Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea

OBJECTIVE—To evaluate the impact of zinc supplementation on the clinical course, stool weight, duration of diarrhoea, changes in serum zinc, and body weight gain of children with acute diarrhoea.
DESIGN—Randomised double blind controlled trial. Children were assigned to receive zinc (20 mg elemental zinc per day) containing multivitamins or control group (zinc-free multivitamins) daily in three divided doses for two weeks.
SETTING—A diarrhoeal disease hospital in Dhaka, Bangladesh.
PATIENTS—111 children, 3 to 24 months old, below 76% median weight for age of the National Center for Health Statistics standard with acute diarrhoea. Children with severe infection and/or oedema were excluded.
MAIN OUTCOME MEASURES—Total diarrhoeal stool output, duration of diarrhoea, rate of weight gain, and changes in serum zinc levels after supplementation.
RESULTS—Stool output was 28% less and duration 14% shorter in the zinc supplemented group than placebo (p = 0.06). There were reductions in median total diarrhoeal stool output among zinc supplemented subjects who were shorter (less than 95% height for age), 239v 326 g/kg (p < 0.04), and who had a lower initial serum zinc (< 14 mmol/l), 279 v 329 g/kg (p < 0.05); a shortening of mean time to recovery occurred (4.7 v 6.2 days, p < 0.04) in those with lower serum zinc. There was an increase in mean serum zinc in the zinc supplemented group (+2.4 v −0.3 µmol/l, p < 0.001) during two weeks of supplementation, and better mean weight gain (120 v 30 g, p < 0.03) at the time of discharge from hospital.
CONCLUSIONS—Zinc supplementation is a simple, acceptable, and affordable strategy which should be considered in the management of acute diarrhoea and in prevention of growth faltering in children specially those who are malnourished.

     

Impact of zinc supplementation on persistent diarrhoea in malnourished Bangladeshi children

To evaluate the impact of zinc supplementation on the clinical recovery and body weight of children with persistent diarrhoea, a randomized, double-blind, controlled trial was conducted in 190 children with persistent diarrhoea aged between 3 and 24 months. Children were randomly allocated to receive either zinc (20 mg d⁻¹) syrup with multivitamin (2 × RDA) or multivitamin alone in three divided daily doses for 2 weeks. The trial was conducted in a diarrhoeal disease hospital in Dhaka, Bangladesh. Duration until clinical recovery (d), impact on body weight and serum zinc level after 2 weeks of zinc supplementation were recorded. The duration of illness was significantly reduced (33%) with zinc supplementation among children who were underweight (≤70% wt/age, p = 0:03). Supplemented male children also had a significant reduction (27%) in duration for recovery compared with unsupplemented children ( p = 0:05). From baseline to convalescence, zinc-supplemented children maintained their serum zinc concentration (13.4 vs 13.6/ μ mol l⁻¹), whereas unsupplemented children had a decrease in serum zinc after the 2 weeks of diarrhoea (13.6 vs 11.8 μ mol l⁻¹, p < 0:03). The mean body weight of the children in the supplemented group was maintained (5.72 vs 5.70 kg, p = 0:62) during hospitalization, unlike that of the control group, in which there was a reduction in body weight (5.75 vs 5.67 kg, p = 0:05). Five children in the unsupplemented group and one child in the zinc-supplemented group died during the 2 weeks of supplementation ( p = 0:06). Zinc supplementation in persistent diarrhoea significantly reduced the length of the recovery period in malnourished children and prevented a fall in body weight and serum zinc concentration, indicating that zinc is a beneficial therapeutic strategy in this high-risk childhood illness.     

Impact of zinc supplementation in malnourished children with acute watery diarrhoea

A double-blind, randomized, controlled clinical trial was conducted on 80 malnourished children with acute dehydrating diarrhoea to evaluate the efficacy of oral supplementation of zinc as an adjunct therapy to oral rehydration solution (ORS). After decoding it was observed that 44 children received zinc sulphate (177 mg/kg/day in three divided doses equivalent to 40 mg elemental zinc) in a syrup form and 36 children received only syrup placebo. Clinical parameters and microbiological findings of stool samples were comparable in the two groups at the time of enrollment. All the children (100 per cent) in the zinc supplemented group and 32 (89 per cent) children in the placebo group recovered within 5 days of hospitalization (p = 0.04). The zinc supplemented group had a significantly shorter duration of diarrhoea (70.4 +/- 10.0 vs. 103.4 +/- 17.1 h; p = 0.0001), passed less liquid stool (1.5 +/- 0.7 vs. 2.4 +/- 0.7kg; p=0.0001), consumed less oral rehydration solution (2.5 +/- 1.0 vs. 3.6 +/- 0.8 litre; p = 0.0001) and other liquids (867.0 +/- 466.1 vs. 1354.7 +/- 675.6 ml; p = 0.0001) as compared to the placebo group. Our findings suggest that zinc supplementation as an adjunct therapy to ORS has beneficial effects on the clinical course of dehydrating acute diarrhoea.     

Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome.

Zinc has been shown to enhance intestinal mucosal repair in patients suffering from acrodermatitis enteropathica; but the impact on mucosal integrity during acute (AD) or persistent (PD) diarrhoea is unknown. One hundred eleven children with AD and 190 with PD aged between 3 and 24 months received, randomly and blind to the investigators, either an elemental zinc supplement of 5 mg/kg body wt/day or placebo in multivitamin syrup for 2 weeks while intestinal permeability and, biochemical and anthropometric markers were serially monitored. The permeability test was administered as an oral dose of 5 g lactulose/l g mannitol in a 20-ml solution followed by a 5-h urine collection. The ratio of the urinary probe sugars was correlated to clinical, biochemical, and microbiological parameters. At presentation, lactulose excretion was increased and mannitol excretion decreased in both AD and PD as compared with age-matched asymptomatic children. The lactulose/mannitol ratio (L/M) was higher in subjects with mucosal invasive pathogens (rotavirus and enteropathogenic Escherichia coli) compared with children excreting Vibrio cholera and enterotoxigenic E. coli. Two-week zinc supplementation significantly reduced lactulose excretion in both AD and PD, whereas the change in mannitol excretion and L/M was similar between study groups in both studies. Changes in lactulose excretion were significantly influenced by zinc supplementation in children with E. coli, Shigella sp., and Campylobacter jejuni stool isolates. The greatest reduction in total lactulose excretion was seen in supplemented children who on presentation were lighter (wt/age less than 80%), thinner (wt/ht less than 85%), and undernourished [middle upper arm circumference (MUAC) less than 12.5 cm] or with hypozincaemia (less than 14 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)     

Double-blind, randomized, controlled trial of zinc or vitamin A supplementation in young children with acute diarrhoea

In a double-blind, controlled trial with a factorial design, 684 patients (aged 6 months to 2 y; excludes 6 early dropouts) with acute watery diarrhoea of 3 d or less and some dehydration, who were attending a hospital, were randomly assigned to 4 groups to receive: (a) vitamin A 4500 microg retinol equivalent daily for 15 d; (b) 14.2 mg elemental zinc as acetate for the first 417 patients and 40 mg of the remaining 273 patients randomized to this group for 15 d; (c) both vitamin A 4500 microg retinol equivalent and zinc at the above doses daily for 15 d; or (d) placebo mixtures for 15 d. Patients were observed in the hospital for 24 h and followed up at home for 15 d. All received ascorbic acid 30 mg with each dose of medicine or placebo. Zinc supplementation was associated with a reduced duration of diarrhoea (13%, p = 0.03) and markedly reduced rate (43%, p = 0.017) of prolonged diarrhoea (>7 d). Vitamin A supplementation was associated with a nonsignificant trend for reduced rate of prolonged diarrhoea (p = 0.089). In conclusion, zinc supplementation as adjunct therapy had a substantial impact on the rate of prolonged diarrhoea and some impact on duration and may be beneficial in children with diarrhoea in developing countries.     

Impact of zinc supplementation in children with acute diarrhoea in Turkey

Objective

Zinc deficiency is prevalent in children in developing countries. Supplemental zinc provides therapeutic benefits in diarrhoea. Our aim was to evaluate the effect of daily zinc supplementation for 14 days on diarrhoea duration, severity, and morbidity in children.

Methods

In a randomised, open label non‐placebo controlled trial, we assessed the efficacy of providing zinc sulfate to 6–60 month old children with acute diarrhoea for 2 weeks followed by 3 months of morbidity surveillance. Children were randomly assigned to zinc (n = 150) and control (n = 130) groups and received 15–30 mg elemental zinc daily.

Results

Supplemented children had significantly improved plasma zinc levels by day 14 of therapy. Zinc deficiency was observed in 2.6% of the treatment and 3.3% of the control group. The mean duration of diarrhoea after starting supplementation was 3.02±2 days in the zinc group and 3.67±3.2 days in the control group. There was no significant difference in diarrhoea duration by treatment group (p>0.05). The number of stools after starting supplementation was 5.8±3.7 and 5.1±3.9 on day 1, 2.9±1.6 and 3.0±2.2 on day 2, and 1.8±1.1 and 1.6±0.9 on day 3 in the zinc and control groups, respectively. There was no significant difference in diarrhoea severity by treatment group (p>0.05). No significant effect was found on the incidence and prevalence of diarrhoea in the zinc compared with the control group.

Conclusion

Our data indicate that supplementing children with acute diarrhoea in Turkey with 3 RDA of elemental zinc for 14 days improved neither diarrhoea duration nor severity despite significant increments in plasma zinc.     

Impact of zinc supplementation in children with acute diarrhoea in Turkey.

OBJECTIVE: Zinc deficiency is prevalent in children in developing countries. Supplemental zinc provides therapeutic benefits in diarrhoea. Our aim was to evaluate the effect of daily zinc supplementation for 14 days on diarrhoea duration, severity, and morbidity in children. METHODS: In a randomised, open label non-placebo controlled trial, we assessed the efficacy of providing zinc sulfate to 6-60 month old children with acute diarrhoea for 2 weeks followed by 3 months of morbidity surveillance. Children were randomly assigned to zinc (n = 150) and control (n = 130) groups and received 15-30 mg elemental zinc daily. RESULTS: Supplemented children had significantly improved plasma zinc levels by day 14 of therapy. Zinc deficiency was observed in 2.6% of the treatment and 3.3% of the control group. The mean duration of diarrhoea after starting supplementation was 3.02+/-2 days in the zinc group and 3.67+/-3.2 days in the control group. There was no significant difference in diarrhoea duration by treatment group (p>0.05). The number of stools after starting supplementation was 5.8+/-3.7 and 5.1+/-3.9 on day 1, 2.9+/-1.6 and 3.0+/-2.2 on day 2, and 1.8+/-1.1 and 1.6+/-0.9 on day 3 in the zinc and control groups, respectively. There was no significant difference in diarrhoea severity by treatment group (p>0.05). No significant effect was found on the incidence and prevalence of diarrhoea in the zinc compared with the control group. CONCLUSION: Our data indicate that supplementing children with acute diarrhoea in Turkey with 3 RDA of elemental zinc for 14 days improved neither diarrhoea duration nor severity despite significant increments in plasma zinc.     

Serum and hair zinc in severely malnourished Bangladeshi children associated with or without acute lower respiratory infection

Objective  To assess the zinc status in Bangladeshi children suffering from severe protein energy malnutrition (severe PEM), acute lower respiratory infection (ALRI), PEM presented with ALRI and to evaluate the relationship of zinc status with aforementioned clinical conditions. Methods  We assessed zinc status by simultaneous estimation of serum and hair zinc of Bangladeshi children less than 5 yr of age suffering from severe PEM, ALRI, severe PEM presented with ALRI and compared them with zinc status of well-nourished healthy children (control) in a hospital based cross sectional four cell study. Zinc concentration was estimated by Flame atomic absorption spectrophotometry. Results  Total one hundred and fifty two children were enrolled and number of children enrolled in severe PEM, ALRI, ALRI with PEM and control were 47, 35, 32 and 38 respectively. Both serum and hair zinc in univariate analysis were found significantly (p<0.05) low in severe PEM, ALRI and severe PEM associated with ALRI. However, in multivariate analysis, when serum and hair zinc were included in the same model, both serum and hair zinc were found to have significant negative association with PEM (p=0.002 & 0.013 respectively) and with ALRI only when ALRI was associated with PEM (p=0.043 and 0.034 respectively). Conclusion  Severe PEM and PEM with ALRI were significantly associated with low zinc status.     

Zinc supplementation in Brazilian children with acute diarrhoea

Although oral rehydration therapy greatly reduces mortality from diarrhoeal diseases, it has little effect on stool frequency. However, there is mounting evidence that zinc is an effective adjunct to the treatment of diarrhoea, although few studies have examined its efficacy in Latin America. This study assessed the efficacy of zinc supplementation in children with acute diarrhoea in Brazil. The study was a double-blind, placebo-controlled, randomised, clinical trial in children <5 years of age attending emergency services in Sergipe, Brazil. Subjects received zinc or vitamin C as placebo. There was a marked reduction in the duration of the diarrhoea (1.1 vs 2.6 days) and of watery stools in the zinc-supplemented group. The efficacy of zinc was independent of the presence of viral enteropathogens in the stools. It is concluded that, similar to studies in India and Bangladesh, zinc could be an important adjunct for treating acute diarrhoea in Brazilian children.     

Management of malnourished children with acute diarrhoea and sugar intolerance

A protocol of nutritional rehabilitation using fermented milk, vegetable oil and caster sugar has been tested on 54 Senegalese children, aged 6-36 months, admitted with acute diarrhoea and malnutrition. At the time of admission, 39 per cent of children were dehydrated and 26 per cent had sugar intolerance. In the course of treatment three went home against medical advice and one died from acute pneumonia with respiratory-heart failure. Among the cases of marasmus there were no differences in mean weight gain between children with sugar intolerance and others despite a longer duration of diarrhoea in the first group. Furthermore, the experimental protocol has never been compromised because of worsening diarrhoea or weight loss. These results indicate that a formula based on fermented milk together with oral rehydration can be used to treat malnourished children with acute diarrhoea and sugar intolerance.     

Management of malnourished children with acute diarrhoea and sugar intolerance

A protocol of nutritional rehabilitation using fermented milk, vegetable oil, and castor sugar has been tested on 54 Senegalese children age 6-36 months admitted with acute diarrhoea and malnutrition. At time of admission, 39 per cent of children were dehydrated and 26 per cent had sugar intolerance. In the course of treatment three absconded and one died from acute pneumonia with respiratory and heart failure. Among those with marasmus there were no differences in mean weight gains between children with sugar intolerance and others, despite a longer duration of diarrhoea in the first group. Furthermore, the treatment protocol has never been compromised because of worsening diarrhoea or weight loss. These results indicate that a formula based on fermented milk together with oral rehydration can be used to treat malnourished children with acute diarrhoea and sugar intolerance.     

Randomised trial of different rates of feeding in acute diarrhoea

OBJECTIVE—To compare the effect of different feeding frequencies on the speed of recovery from diarrhoea.
METHODS—A randomised, non-blinded trial provided 0.452 MJ/kg/day as either 6 or 12 feeds of cows'' milk each day to 262 hospitalised male infants aged 3-12 months with acute diarrhoea. Stool frequency, stool weight, body weight, and diarrhoea complications were monitored until recovery or for 14days.
RESULTS—A proportional hazards regression model controlling for age, diarrhoea aetiology, and severity of dehydration on admission revealed that the frequently fed group had a significantly shorter duration of diarrhoea (hazards ratio, 1.29; 95% confidence interval, 1.002 to 1.653). Frequently fed infants had a significantly greater weight gain and significantly lower faecal frequency and faecal weight.
CONCLUSIONS—Breast feeding remains the preferred method of feeding infants with acute diarrhoea, but feeding cows'' milk to adequately nourished infants with acute diarrhoea is safe and is more rapidly effective if provided in frequent feeds with low energy loads.
     

Randomised trial of different rates of feeding in acute diarrhoea.

OBJECTIVE: To compare the effect of different feeding frequencies on the speed of recovery from diarrhoea. METHODS: A randomised, non-blinded trial provided 0.452 MJ/kg/day as either 6 or 12 feeds of cows' milk each day to 262 hospitalised male infants aged 3-12 months with acute diarrhoea. Stool frequency, stool weight, body weight, and diarrhoea complications were monitored until recovery or for 14 days. RESULTS: A proportional hazards regression model controlling for age, diarrhoea aetiology, and severity of dehydration on admission revealed that the frequently fed group had a significantly shorter duration of diarrhoea (hazards ratio, 1.29; 95% confidence interval, 1.002 to 1.653). Frequently fed infants had a significantly greater weight gain and significantly lower faecal frequency and faecal weight. CONCLUSIONS: Breast feeding remains the preferred method of feeding infants with acute diarrhoea, but feeding cows' milk to adequately nourished infants with acute diarrhoea is safe and is more rapidly effective if provided in frequent feeds with low energy loads.     

Double blind, randomised controlled clinical trial of hypo-osmolar oral rehydration salt solution in dehydrating acute diarrhoea in severely malnourished (marasmic) children

AIMS—To compare the clinical efficacy of hypo-osmolar oral rehydration salt (ORS) solution (224 mmol/l) and standard ORS solution (311 mmol/l) in severely malnourished (marasmic) children having less than 60% Harvard standard weight for age with dehydrating acute watery diarrhoea.
METHODS—In a double blind, randomised, controlled trial, 64 children aged 6-48 months were randomly assigned standard (n = 32) or hypo-osmolar ORS (n = 32).
RESULTS—Stool output (52.3 v 96.6 g/kg/day), duration of diarrhoea (41.5 v 66.4 hours), intake of ORS (111.5 v 168.9 ml/kg/day), and fluid intake (214.6 v 278.3 ml/kg/day) were significantly less in the hypo-osmolar group than in the standard ORS group. Percentage of weight gain on recovery in the hypo-osmolar group was also significantly less (4.3 v 5.4% of admission weight) than in the standard ORS group. A total of 29 (91%) children in the standard ORS group and 32 (100%) children in the hypo-osmolar group recovered within five days of initiation of therapy. Mean serum sodium and potassium concentrations on recovery were within the normal range in both groups.
CONCLUSION—Our findings suggest that hypo-osmolar ORS has beneficial effects on the clinical course of dehydrating acute watery diarrhoea in severely malnourished (marasmic) children. Furthermore, children did not become hyponatraemic after receiving hypo-osmolar ORS.

     

Double blind, randomised controlled clinical trial of hypo-osmolar oral rehydration salt solution in dehydrating acute diarrhoea in severely malnourished (marasmic) children.

AIMS: To compare the clinical efficacy of hypo-osmolar oral rehydration salt (ORS) solution (224 mmol/l) and standard ORS solution (311 mmol/l) in severely malnourished (marasmic) children having less than 60% Harvard standard weight for age with dehydrating acute watery diarrhoea. METHODS: In a double blind, randomised, controlled trial, 64 children aged 6-48 months were randomly assigned standard (n = 32) or hypo-osmolar ORS (n = 32). RESULTS: Stool output (52.3 v 96.6 g/kg/day), duration of diarrhoea (41.5 v 66.4 hours), intake of ORS (111.5 v 168.9 ml/kg/day), and fluid intake (214.6 v 278.3 ml/kg/day) were significantly less in the hypo-osmolar group than in the standard ORS group. Percentage of weight gain on recovery in the hypo-osmolar group was also significantly less (4.3 v 5.4% of admission weight) than in the standard ORS group. A total of 29 (91%) children in the standard ORS group and 32 (100%) children in the hypo-osmolar group recovered within five days of initiation of therapy. Mean serum sodium and potassium concentrations on recovery were within the normal range in both groups. CONCLUSION: Our findings suggest that hypo-osmolar ORS has beneficial effects on the clinical course of dehydrating acute watery diarrhoea in severely malnourished (marasmic) children. Furthermore, children did not become hyponatraemic after receiving hypo-osmolar ORS.     

A controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants

A controlled, randomized trial was conducted in 50 infants with acute dehydrating diarrhea to evaluate the effect of oral zinc supplementation in acute diarrhea. After completion of rehydration, 25 infants in Group A received oral zinc sulfate (20 mg elemental zinc twice daily) and an equal number in Group B were given placebo (glucose). Both groups were comparable with respect to various initial characteristics including nutritional status, diarrheal disease, serum alkaline phosphatase, and serum and rectal mucosal zinc content. During therapy all the assessed parameters of zinc status (serum alkaline phosphatase and serum and rectal zinc) recorded significant elevation and reduction in Groups A and B, respectively. At recovery the zinc status of Group A was significantly better and was nearer that of healthy controls. The diarrheal duration and frequency in the zinc-supplemented group were lower, but the differences were not significant (0.05 less than p less than 0.1). However, when only subjects with relatively severe initial zinc depletion (rectal zinc lower than the 15th percentile of healthy controls; 11 in Group A and 14 in Group B) were considered, the diarrheal duration and frequency were significantly (p less than 0.05 and p less than 0.01, respectively) lower in the zinc-supplemented cases. Weight gain in both groups was similar. It is concluded that oral zinc administration in acute diarrhea can replenish body zinc status and this may shorten the diarrheal duration and frequency in children with relatively severe zinc depletion.     

Diagnosis and treatment of severely malnourished children with diarrhoea

Children with severe acute malnutrition complicated by diarrhoea require special care due to their unique physiological vulnerability and increased mortality risks. A systematic literature review (1950–2013) was conducted to identify the most effective diagnostic and therapeutic measures for the community‐based management of severely malnourished children with diarrhoea. No studies directly addressed this question, so the search was broadened to include inpatient care. Of the 129 studies identified, 32 were selected for full review and found to contain varying degrees of indirectness, inconsistency and bias. Evidence from diagnostic studies point to the use of both prolonged and persistent diarrhoea as morbidity markers, rapid hypoglycaemia diagnosis and the frequent aetiological role of Cryptosporidium. Therapeutic studies suggest benefits from routine antiparasitic medication and feeding regimens with ready‐to‐use‐therapeutic foods, lactose‐free diets and zinc supplementation. Existing rehydration treatment guidelines were affirmed, but the utility of glutamine and low osmolarity feeds were inconclusive.