
Adapted from Szajewska et al.(70).

The authors interpreted the data to show that the most consistent effect was with lactobacillus GG although other probiotic strains may also be effective. The available data are not sufficient to allow any firm conclusions with regard to efficacy by the type of strain used in these trials.

Overall, evidence is consistent with modest but significant benefit of probiotics in the treatment of acute gastroenteritis in infants and children. Unfortunately, none of the studies in the review reported stool output data and a firm recommendation on the practical importance of this treatment must await trials that measure impact on this important outcome. Future trials should use carefully selected and precisely defined probiotic strains to allow judgment on individual products.

Conclusions

The challenge ahead is to implement more widely the current treatment package. Efforts must also continue to discover a clinically useful anti-secretory agent for all cases of diarrhea, newer agents against cholera, shigella and protozoal diarrheas. The recent interventions reported here represent a useful change in the current treatment package but not a major leap forward. In deciding the relevance of new interventions in developing country programs, several factors need consideration. These include the likelihood that their introduction will displace oral rehydration solutions in a cost competition and on the other hand, potential reduction in unwarranted antibiotic use.

Key Messages

• New generation reduced osmolarity oral rehydration solutions are preferred for prevention and treatment of diarrheal dehydration. • Severely malnourished children with diarrheal dehydration benefit from potassium supplements. • Antibiotics are useful only in small number of diarrhea cases particularly those due to shigella and vibrio cholerae. • Zinc treatment leads to a modest reduction in duration and severity of acute diarrhea but the role of other micronutrients needs more evaluation. • Benefit of probiotics in the treatment of acute diarrhea is modest but more trials are needed for a firm recommendation.

 References