In humans, dietary fiber is mainly degraded in the large intestine by bacterial flora, which liberates short-chain fatty acids (SCFAs) (1). These compounds serve as a metabolic fuel for the colonocytes (2,3), stimulate epithelial cell proliferation (4), and exert a trophic effect on colonic mucosa (5). The SCFAs are also absorbed by the colon (6,7). Absorption of SCFAs is associated with stimulation of sodium transport from the colon in several species including humans (8–10). This effect may be particularly important in acute diarrheal diseases in which fasting and purging may deplete SCFAs in the colon (11,12) and cause colonic dysfunction (12,13). Luminal SCFA levels in the colon may therefore influence the clinical course of acute diarrheal diseases. Recently, the production of SCFAs in the colon has been shown to be clinically beneficial in cholera (14).
At ICDDR,B a pilot study (15) has evaluated the effect of green plantain or pectin-containing diets in the treatment of children with persistent diarrhea. The children receiving either green plantain or pectin had significantly less stool output and duration of diarrhea. Partially hydrolyzed guar gum (Benefiber) is a soluble fiber that completely dissolves in water and is fermented in the colon liberating SCFAs (16). Patients in intensive care fed enteral nutrition formulas supplemented with Benefiber had a decreased incidence of diarrhea compared with control subjects (17). No clinical study has been performed with this product as an antidiarrheal therapy in infectious diarrhea. It was hypothesized that Benefiber, added to WHO ORS, would enhance colonic absorption of salt and water and thereby improve the course of acute diarrheal illness. The present study was performed to evaluate the efficacy of BF-supplemented WHO ORS in the treatment of acute noncholera diarrhea in children.
PATIENTS AND METHODS
The study was conducted at the Clinical Research and Service Centre of the ICDDR,B: Centre for Health and Population Research, and the protocol was approved by the ICDDR,B Research Review and Ethical Committees. Patients eligible for the study were male children between the ages of 4 and 18 months with acute watery diarrhea of less than 48 hours' duration and without blood and mucus, absence of Vibrio cholerae in initial stool and rectal swabs examined by dark-field microscopy, no antimicrobial therapy before admission to the hospital, and absence of severe dehydration or severe infection (e.g., pneumonia, septicemia, meningitis) and edema. Written informed consent was obtained from parents or legal guardian.
Children remained in the hospital throughout the study period. Initial evaluation included a standard clinical history and physical examination with anthropometry. Dehydration status was assessed according to the WHO guideline (18). Laboratory investigations included stool microscopic examination for leukocytes, red blood cells, and parasites (including Giardia lamblia, Entamoeba histolytica, and Cryptosporidium); stool was cultured for Shigella, Salmonella, V. cholerae, and Campylobacter jejuni by standard methods and for rotavirus by enzyme-linked immunosorbent assay (ELISA).
The sample size was estimated on the basis of previous study data in which patients treated with WHO ORS had a mean stool output of 210 ± 106 (standard deviation [SD]) g/kg per day (19). A sample size of 75 per group was determined with the expectation of a 25% stool output reduction with the new treatment, assuming a 15% withdrawal rate, and considering 5% to be the level of significance and 80% power.
After enrollment, children were randomly assigned to one of the two treatment groups: BF-supplemented (20 g/L Benefiber) WHO ORS or standard WHO ORS. A randomization list was prepared using a random number table compiled by a statistician not involved in the study. Serially numbered sealed identical envelopes were prepared by the statistician containing the name of the ORS inside. The envelopes were supplied to the pharmacist of the centre who prepared the ORS solutions according to the list. The two ORSs were identical in appearance and were supplied in a clean 1-L bottle marked only with the patient's name and study number for identity. For analysis a code (group A or B) was provided to the investigators, without disclosing the patients' identities. After the data analysis tables were prepared, group identity was provided for preparation of the final report.
After admission, the children were rehydrated with the assigned ORS (10–12 mL/kg body weight per hour) during a period of 4 to 6 hours. Ongoing stool losses were replaced with the same ORS with a minimum volume equal to the loss of watery stool until diarrhea ceased. The ORSs were discarded 12 hours after preparation.
Breast milk was allowed as desired. Supplementary feeding (milk, cereal, and a vegetable oil mixture containing 68 kcal/100 mL) was also provided according to standard hospital practice; partially breast-fed children were offered 75 kcal/kg per day and the non–breast-fed children were supplied with 110 kcal/kg per day. Additional feedings were allowed to children on demand.
The children were placed on a “cholera cot,” and a pediatric urine collector was applied to collect urine separately. Stool weight, supplemented food, and body weight were measured with an electronic scale (Sartorius, Göttingen, Germany) with a precision of 1 g. ORS, plain water, and urine were measured with a calibrated cylinder. All intakes (ORSs, plain water, and food) and output (stool, urine, and vomitus) measurements were summarized every 8 hours. Body weight was also measured every 8 hours until the children were discharged. Clinical evaluation was performed every morning and evening. Cessation of diarrhea was defined as the appearance of soft or formed stool and/or no stool for 16 hours. Therapeutic success was defined as the cessation of diarrhea within 7 days (study period) of inclusion in the study treatment. Duration of diarrhea was calculated as the duration in hours from the time of randomization to the last watery or loose stool. Patients were withdrawn from the study if their parents or legal guardian withdrew consent, if transferred to other units for treatment of severe underlying illness, or if diarrhea continued for more than 7 days after randomization. Data collected on patients withdrawn from the study were included in the analysis up to the time of withdrawal.
All data were analyzed by microcomputer (StatPack Gold; Walonick Associates, Minneapolis, MN, U.S.A.; analyzed by SPSS/PC, SPSS, Inc., Chicago, IL, U.S.A.). Continuous variables were compared between the groups with Student's t-test, and χ2 test was used for dichotomous variables. A nonparametric test (Mann–Whitney) was used for comparison of the skewed data. A survival plot was constructed for the duration of diarrhea and compared between the groups with a log rank test.
One hundred sixty-two children were eligible to participate in the study. Of these, 12 patients were not included in the study, because their parents refused consent. After randomization, parents of two patients from each group withdrew their consent before the study was completed. Of the 150 patients randomized, 75 received BF-supplemented WHO ORS, and 75 received WHO ORS. Clinical characteristics at admission were comparable between the groups except body weight, and the difference in body weight was clinically insignificant (Table 1). Duration of diarrhea after hospital admission was significantly reduced in the BF-supplemented WHO ORS–treated group (mean ± SD, 74 ± 37 vs. 90 ± 50 hours, P = 0.03;Table 2). The survival analysis for duration of diarrhea also showed a reduction in the BF-supplemented WHO ORS–treated group (Fig. 1) compared with the control group (P = 0.025, log rank test). There was less stool output from days 2 through 7 in the patients treated with BF-supplemented WHO ORS compared with children treated with WHO ORS, although the reduction was not statistically significant except on day 7 (data not shown). Although not significant, total stool weight for the same period (day 1 through day 7) was reduced by 18% in the BF-supplemented WHO ORS–treated group compared with the WHO ORS group (Table 2). There was also less ORS intake in the group receiving BF-supplemented WHO ORS, but the difference was not significant (Table 2). Total water intake and total urine output (both in milliliters per kilogram body weight) were similar in both groups (Table 2). Energy intake from the supplementary food was not different between the treatment groups. Mean body weight gain was greater in the BF-supplemented WHO ORS–treated group compared with the control group, although the variation was wide (Table 2).
Standard therapy for acute childhood diarrhea includes oral rehydration therapy, proper feeding, and antimicrobial drugs, if indicated. Since its development, efforts have been made to improve the efficacy of oral rehydration solution in the treatment of diarrheal diseases. Until recently, most studies were designed to improve the small intestinal absorption efficiency of oral rehydration solution during the treatment of acute diarrhea (20). The present study was designed to improve the colonic absorption/salvage of water and electrolytes that pass through the colon by the addition of Benefiber without increasing the osmolality of ORS.
The results of the present study demonstrate that Benefiber, added to WHO ORS, enhanced recovery from acute watery diarrhea in children compared with WHO ORS alone, by reducing the duration of diarrhea and stool output. Reduction of stool weight in the Benefiber-treated group was less impressive than the reduction in time to recovery from diarrhea. A similar finding was also demonstrated in another study (21). Soy polysaccharide, a soluble fiber, reduced the duration of diarrhea but not fecal weight, in children with acute diarrhea (compared with control diet) when added to the diet. A possible explanation is the increased amount of fecal bacteria that may have proliferated because the energy that is provided from the intraluminal fermentation of Benefiber contributes some fecal weight (22).
The enhancement of recovery from acute diarrhea in children treated with Benefiber-supplemented ORS was probably the result of fermentation of Benefiber by colonic bacteria to SCFAs which then stimulated colonic absorption of fluid and electrolytes. Estimation of the level of fecal SCFAs would help to substantiate the proposed mechanism. Unfortunately, estimation of fecal SCFAs was not attempted because of difficulty in its estimation. Also fecal SCFA concentration does not necessarily reflect production. The beneficial effect of Benefiber could also have been attributed to slowing (permitting more time for absorption) of intestinal transit time, although Benefiber has not been shown to increase orocecal transit time, but has increased colonic transit time (23). The colon is thought to be the major site of action of dietary fiber.
With a similar hypothesis, Ramakrishna et al. (14) have performed a study using WHO ORS supplemented with an amylase-resistant starch in the treatment of adolescent and adult cholera. The addition of resistant starch to the oral rehydration solution significantly reduced the duration of diarrhea and stool weights after 12 hours of treatment. The mechanisms that explain the beneficial effect of resistant starch in the treatment of cholera support our findings, although the cause of diarrhea is different. Further studies are warranted to evaluate the beneficial effect of resistant starch in noncholera diarrhea in children. It is expected that the composition of oral rehydration solution that can maximally use the whole absorptive surface of small and large intestine may evolve as an improved oral rehydration solution.
Cereal-based oral rehydration solutions have been shown to reduce the stool output and duration in acute diarrhea (24). Although not discussed in earlier reports, one of the mechanisms involved may be that the undigested polysaccharides reach the colon, undergo fermentation, and liberate the SCFAs. Mechanisms and site of action of dietary fibers as an antidiarrheal agent may also depend on its physical properties. A viscosity-enhancing agent (carboxymethyl cellulose) added to ORS increased water and sodium absorption in a rat model of chronic osmotic diarrhea (25). Benefiber is much less viscous in solution than in its native form (guar gum).
Gum arabic, a soluble fiber has been demonstrated to promote sodium and water absorption from oral rehydration solutions in two models of diarrhea (26). The emulsifying property of gum arabic that results in greater accessibility of electrolytes and associated water to the microvillus membrane is thought to be the cause of its proabsorptive effect. The emulsifying effect of the present study fiber is uncertain. More studies are needed to elucidate the different antidiarrheal factors of various soluble fibers.
Therapeutic application of dietary fibers or fiber-containing food including amylase-resistant starch is yet to be established in the treatment of diarrhea. Rice-based ORS has been used in the treatment of watery diarrhea in ICDDR,B and other centers in Bangladesh. However, some disadvantages (too thick to feed young infants and shorter stability) limit its use universally. Benefiber, however, if added to WHO ORS makes a clear solution without altering its taste and stability. In Bangladesh, soluble fiber, especially pectin-containing green fruits and vegetables (e.g., wood apple and green plantain), have been used traditionally as antidiarrheal agents in patients with diarrhea who expect early recovery (personal observation), and its beneficial effect has been validated recently (15).
In conclusion, the results of the present study showed that Benefiber, if added to ORS, facilitates recovery from acute watery diarrhea in children, demonstrating its potential as a new antidiarrheal therapy for diarrheal disease.
This research was supported by Novartis Nutrition, Bern, Switzerland and the ICDDR,B Centre for Health and Population Research. The Centre is supported by the following countries, donor agencies and others that share its concern for the health and population problems of developing countries: The aid agencies of the governments of Australia, Bangladesh, Belgium, Canada, European Union, Japan, the Netherlands, Norway, Saudi Arabia, Sweden, Switzerland, the United Kingdom, and the United States; United Nations agencies: United Nations Development Programme (UNDP), United Nations Children's Emergency Fund, and the World Health Organization; International organizations: International Atomic Energy Agency, International Centre for Research on Women, International Development Research Centre, Population Council, Swiss Red Cross, and the World Bank; Foundations: Aga Khan Foundation, Child Health Foundation, Ford Foundation, George Mason Foundation, and Rockefeller Foundation; Medical research organizations: International Life Sciences Institute, National Institutes of Health, New England Medical Center, Northfield Laboratories, Procter and Gamble, Rhone Poulenc Rorer, and Thrasher Research Fund; Universities: Johns Hopkins University, Karolinska Institute, Loughborough University, London School of Hygiene and Tropical Medicine; University of Alabama at Birmingham, University of Goteborg, University of Pennsylvania, and University of Virginia; Others: American Express Bank, Helen Keller International, Lederle Praxis, NRECA International Ltd., The Rand Corporation, Save the Children Fund-, U.S.A., Social Development Center of the Philippines, UCB Osmotic Ltd., and Wander AG.
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