Modified ORS Solution for Severely Malnourished Children
Condition: Malnourished Children With Watery Diarrhoea
MeSH terms: Malnutrition; Diarrhea
Study type: Interventional
Phase: Phase 2

Summary: 
      Diarrhoea and malnutrition are the common childhood illnesses responsible for higher deaths
      in developing counties. Physiologically, malnourished children excrete lower amounts of salts
      and water in diarrhoeal stools, and they also are unable to handle excessive salts and water
      load. Some times they are found to be hyponatraemic due to the shift of sodium inside the
      cells (inefficient Na+ /K+ pump), and fluids containing higher amounts of sodium (such as the
      standard ORS) may lead to further increase in the intracellular sodium, fluid overload and
      heart failure. They also have depleted in potassium stores in the body. Recently, the WHO
      recommended a special ORS formulation, known as ReSoMal, for management of diarrhoea in
      severely malnourished children that contains a lower amount of sodium (45mmol/L) and higher
      amount of potassium (40 mmol/L) than the standard WHO-ORS. It is felt that an ORS containing
      lower sodium and higher potassium concentration may be useful in correcting hypokalemia, and
      in lowering the risks of excess sodium and /or overhydration, in severely malnourished
      children with diarrhoea. The safety of ReSoMaL is, however, still in question due to the risk
      of hyponatraemia, including symptomatic hyponatraemia, especially in the treatment of severe
      watery diarrhoea due to Vibrio cholerae and ETEC where loss of sodium in the stool exceeds
      than that is contained in ReSoMal. Thus an ORS solution with modest concentration of sodium
      (75 mmol/L) and higher concentration of potassium (40 mmol/L) have been suggested for the
      treatment of diarrhoea in these children. To improve the efficacy of oral rehydration, in
      terms of reducing the severity of purging and diarrhoea duration, different approaches
      (changing the substrates/ reducing the sodium and glucose concentration and osmolarity) have
      been tried with limited success. Benefiber (partially hydrolysed guar gum), a soluble fiber
      if added to a ORS solution is expected to be fermented in the colon liberating short chain
      fatty acids (SCFAs). SCFAs stimulate sodium and water absorption from the colon, and they
      have trophic effect, act as a fuel source for the colonocytes, have antibacterial properties
      and stimulates the production commensal flora, thereby may enhance recovery from acute
      diarrhoea in severely malnourished children. The aims of our proposed study are to examine
      whether an ORS solution with a modest concentration of sodium will prevent the occurrence of
      hyponatraemia including symptomatic hyponatraemia, and also whether addition of benefiber
      will improve the efficacy of ORS solution. This will be a randomized, double blind,
      controlled clinical trial in 186 children with severe malnutrition and watery diarrhoea (62
      in each of the three treatment groups) to compare the efficacy of (i) the currently
      recommended ORS with some modofication(Na+ 75 mmol/L and K40 momol/L and minerals-Zinc,
      copper and magnesium), (ii) ReSoMal (Na+ 45 mmol/L), (iii) Currently recommended ORS (Na+ 75
      mmol/L, K 40 momol/L and added minerals) with added Benefiber (25 grams/L), in the treatment
      of acute watery diarrhoea in children with severe malnutrition
    

Detailed description: 
      Study Design This will be a randomized, double-blind, controlled clinical trial to assess the
      efficacy of three different modified ORSs: (i) Currently recommended ORS with some
      modification (Na+ 75, K 40 mmol/L and added minerals); (ii) Resomal (Na+ 45); (iii) Currently
      recommended ORS (Na+ 75 , K 40 mmol/L and added minerals) with added benefiber (25 grams/L)
      in the treatment of acute watery diarrhoea in children with severe malnutrition.

      STUDY POPULATION Children of either sex, aged 6 months to 3 years, presenting with acute
      watery diarrhoea of <7 days duration will be screened.

      Sample Size

      The sample size of this study has been determined based on the followings:

        1. Persistence of hyponatraemia: We anticipate that 10% of the children will remain
           hyponatraemic in the Modified ORS-1 treatment group compared to 30% children in the
           Modified ORS-2 (ReSoMal). Assuming 5% level of significance and 80% power, the sample
           size in each group is 60.

        2. Recovery from diarrhoea: In a recent clinical trial33 of ORS solution in severely
           malnourished children with acute watery diarrhoea, the mean +SD duration of diarrhoea
           was 66 (32) h. We anticipate that a 25% reduction in the diarrhoea duration in children
           receiving Benefiber-added ORS. Considering 5% level of significance and 80% power the
           required sample size in each group is 59.

        3. Anticipating a drop out of around 5% we need 62 children in each group. Randomization

           After enrolment into the study the patient will be randomized to receive one of the
           following three solutions:

        4. Case Management:

           Following the standardized protocol for management of severely malnourished children
           used at ICDDR,B hospital 20,23.

           5.1 Fluid therapy (oral) Dehydration will be assessed according to the WHO guidelines,
           modified for in our last multicentre clinical trial of reduced osmolarity ORS in adult
           cholera and children with watery diarrhoea (17). In children with some dehydration, the
           fluid deficit will be corrected with the assigned ORS @ 10ml/kg/hr for the first two
           hours, then 5ml /kg/hr until the deficit will be corrected. In addition, on going stool
           looses will be replaced @ 5-10 ml/kg/hr after each watery stool. For high purging
           patient, the ORS intake will be adjusted according to the ongoing stool loss. ORS
           therapy will be continued until diarrhoea ceased. Children with severe dehydration,
           initial rehydration will be done with IV fluid(cholera saline) until the patient is out
           of shock or disappearance of signs of severe dehydration then the rest of the
           rehydration will be done as for rehydration in patients with some dehydration as
           described above.

           5.2 Management of infection: Children without apparent extraintestinal infection will
           receive Inj ampicillin 100 mg/kg.24 h in 3 divided doses and Inj. Gentamicin @ 5ml/kg.24
           h in 2 divided doses for 5 days. Children with lower respiratory tract infection will
           receive Inj. Ceftriaxone 75 mg /kg.day for 5 days, and those with cholera will receive
           syrup Azithromycin 20 mg/kg once within 20 minutes of randomization.

           5.3 Diet: Mothers will be advised to continue breastfeeding. Supplementary feeding with
           milk suji (milk, rice powder mixture, energy 70 kcal/100ml) will be given 10 ml/Kg.feed
           two hourly for day 1 and increased slowly up to 150 Kcal/Kg.day over 7 days according to
           demand. If the child has poor appetite, or is weak, or has painful stomatitis or
           glossitis, food will be delivered through nasogastric tube until able to take food
           orally. Additionally, semisolid foods (Rice, lentil, vegetable etc.) will be given to
           older children during convalescent and rehabilitation phase.

           5.4 Vitamin and Mineral Supplements Children older than one year without xeropthalmia
           will be given 200,000 units of vitamin A and those 6-12 months age will be given 100,000
           units of vitamin A on admission. Children with xeropthalmia will receive the same dose
           on three occasions: on admission, on the following day, and at discharge. Folic acid
           1.25 mg and elemental zinc 2 mg/kg will be given until discharge and some medicine will
           be supplied with the patient to continue upto 15 days. Children will also receive
           multivitamin drops (1 ml contains Vit A palmitate 5000 IU, vitamin D 1000 IU, thiamine
           hydrochloride 1.6 mg, riboflavin 1 mg, pyridoxine hydrochloride 1 mg, nicotinamide 10
           mg, calcium D- pantothenate 5 mg, and ascorbic acid 50 mg) in a dose of 1 ml twice daily
           until discharge and some medicine will be supplied with the patient to continue upto 15
           days (half the dose for infants, aged <1 year). Hypoglycemia (blood glucose <3.0 mmol/L)
           will be managed with 50 ml 10% glucose orally or by nasogastric tube. Inj 25% glucose 2
           ml/kg will be given if the level of blood glucose below 1.5 mmol/L. Hyponatraemia (serum
           sodium <115 mmol/L with or without symptoms) will be managed with Inj. 3% NaCl 12 ml/kg
           I/V slowly over 4 hours.

        5. Measurements 6.1 Fluids intakes ( IV, ORS and water) every 6 hours IV fluid will be
           infused through a calibrated soluset, the amount infused will be noted every 6 hours if
           the patient is receiving; ORS will be supplied after measuring with a calibrated
           cylinder and the amount of intake will be noted every 6 hours, if any left over that
           will be deducted from previous offer. Water will also be measured in a similar way.

      6.2 Output (stool, urine and vomit) every 6 hours. Stool will be collected in a bucket of
      known weight beneath the cholera cot with a central hole and measured every 6 hours with an
      electronic scale of a precision of 1g. Urine will be collected by pediatric urine collector
      bag and measured with a calibrated cylinder in ml. Vomit will be collected in a pre-weighed
      bowl and measured with an electronic scale 6.3 Food intake every 6 hours The children will be
      offered a defined food of known calorie after measuring with an electronic scale of precision
      of 1g. Any left over will be measured and subtracted from the amount offered and amount
      ingested will be recorded every 6 hours. The calorie intake will be estimated from the amount
      of diet the child consumed.

      6.4 Nude body weight will be measured at admission, after rehydration and every 6 hours until
      recovery of diarrhoea and then at the end of every 24 hours and at discharge
    

Intervention name(s): Modified ORS-1; Modified ORS-2 (ReSoMal); Modified ORS-3 (Benefibre)
Intervention type(s): Other; Other; Other
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diarrhoea;; Severe malnutrition;; Benefiber;; ReSoMal;; modified ORS