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Efficacy and safety of a modified oral rehydration solution (ReSoMaL) in the treatment of severely malnourished children with watery diarrhea
EFFICACY AND SAFETY OF A MODIFIED ORAL REHYDRATION SOLUTION (RESOMAL) IN THE TREATMENT OF SEVERELY MALNOURISHED CHILDREN WITH WATERY DIARRHEA N. H. ALAM, MD, JENA D. HAMADANI, MBBS, NAHRINA DEWAN, MBBS, AND GEORGE J. FUCHS, MD
Objectives Efficacy, development of overhydration, and correction of electrolyte disturbances of severely malnourished children with acute diarrhea using a modified oral rehydration solution for malnourished children (termed ReSoMaL and recommended by the World Health Organization [WHO]) were evaluated and compared with standard WHO-oral rehydration solution (ORS). Study design
Children age 6 to 36 months with severe malnutrition and acute watery diarrhea were randomized to ReSoMaL (n = 65) or standard WHO-ORS (n = 65). Major outcome measures included the number of children who developed overhydration and the number who corrected hypokalemia.
Results The numbers of children who developed overhydration were not significantly different (ReSoMaL vs WHO-ORS, 5% vs 12%, P = .2). ReSoMaL corrected basal hypokalemia in a greater proportion of children by 24 hours (36% vs 5%, P = .0006) and 48 hours (46% vs 16%, P = .004) compared with WHO-ORS. More children on ReSoMaL than WHO-ORS remained hyponatremic at 48 hours (29% vs 10%, P = .017). Three children in the ReSoMaL group developed severe hyponatremia by 24 hours, with one experiencing hyponatremic convulsions (serum sodium, 108 mmol/L). Conclusions ReSoMaL has a large beneficial effect on potassium status compared with standard ORS. However, ReSoMaL therapy may result in symptomatic hyponatremia and seizures in patients with severe diarrhea. (J Pediatr 2003;143:614-9)
evere malnutrition remains an important cause of childhood mortality in developing countries.1,2 Mortality rates of severely malnourished children, the majority of whom have diarrheal disease, remain high (20%-49%) primarily because of flawed case management, although lower rates are attainable.3 The use of standard World Health Organization (WHO)-oral rehydration solution (ORS) in severely malnourished children has been criticized because of its relatively higher concentration of sodium and lower concentration of potassium than may be considered appropriate in these children.4 Despite having excess total body sodium, malnourished children are typically hyponatremic because of an intracellular shift of sodium related to an inefficient Na+/K+ pump.5 In addition, malnourished children excrete less sodium and water, and are unable to handle excessive sodium and water loads. Fluids containing large quantities of sodium, including standard ORS, may further increase intracellular sodium and increase the risk of fluid overload and heart failure.6 Children with severe malnutrition are also depleted in potassium stores, aggravated by diarrhea through excess fecal potassium excretion.7-9 Hypokalemia in malnourished children with diarrhea is associated with a higher risk of death, perhaps because of cardiac arrhythmia.10,11 Standard ORS has also been shown to be less uniformly successful in correcting potassium deficits in certain children with diarrhea.12 The WHO has recently changed their recommendation for severely malnourished children to an alternative ORS, termed ReSoMaL (oral rehydration solution for malnourished children), which contains lower and higher concentrations of sodium and potassium, respectively, as well as glucose and selected minerals.13,14 Although promoted, ReSoMaL efficacy and
S
ORS ReSoMaL
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Oral rehydration solution Oral rehydration solution for malnourished children
WHO
World Health Organization
From ICDDR,B, Centre for Health and Population Research, Dhaka, Bangladesh; and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Supported by a grant from the World Health Organization (grant no. C6/ 181/377). Submitted for publication Dec 6, 2002; revision received June 5, 2003; accepted Aug 8, 2003. Reprint requests: George J. Fuchs, MD, University of Arkansas for Medical Sciences, Department of Pediatrics, Mail Slot 512-7, Little Rock, AR 72205. E-mail: [email protected]. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00500-6
safety have not been evaluated in a controlled clinical trial. We therefore undertook such a trial to evaluate whether this modified ORS (ReSoMaL) is more effective than standard ORS in correcting the potassium deficit and reducing the occurrence of overhydration during rehydration of severely malnourished children with acute watery diarrhea.
PATIENTS AND METHODS This double-blind, controlled study was conducted at the Clinical Research and Service Centre of ICDDR,B: Centre for Health and Population Research, Dhaka, Bangladesh. The Ethical Review Committee of ICDDR,B approved the protocol, and voluntary, informed consent was obtained from parents of the children before study enrolment. Eligible children were age 6 to 36 months of either gender with a history of watery diarrhea for #10 days and severe malnutrition (weight for length <70% of the National Center for Health Statistics median or with bilateral pedal edema). Children with bloody diarrhea, severe dehydration requiring intravenous fluids, or signs of severe infection (eg, severe pneumonia, sepsis, meningitis) were excluded from the study. All children remained in the study until diarrhea resolved, after which they were transferred to a nutritional rehabilitation unit or home-based nutritional follow-up program of the Clinical Research and Service Centre. On enrollment, a clinical history was taken and a physical examination was performed. Laboratory investigations on admission included a blood test for hematocrit, total and differential white blood cell count, and serum protein and albumin; serum electrolytes on admission and at 24 hours and 48 hours; stool microscopy for leukocytes, red blood cells, and parasites (including Giardia lamblia, Entamoeba histolytica, and Cryptosporidium); stool culture for Salmonella, Shigella, and Vibrios; and stool culture for rotavirus by enzymelinked immunosorbent assay; urine for microscopy and culture and chest radiograph were obtained if clinically indicated.
Outcomes Primary outcomes were the number of children developing overhydration and number of children with correction of basal hypokalemia after 24 and 48 hours of treatment. Secondary outcome was the number of children remaining hyponatremic at 24 and 48 hours of treatment.
Sample Size The sample size was estimated based on an expected reduction of persistence of hypokalemia from 33% with standard WHO-ORS to 12% with ReSoMaL.12 Considering a 5% level of significance, 80% power, and 10% dropout, the sample size was calculated to be 65 in each group. Although no reliable data exist on the development of overhydration quantified objectively, a sample size of 52 in each group was estimated, assuming a 20% difference in the development of overhydration between the groups (25% of WHO-ORS group and 5% of ReSoMaL group considered to develop over-
hydration), with a 5% level of significance, 80% power, and 10% dropout. Finally, we studied 65 patients in each group.
Randomization Children were assigned on enrollment by using a randomization list following a permuted table of variable length to either ReSoMaL (Na 45 mmol/L, K 40 mmol/L, Cl 76 mmol/L, citrate 7 mmol/L, Mg 6 mmol/L, Zn 300 lmol/ L, Cu 45 lmol/L, glucose 125 mmol/L, osmolarity 300 mmol/L) or standard ORS (Na 90 mmol/L, K 20 mmol/L, Cl 80 mmol/L, citrate 10 mmol/L, glucose 111 mmol/L, osmolarity 311 mmol/L). A randomization list was prepared by WHO, Geneva, and serially numbered, sealed envelopes were supplied to the pharmacist of ICDDR,B. According to the list inside the envelopes, the pharmacist prepared the ORS in a clean bottle marked with the patient’s name and study number without marking the identity of the solution. The two types of ORS solutions were identical in appearance. The code in the form of A and B, without disclosing the identity, was provided to the investigators for analysis. After preparing the data analysis tables, the group identity was disclosed for preparation of the final report.
Case Management After randomization, the children were treated following the protocol of the WHO manual for the standardized treatment of severely malnourished children and as validated at ICDDR,B.13,15 All children received acute and rehabilitation phase treatment until discharged.
Fluid Therapy Dehydration was categorized according to the modified WHO guidelines.16 Fluid deficit was corrected with 10 mL/ kg/h of the assigned ORS given over the first 2 hours, then 5 mL/kg/h over a period of 10 to 12 hours until the deficit was corrected. Ongoing stool losses were corrected with 5 to 10 mL/kg after each watery or loose stool. In patients with high purging rates, fluid intake was adjusted according to the ongoing stool output. ORS therapy was continued until diarrhea ceased. Treatment of infection and other complications, nutritional therapy, and other aspects of case management were provided consistent with the WHO guidelines and as described elsewhere, with exception of antimicrobial for pneumonia. Our children with pneumonia received intramuscular or intravenous ceftriaxone 75 mg/kg/d once daily for 5 days and gentamicin 5 mg/kg/day in two divided doses.15
Measurements 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, Germany) with a precision of 1.0 g. All intakes (ORS solutions, plain water, and food) and outputs (stool, urine, and vomitus) were quantified every 6 hours. Body weight,
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Table I. Admission characteristics of severely malnourished children randomized to ReSoMaL or WHO-ORS Variable Age (mo) Sex (n), M/F Body weight (kg) Weight-for-age % of NCHS median Z score Weight-for-length % of NCHS median Z score Breast-feed (n), Yes/No Duration of diarrhea before admission (h) No. of stools in 24 h before admission Dehydration status (n) None/some Edema present, n (%) Stool pathogen (n) Vibrio cholerae Shigella Salmonella Other vibrios Rotavirus
ReSoMaL n = 65
WHO-ORS n = 65
15 ± 7 39/26 5.22 ± 0.92
15 ± 6 42/23 5.26 ± 0.95
50 ± 7 4.7 ± 1
51 ± 7 4.6 ± 0.7
66 ± 4 3.6 ± 0.6 45/21 77 ± 62
66 ± 3 3.5 ± 0.5 47/17 74 ± 59
12.5 ± 5
14 ± 9
21/45
23/42
15/65 (23)
14/65 (22)
18/65 5/65 2/65 3/65 10/65
19/65 (29) 2/65 (3) 0/65 5/65 (8) 12/65 (18)
(28) (8) (3) (5) (15)
Values are mean ± SD and number (%) unless otherwise indicated.
vital signs (pulse, temperature, and respiration), and other evidence of overhydration (eg, puffy face, pedal edema, respiratory hurry/distress) were recorded every 6 hours. Overhydration was defined as >5% weight gain after correction of dehydration at any time during the study period with any of the following signs: periorbital edema/ puffy face, increased heart rate (>160/m), or increased respiration (>60/min). Hypokalemia was defined as serum potassium <3.5 mmol/L, hyperkalemia as serum potassium >5.5 mmol/L, hyponatremia as serum sodium <130 mmol/ L, and hypernatremia as serum sodium >150 mmol/L. Duration of diarrhea was calculated as the time in hours from the time of randomization to the last watery stool followed by two consecutive soft/formed stools or no stool for 12 hours. Children withdrawn from the study were any child requiring intravenous fluid therapy for severe dehydration, septic shock, or convulsion; children with concomitant illness requiring more intensive care; patients with severe hyperkalemia (serum potassium $6.0 mmol/L); patients with severe hypokalemia (serum potassium #1.5 mmol/L with or without symptoms or <2.5 mmol/L with symptoms); and patients with severe hyponatremia (serum sodium <120 mmol/L with symptoms or <115 mmol/L with or without symptoms). 616
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Data Analysis Continuous variables were compared between the groups with the Student t test, and the v2 test/Fisher exact test was used to compare the noncontinuous variables by using SPSS PC+ (SPSS, Chicago, IL). For patients withdrawn from the study, data collected until the time of withdrawal were included in the analysis.
RESULTS A total of 296 children were screened for eligibility, of whom 130 were enrolled (65 in the WHO-ORS group and 65 in the ReSoMaL group) between the period of February 1998 to January 2000. Twelve children were withdrawn from the study: seven from the ReSoMaL group (three for development of severe dehydration requiring intravenous fluids, and one each for symptomatic hypokalemia, severe hyperkalemia at 0 hours, severe pneumonia, and symptomatic hyponatremia—Na 108 mmol/L with seizure) and five from the WHOORS group (one each for symptomatic hypokalemia, severe dehydration, and severe pneumonia, and two through parental withdrawal). The child in the ReSoMaL group who developed hyponatremia-associated seizure had a high purging rate (18 g/kg/h) during the first 24-hour period. Baseline clinical characteristics such as age, body weight, weight for age, weight for length, breast-feeding status, edematous state, and dehydration status were comparable between the groups (Table I). Stool microbiology showed similar isolation rates for all pathogens and a predominance of Vibrio cholerae and rotavirus in both groups; tests for diarrheagenic Escherichia coli were not performed in this study. Most of the children were equally and adequately rehydrated with ORS in both groups (ReSoMaL vs WHO-ORS, 76% vs 81%, P = .68; Table II). More children in the WHO-ORS group than the ReSoMaL group developed overhydration (8 vs 3), although the difference was not significant (P = .2; Table II). On admission, 60% (39) and 68% (44) of the children in the ReSoMaL and WHO-ORS groups, respectively, were hypokalemic, and which was corrected in a greater number of children in the ReSoMaL vs WHO-ORS group by 24 hours (14 vs 2, P = .0006) and by 48 hours (18 vs 7, P = .004). The mean serum potassium concentrations at 24 and 48 hours were correspondingly and significantly greater in the ReSoMaL than the WHO-ORS group. In contrast, more children in the ReSoMaL group than in the WHO-ORS group were hyponatremic at 24 hours (24 vs 15, P = .09) and at 48 hours (17 vs 6, P = .017), and three children in the ReSoMaL group developed severe hyponatremia. Mean serum sodium concentrations at 24 and 48 hours were also significantly lower in the ReSoMaL group (Table II). A subgroup analysis excluding children with cholera (known to have high fecal sodium losses) demonstrated no significant differences between the groups in the proportion of children with hyponatremia at 24 and 48 hours (Table III). Of note, the lone child who developed hyponatremic-associated seizure, who was in the ReSoMaL group, did not have cholera. Stool output, urine output, ORS intake, water intake, calorie intake The Journal of Pediatrics November 2003
Table II. Outcome of rehydration of severely malnourished children with ReSoMaL or WHO-ORS Variables No. of children adequately rehydrated at 12 h No. of over hydration Basal hypokalaemia (K+ <3.5 mmol/L) Corrected at 24 h Corrected at 48 h Serum potassium (mmol/L) 0h 24 h 48 h Hyponatraemia (serum Na+ <130 mmol/L) 0h 24 h 48 h Severe Hyponatraemia (serum Na+ # 120 mmol/L) 0h 24 h 48 h Serum sodium (mmol/L) 0 24 h 48 h
ReSoMaL n = 65
WHO-ORS n = 65
OR (95% CI)
P value
51/63 (81%) 8/65 (12%) 44/65 (68%) 2/44 (5%) 7/44 (16%)
0.16 (0.29, 1.96) 0.3 (0.1, 1.5) 0.7 (0.3, 1.6) 12.3 (2.4, 117) 4.8 (1.5, 15.6)
.68 .20 .47 .0006 .004
3.3 ± 1 4.0 ± 1 4.6 ± 0.8
3.3 ± 1 3.2 ± 0.7 3.4 ± 0.8
<0.08 ( 0.3, 0.4)* (0.49, 1.1)* 1.2 (0.3, 1.0)*
.7 .001 .001
25/65 (38%) 24/62 (39%) 17/59 (29%)
19/65 (29%) 15/64 (23%) 6/60 (10%)
1.5 (0.7, 3.4) 2.1 (0.9, 4.8) 3.6 (1.2, 12.2)
.35 .09 .017
0/65 3/62 (5%) 0
1/65 (2%) 1/64 (2%) 0
0 (0, 39) 3.2 (0.3, 171)
132.1 ± 6 130.5 ± 6 132.1 ± 4
132.9 ± 8 133.3 ± 6 134.5 ± 4
45/59 3/65 39/65 14/38 18/38
(76%) (5%) (60%) (36%) (47%)
0.8 ( 3.3, 1.7)* 2.8 ( 4.9, 0.7)* 2.4 ( 3.9, 1.0)*
1.0 .36
.51 .01 .001
Data presented as mean ± SD and number (%) unless otherwise indicated. Na+, Sodium; K+, potassium; NS, non-significant. *Difference between means (95% CI).
from supplemented food, and duration of diarrhea and weight gain before discharge were similar between groups, nor were there any differences in primary or secondary outcome variables between children with marasmus compared with kwashiorkor (data not shown). The children withdrawn from the study were also followed, and final outcome was recorded. No child from either group died.
DISCUSSION Results of this randomized, controlled efficacy and safety trial of ReSoMaL demonstrate that this modified ORS corrects dehydration in severely malnourished children with diarrhea. Although currently recommended, there is little experience with ReSoMaL in the treatment of diarrhea in severely malnourished children, and its efficacy in relation to patient characteristics has not been previously reported.13,5 In an experimental absorption study using perfusion techniques in human adult volunteers, water and sodium absorption was less efficient with ORS containing low (45 mmol/L) compared with higher (Na 60 mmol/L or Na 90 mmol/L) concentrations of sodium.17 Yet in our study, water and sodium absorption with low-sodium ReSoMaL did not seem to be less efficient than with standard WHO-ORS as evidenced by correction of dehydration and stool output. One of the primary theoretical advantages of ReSoMaL is to prevent
the development of overhydration, heart failure, or both; however, this advantage was not established in our study, perhaps because there were very few children in either of the ORS groups that had overhydration or fluid overload. Nor did any child in either group develop heart failure by clinical examination criteria. Although concern has been expressed about the development of heart failure with standard WHOORS in the treatment of severely malnourished children with diarrhea, published reports do not reinforce this concern.5,14,18,19Potassium depletion universally accompanies severe malnutrition and is believed to represent a significant risk for sudden death in malnourished children. Compared with WHO-ORS, ReSoMaL therapy corrected hypokalemia in a much greater proportion of children and in a shorter time. This finding provides a convincing rationale to increase the concentration of potassium in a modified ORS such as ReSoMaL for use in these children. Persistence of hyponatremia at 24 and 48 hours was evident in a greater proportion of children in the ReSoMaL than standard ORS group, especially in children with diarrhea of high purging rates caused by V cholerae and enterotoxigenic E coli. Consistent with persistence of hyponatremia, three children in the ReSoMaL group also developed severe hyponatremia by 24 hours after initiating rehydration. Of note, when children with cholera were excluded from analysis, the risk of remaining hyponatremic was similar in both groups.
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Table III. Hyponatremia (serum <130 mmol) in malnourished children with noncholera and cholera diarrhea treated with the different ORSs Non-cholera diarrhea
0h 24 h 48 h
Cholera diarrhea
ReSoMaL n = 47
Standard n = 46
OR (95% CI)
P value
ReSoMaL n = 18
Standard n = 19
OR (95% CI)
P value
13/47 (28) 11/47 (23) 7/47 (15)
11/46 (24) 7/46 (15) 4/46 (9)
1.2 (0.4, 3.5) 1.7 (0.5, 5.8) 1.84 (0.4, 8.2)
.86 .52 .55
12/18 (67) 13/18 (72) 10/11 (56)
9/19 (47) 8/19 (42) 2/19 (11)
2.2 (0.5, 10) 3.6 (0.8, 18) 10.63 (1.6, 92.1)
.65 .09 .01
Data are n (%).
In our experience, moderate hyponatremia (serum sodium >120 to <130 mmol/L) without any specific symptoms (eg, lethargy, alteration of mental status, and so forth) in severely malnourished children has little clinical significance other than indicating a pathophysiologic process during illness. In contrast, severe hyponatremia (<120 mmol/L) associated with symptoms precipitated during treatment of the acute phase has great clinical significance and should be managed with urgent intervention. The single child who developed convulsions, who was in the ReSoMaL-treated group, did not have cholera but had high purging and ORS consumption rates (stool rate, 18 g/kg/h, and ORS intake, 22 mL/kg/h) during the first 24 hours of treatment and exhibited a rapid decline of serum sodium (from 127 mmol/L at 0 hours to Na 108 mmol/L at 24 hours). The convulsion was successfully managed with anticonvulsant therapy and restoration of serum sodium to normal by infusing 3% sodium chloride 12 mL/kg/h over a period of 4 hours. Although we cannot absolutely exclude other possible electrolyte abnormalities as the cause of the seizure, this serious adverse effect should limit the use of ReSoMaL in its current formulation in severely malnourished children with diarrhea, especially those with high purging rates. Based on conventional concepts of the pathophysiology of severe malnutrition and sodium metabolism, the observation of greater and consequential hyponatremia with the use of ReSoMaL was not expected. Severely malnourished children have excess total body and intracellular sodium even in the presence of reduced sodium concentration in the blood, ie, hyponatremia.20 During the acute phase of recovery, a shift of intracellular sodium to the intravascular compartment occurs, accompanied later by excretion of large quantities of sodium in the urine. The results of our study suggest that the rate of urinary sodium excretion surpasses that of intracellular to extracellular shift of sodium in a clinically significant manner. An ORS with sodium concentration reduced to the level contained in ReSoMaL does not seem to be supported by the results of our study. In recent years, there has been growing interest about the use of hypotonic or reduced osmolarity ORS (lower sodium and lower glucose ORS) in the treatment of diarrhea, because some clinical studies have demonstrated better efficacy, especially in reduced need for unscheduled intravenous fluids.21-27 Based on these findings, a WHO/UNICEF expert committee meeting28 recommended a revised formulation of 618
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reduced-osmolarity ORS (Na 75, Cl 65, K 20, citrate 20, glucose 75 mosmol/L, osmolarity 245 mosmol/L) for use in children and adults for all causes of diarrhea, including cholera; however, the issue of the best ORS remains controversial, and criticism persists.29,30 Reduced osmolarity ORS with higher potassium and added micronutrients has never been evaluated in the treatment of severely malnourished children with diarrhea. The rationale for other micronutrients in ReSoMaL including magnesium, zinc, and copper is mainly to replace those micronutrients in which severely malnourished children are known to be deficient and in which deficiency is known to increase risk of adverse outcome.5 These micronutrients (especially zinc) may influence recovery from diarrhea; however, we were unable to evaluate this possibility, because the standard WHO-ORS group also received supplements as part of our routine practice for the treatment of severely malnourished children.15,31 We conclude that ReSoMaL and standard WHO-ORS were similarly efficacious in the rehydration of severely malnourished children with diarrhea and dehydration. Compared with children receiving standard ORS, children receiving ReSoMaL had significantly better potassium status and less hypokalemia but also had a tendency to remain hyponatremic and to develop hyponatremia, including symptomatic hyponatremia in those with high purging. A modified ORS such as ReSoMaL but with a higher sodium concentration (Na 75 mmol/L) than the current formulation would be expected to have meaningful advantages compared with standard ORS in the treatment of severely malnourished children; however, the recommendation for universal use without qualifications of ReSoMaL in its current formulation should be reconsidered. Dr Alam was involved in proposal and protocol development, all phases and management of the study, data analysis, and manuscript preparation. Dr Hamadani was involved in clinical treatment of the study patients and assisted in manuscript preparation. Dr Dewan was involved in proposal and protocol development and clinical care of the study patients. Prof Fuchs was involved in proposal and protocol development, data analysis, and manuscript preparation. ICDDR,B acknowledges with gratitude the commitment of WHO to the Centre’s research efforts. We express our sincere appreciation to Dr Oliver Fontaine, WHO, Geneva, for his review of the protocol and for supplying the ReSoMaL used in the study. We also thank Dr Pippa Simpson for her advice on the statistical analyses. The Journal of Pediatrics November 2003
REFERENCES 1. Chen LC, Rahman M, Sarder AM. Epidemiology and causes of death among children in a rural area of Bangladesh. Int J Epidemiol 1980;9: 25-33. 2. Bhandari N, Bhan MK, Sazawal S. Mortality associated with acute watery diarrhoea, dysentery, and persistent diarrhoea in rural North India. Acta Paediatr Suppl 1992;381:3-6. 3. Schofield C, Ashworth A. Why have mortality rates for severe malnutrition remained so high? Bull WHO 1996;74:223-9. 4. Briend A, Golden MH. Treatment of severe child malnutrition in refugee camps. Eur J Clin Nutr 1993;47:750-4. 5. Finberg L. Malnutrition: marasmus and kwashiorkor. In: Water and electrolytes in pediatrics. 2nd ed. Philadelphia: WB Saunders Co; 1993. p. 175. 6. Golden MHN. Severe malnutrition. In: Weatherall DJ, Ledingham JGG, Warell DA (eds). The Oxford textbook of medicine. Oxford: Oxford University Press; 1996. p. 1278-96. 7. Mann MD, Bowe MD, Hansen JDL. Potassium in protein calorie malnutrition. South Afr Med J 1972;46:2062-4. 8. Alleyne GAO. Studies on total body potassium in infantile malnutrition: the relation to body fluid spaces and urinary creatinine. Clin Sci 1968;34: 199-209. 9. Zaman K, Islam MR, Baqui AH, Yunus M. Hypokalaemia in children with diarrhoea in rural Bangladesh. Ind J Med Res 1985;81:169-74. 10. Mittal SK, Saxena S, Mundkur N, Srivastava G, Gupta S. Acute diarrhoea in malnourished children: clinical, biochemical and bacteriological profile. Indian Pediatr 1980;17:247-54. 11. Chhabra A, Patwary AK, Aneja S, Chandra J, Anand VK, Ahluwalia TP. Neuromuscular manifestations of diarrhoea related hypokalaemia. Indian Pediatr 1995;32:409-15. 12. Ahmed SM, Islam MR, Kabir I. Efficacy of oral rehydration solution in correcting serum potassium deficit of children with acute diarrhoea in Bangladesh. J Trop Pediatr 1988;34:24-7. 13. WHO. Management of severe malnutrition: a manual for physicians and other senior health workers. Geneva (Switzerland): WHO; 1999. 14. WHO. Management of the child with a serious infection or severe malnutrition: guidelines for care at the first-referral level in developing countries. Geneva (Switzerland): WHO; 2000. 15. Ahmed T, Ali M, Ullah MM, Choudhury A, Haque ME, Salam MA, et al. Mortality in severely malnourished children with diarrhoea and use of a standardised protocol. Lancet 1999;353:1919-22. 16. Alam NH, Majumder RN, Fuchs GJ, CHOICE Study Group. Efficacy and safety of oral rehydration solution with reduced osmolarity in adults with cholera: a randomised double-blind clinical trial. Lancet 1999;354:296-9.
17. Hunt JB, Elliot EJ, Fairclough PD, Clark ML, Farthing MJG. Water and salt absorption from hypotonic glucose-electrolyte solutions in human jejunum. Gut 1992;55:479-83. 18. Dutta P, Bhattacharya SK, Dutta D, Mitra U, Bhattacharya MK, Rasaily R, et al. Oral rehydration solution containing 90 mmol sodium is safe and useful in treating diarrhoea in severely malnourished children. J Diarrhoeal Dis Res 1991;9:118-22. 19. Nagpal A, Aneja S. Oral rehydration therapy in severely malnourished children with diarrhoeal dehydration. Ind J Pediatr 1992;59:313-9. 20. Waterlow JC. Electrolytes and major minerals. In: Waterlow JC, editor. Protein energy malnutrition. London: Edward Arnold; 1992. p. 40-53. 21. Faruque ASG, Mahlanabis D, Hamadini JD, Zetterstrom R. Reduced osmolarity oral rehydration salt in cholera. Scand J Infect Dis 1996;28:87-90. 22. Mahalanabis D, Faruque ASG, Hoque SS. Hypotonic oral rehydration solution in acute diarrhoea: a controlled clinical trial. Acta Paediatr 1995;84:289-93. 23. Dutta D, Bhattacharya MK, Dela AK, Sarker D. Evaluation of oral hypo-osmolar glucose based and rice based oral rehydration solutions in the treatment of cholera in children. Acta Paediatr 2000;37:952-60. 24. CHOICE study group. Multicentre, randomized, double blind clinical trial to evaluate the efficacy and safety of a reduced osmolarity oral rehydration salts solution in children with acute watery diarrhea. Pediatrics 2001;107: 613-8. 25. Dutta P, Mitra U, Manna B, Niyogi SK, Roy K, Mondol C, et al. Double blind, randomised controlled clinical trial of hypo-osmolar oral rehydration salt solution in dehydrating acute diarrhoea in severely malnourished (marasmic) children. Arch Dis Child 2001;84:237-40. 26. Sarker SA, Mahalanabis D, Alam NH, Sharmin S, Khan AM, Fuchs GJ. Reduced osmolarity oral rehydration solution for persistent diarrhea in infants: a randomized controlled clinical trial. J Pediatr 2001;138: 532-8. 27. Hahn SK, Kim YJ, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhoea in children: systematic review. BMJ 2001;323:81-5. 28. WHO/UNICEF. Reduced osmolarity oral rehydration salts (ORS) formulation. A report from a meeting of experts jointly organized by UNICEF and WHO, UNICEF House, New York, NY. WHO/FCH/CAH/01.22. 29. Fuchs GJ. A better oral rehydration solution? An important step, but not a leap forward. BMJ 2001;323:59-60. 30. Hirschorn N, Nalin DR, Cash RA, Greenough WB, III Formulation of oral rehydration solution. Lancet 2002;360:340-1. 31. Roy SK, Tomkins AM, Mahalanabis D, Akramuzzaman SM, Haider R, Fuchs GJ. Impact of zinc supplementation on persistent diarrhoea in malnourished Bangladeshi children. Acta Paediatr 1998;87:1235-9.
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Objectives Efficacy, development of overhydration, and correction of electrolyte disturbances of severely malnourished children with acute diarrhea using a modified oral rehydration solution for malnourished children (termed ReSoMaL and recommended by the World Health Organization [WHO]) were evaluated and compared with standard WHO-oral rehydration solution (ORS). Study design
Children age 6 to 36 months with severe malnutrition and acute watery diarrhea were randomized to ReSoMaL (n = 65) or standard WHO-ORS (n = 65). Major outcome measures included the number of children who developed overhydration and the number who corrected hypokalemia.
Results The numbers of children who developed overhydration were not significantly different (ReSoMaL vs WHO-ORS, 5% vs 12%, P = .2). ReSoMaL corrected basal hypokalemia in a greater proportion of children by 24 hours (36% vs 5%, P = .0006) and 48 hours (46% vs 16%, P = .004) compared with WHO-ORS. More children on ReSoMaL than WHO-ORS remained hyponatremic at 48 hours (29% vs 10%, P = .017). Three children in the ReSoMaL group developed severe hyponatremia by 24 hours, with one experiencing hyponatremic convulsions (serum sodium, 108 mmol/L). Conclusions ReSoMaL has a large beneficial effect on potassium status compared with standard ORS. However, ReSoMaL therapy may result in symptomatic hyponatremia and seizures in patients with severe diarrhea. (J Pediatr 2003;143:614-9)
evere malnutrition remains an important cause of childhood mortality in developing countries.1,2 Mortality rates of severely malnourished children, the majority of whom have diarrheal disease, remain high (20%-49%) primarily because of flawed case management, although lower rates are attainable.3 The use of standard World Health Organization (WHO)-oral rehydration solution (ORS) in severely malnourished children has been criticized because of its relatively higher concentration of sodium and lower concentration of potassium than may be considered appropriate in these children.4 Despite having excess total body sodium, malnourished children are typically hyponatremic because of an intracellular shift of sodium related to an inefficient Na+/K+ pump.5 In addition, malnourished children excrete less sodium and water, and are unable to handle excessive sodium and water loads. Fluids containing large quantities of sodium, including standard ORS, may further increase intracellular sodium and increase the risk of fluid overload and heart failure.6 Children with severe malnutrition are also depleted in potassium stores, aggravated by diarrhea through excess fecal potassium excretion.7-9 Hypokalemia in malnourished children with diarrhea is associated with a higher risk of death, perhaps because of cardiac arrhythmia.10,11 Standard ORS has also been shown to be less uniformly successful in correcting potassium deficits in certain children with diarrhea.12 The WHO has recently changed their recommendation for severely malnourished children to an alternative ORS, termed ReSoMaL (oral rehydration solution for malnourished children), which contains lower and higher concentrations of sodium and potassium, respectively, as well as glucose and selected minerals.13,14 Although promoted, ReSoMaL efficacy and
S
ORS ReSoMaL
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Oral rehydration solution Oral rehydration solution for malnourished children
WHO
World Health Organization
From ICDDR,B, Centre for Health and Population Research, Dhaka, Bangladesh; and the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Supported by a grant from the World Health Organization (grant no. C6/ 181/377). Submitted for publication Dec 6, 2002; revision received June 5, 2003; accepted Aug 8, 2003. Reprint requests: George J. Fuchs, MD, University of Arkansas for Medical Sciences, Department of Pediatrics, Mail Slot 512-7, Little Rock, AR 72205. E-mail: [email protected]. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00500-6
safety have not been evaluated in a controlled clinical trial. We therefore undertook such a trial to evaluate whether this modified ORS (ReSoMaL) is more effective than standard ORS in correcting the potassium deficit and reducing the occurrence of overhydration during rehydration of severely malnourished children with acute watery diarrhea.
PATIENTS AND METHODS This double-blind, controlled study was conducted at the Clinical Research and Service Centre of ICDDR,B: Centre for Health and Population Research, Dhaka, Bangladesh. The Ethical Review Committee of ICDDR,B approved the protocol, and voluntary, informed consent was obtained from parents of the children before study enrolment. Eligible children were age 6 to 36 months of either gender with a history of watery diarrhea for #10 days and severe malnutrition (weight for length <70% of the National Center for Health Statistics median or with bilateral pedal edema). Children with bloody diarrhea, severe dehydration requiring intravenous fluids, or signs of severe infection (eg, severe pneumonia, sepsis, meningitis) were excluded from the study. All children remained in the study until diarrhea resolved, after which they were transferred to a nutritional rehabilitation unit or home-based nutritional follow-up program of the Clinical Research and Service Centre. On enrollment, a clinical history was taken and a physical examination was performed. Laboratory investigations on admission included a blood test for hematocrit, total and differential white blood cell count, and serum protein and albumin; serum electrolytes on admission and at 24 hours and 48 hours; stool microscopy for leukocytes, red blood cells, and parasites (including Giardia lamblia, Entamoeba histolytica, and Cryptosporidium); stool culture for Salmonella, Shigella, and Vibrios; and stool culture for rotavirus by enzymelinked immunosorbent assay; urine for microscopy and culture and chest radiograph were obtained if clinically indicated.
Outcomes Primary outcomes were the number of children developing overhydration and number of children with correction of basal hypokalemia after 24 and 48 hours of treatment. Secondary outcome was the number of children remaining hyponatremic at 24 and 48 hours of treatment.
Sample Size The sample size was estimated based on an expected reduction of persistence of hypokalemia from 33% with standard WHO-ORS to 12% with ReSoMaL.12 Considering a 5% level of significance, 80% power, and 10% dropout, the sample size was calculated to be 65 in each group. Although no reliable data exist on the development of overhydration quantified objectively, a sample size of 52 in each group was estimated, assuming a 20% difference in the development of overhydration between the groups (25% of WHO-ORS group and 5% of ReSoMaL group considered to develop over-
hydration), with a 5% level of significance, 80% power, and 10% dropout. Finally, we studied 65 patients in each group.
Randomization Children were assigned on enrollment by using a randomization list following a permuted table of variable length to either ReSoMaL (Na 45 mmol/L, K 40 mmol/L, Cl 76 mmol/L, citrate 7 mmol/L, Mg 6 mmol/L, Zn 300 lmol/ L, Cu 45 lmol/L, glucose 125 mmol/L, osmolarity 300 mmol/L) or standard ORS (Na 90 mmol/L, K 20 mmol/L, Cl 80 mmol/L, citrate 10 mmol/L, glucose 111 mmol/L, osmolarity 311 mmol/L). A randomization list was prepared by WHO, Geneva, and serially numbered, sealed envelopes were supplied to the pharmacist of ICDDR,B. According to the list inside the envelopes, the pharmacist prepared the ORS in a clean bottle marked with the patient’s name and study number without marking the identity of the solution. The two types of ORS solutions were identical in appearance. The code in the form of A and B, without disclosing the identity, was provided to the investigators for analysis. After preparing the data analysis tables, the group identity was disclosed for preparation of the final report.
Case Management After randomization, the children were treated following the protocol of the WHO manual for the standardized treatment of severely malnourished children and as validated at ICDDR,B.13,15 All children received acute and rehabilitation phase treatment until discharged.
Fluid Therapy Dehydration was categorized according to the modified WHO guidelines.16 Fluid deficit was corrected with 10 mL/ kg/h of the assigned ORS given over the first 2 hours, then 5 mL/kg/h over a period of 10 to 12 hours until the deficit was corrected. Ongoing stool losses were corrected with 5 to 10 mL/kg after each watery or loose stool. In patients with high purging rates, fluid intake was adjusted according to the ongoing stool output. ORS therapy was continued until diarrhea ceased. Treatment of infection and other complications, nutritional therapy, and other aspects of case management were provided consistent with the WHO guidelines and as described elsewhere, with exception of antimicrobial for pneumonia. Our children with pneumonia received intramuscular or intravenous ceftriaxone 75 mg/kg/d once daily for 5 days and gentamicin 5 mg/kg/day in two divided doses.15
Measurements 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, Germany) with a precision of 1.0 g. All intakes (ORS solutions, plain water, and food) and outputs (stool, urine, and vomitus) were quantified every 6 hours. Body weight,
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Table I. Admission characteristics of severely malnourished children randomized to ReSoMaL or WHO-ORS Variable Age (mo) Sex (n), M/F Body weight (kg) Weight-for-age % of NCHS median Z score Weight-for-length % of NCHS median Z score Breast-feed (n), Yes/No Duration of diarrhea before admission (h) No. of stools in 24 h before admission Dehydration status (n) None/some Edema present, n (%) Stool pathogen (n) Vibrio cholerae Shigella Salmonella Other vibrios Rotavirus
ReSoMaL n = 65
WHO-ORS n = 65
15 ± 7 39/26 5.22 ± 0.92
15 ± 6 42/23 5.26 ± 0.95
50 ± 7 4.7 ± 1
51 ± 7 4.6 ± 0.7
66 ± 4 3.6 ± 0.6 45/21 77 ± 62
66 ± 3 3.5 ± 0.5 47/17 74 ± 59
12.5 ± 5
14 ± 9
21/45
23/42
15/65 (23)
14/65 (22)
18/65 5/65 2/65 3/65 10/65
19/65 (29) 2/65 (3) 0/65 5/65 (8) 12/65 (18)
(28) (8) (3) (5) (15)
Values are mean ± SD and number (%) unless otherwise indicated.
vital signs (pulse, temperature, and respiration), and other evidence of overhydration (eg, puffy face, pedal edema, respiratory hurry/distress) were recorded every 6 hours. Overhydration was defined as >5% weight gain after correction of dehydration at any time during the study period with any of the following signs: periorbital edema/ puffy face, increased heart rate (>160/m), or increased respiration (>60/min). Hypokalemia was defined as serum potassium <3.5 mmol/L, hyperkalemia as serum potassium >5.5 mmol/L, hyponatremia as serum sodium <130 mmol/ L, and hypernatremia as serum sodium >150 mmol/L. Duration of diarrhea was calculated as the time in hours from the time of randomization to the last watery stool followed by two consecutive soft/formed stools or no stool for 12 hours. Children withdrawn from the study were any child requiring intravenous fluid therapy for severe dehydration, septic shock, or convulsion; children with concomitant illness requiring more intensive care; patients with severe hyperkalemia (serum potassium $6.0 mmol/L); patients with severe hypokalemia (serum potassium #1.5 mmol/L with or without symptoms or <2.5 mmol/L with symptoms); and patients with severe hyponatremia (serum sodium <120 mmol/L with symptoms or <115 mmol/L with or without symptoms). 616
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Data Analysis Continuous variables were compared between the groups with the Student t test, and the v2 test/Fisher exact test was used to compare the noncontinuous variables by using SPSS PC+ (SPSS, Chicago, IL). For patients withdrawn from the study, data collected until the time of withdrawal were included in the analysis.
RESULTS A total of 296 children were screened for eligibility, of whom 130 were enrolled (65 in the WHO-ORS group and 65 in the ReSoMaL group) between the period of February 1998 to January 2000. Twelve children were withdrawn from the study: seven from the ReSoMaL group (three for development of severe dehydration requiring intravenous fluids, and one each for symptomatic hypokalemia, severe hyperkalemia at 0 hours, severe pneumonia, and symptomatic hyponatremia—Na 108 mmol/L with seizure) and five from the WHOORS group (one each for symptomatic hypokalemia, severe dehydration, and severe pneumonia, and two through parental withdrawal). The child in the ReSoMaL group who developed hyponatremia-associated seizure had a high purging rate (18 g/kg/h) during the first 24-hour period. Baseline clinical characteristics such as age, body weight, weight for age, weight for length, breast-feeding status, edematous state, and dehydration status were comparable between the groups (Table I). Stool microbiology showed similar isolation rates for all pathogens and a predominance of Vibrio cholerae and rotavirus in both groups; tests for diarrheagenic Escherichia coli were not performed in this study. Most of the children were equally and adequately rehydrated with ORS in both groups (ReSoMaL vs WHO-ORS, 76% vs 81%, P = .68; Table II). More children in the WHO-ORS group than the ReSoMaL group developed overhydration (8 vs 3), although the difference was not significant (P = .2; Table II). On admission, 60% (39) and 68% (44) of the children in the ReSoMaL and WHO-ORS groups, respectively, were hypokalemic, and which was corrected in a greater number of children in the ReSoMaL vs WHO-ORS group by 24 hours (14 vs 2, P = .0006) and by 48 hours (18 vs 7, P = .004). The mean serum potassium concentrations at 24 and 48 hours were correspondingly and significantly greater in the ReSoMaL than the WHO-ORS group. In contrast, more children in the ReSoMaL group than in the WHO-ORS group were hyponatremic at 24 hours (24 vs 15, P = .09) and at 48 hours (17 vs 6, P = .017), and three children in the ReSoMaL group developed severe hyponatremia. Mean serum sodium concentrations at 24 and 48 hours were also significantly lower in the ReSoMaL group (Table II). A subgroup analysis excluding children with cholera (known to have high fecal sodium losses) demonstrated no significant differences between the groups in the proportion of children with hyponatremia at 24 and 48 hours (Table III). Of note, the lone child who developed hyponatremic-associated seizure, who was in the ReSoMaL group, did not have cholera. Stool output, urine output, ORS intake, water intake, calorie intake The Journal of Pediatrics November 2003
Table II. Outcome of rehydration of severely malnourished children with ReSoMaL or WHO-ORS Variables No. of children adequately rehydrated at 12 h No. of over hydration Basal hypokalaemia (K+ <3.5 mmol/L) Corrected at 24 h Corrected at 48 h Serum potassium (mmol/L) 0h 24 h 48 h Hyponatraemia (serum Na+ <130 mmol/L) 0h 24 h 48 h Severe Hyponatraemia (serum Na+ # 120 mmol/L) 0h 24 h 48 h Serum sodium (mmol/L) 0 24 h 48 h
ReSoMaL n = 65
WHO-ORS n = 65
OR (95% CI)
P value
51/63 (81%) 8/65 (12%) 44/65 (68%) 2/44 (5%) 7/44 (16%)
0.16 (0.29, 1.96) 0.3 (0.1, 1.5) 0.7 (0.3, 1.6) 12.3 (2.4, 117) 4.8 (1.5, 15.6)
.68 .20 .47 .0006 .004
3.3 ± 1 4.0 ± 1 4.6 ± 0.8
3.3 ± 1 3.2 ± 0.7 3.4 ± 0.8
<0.08 ( 0.3, 0.4)* (0.49, 1.1)* 1.2 (0.3, 1.0)*
.7 .001 .001
25/65 (38%) 24/62 (39%) 17/59 (29%)
19/65 (29%) 15/64 (23%) 6/60 (10%)
1.5 (0.7, 3.4) 2.1 (0.9, 4.8) 3.6 (1.2, 12.2)
.35 .09 .017
0/65 3/62 (5%) 0
1/65 (2%) 1/64 (2%) 0
0 (0, 39) 3.2 (0.3, 171)
132.1 ± 6 130.5 ± 6 132.1 ± 4
132.9 ± 8 133.3 ± 6 134.5 ± 4
45/59 3/65 39/65 14/38 18/38
(76%) (5%) (60%) (36%) (47%)
0.8 ( 3.3, 1.7)* 2.8 ( 4.9, 0.7)* 2.4 ( 3.9, 1.0)*
1.0 .36
.51 .01 .001
Data presented as mean ± SD and number (%) unless otherwise indicated. Na+, Sodium; K+, potassium; NS, non-significant. *Difference between means (95% CI).
from supplemented food, and duration of diarrhea and weight gain before discharge were similar between groups, nor were there any differences in primary or secondary outcome variables between children with marasmus compared with kwashiorkor (data not shown). The children withdrawn from the study were also followed, and final outcome was recorded. No child from either group died.
DISCUSSION Results of this randomized, controlled efficacy and safety trial of ReSoMaL demonstrate that this modified ORS corrects dehydration in severely malnourished children with diarrhea. Although currently recommended, there is little experience with ReSoMaL in the treatment of diarrhea in severely malnourished children, and its efficacy in relation to patient characteristics has not been previously reported.13,5 In an experimental absorption study using perfusion techniques in human adult volunteers, water and sodium absorption was less efficient with ORS containing low (45 mmol/L) compared with higher (Na 60 mmol/L or Na 90 mmol/L) concentrations of sodium.17 Yet in our study, water and sodium absorption with low-sodium ReSoMaL did not seem to be less efficient than with standard WHO-ORS as evidenced by correction of dehydration and stool output. One of the primary theoretical advantages of ReSoMaL is to prevent
the development of overhydration, heart failure, or both; however, this advantage was not established in our study, perhaps because there were very few children in either of the ORS groups that had overhydration or fluid overload. Nor did any child in either group develop heart failure by clinical examination criteria. Although concern has been expressed about the development of heart failure with standard WHOORS in the treatment of severely malnourished children with diarrhea, published reports do not reinforce this concern.5,14,18,19Potassium depletion universally accompanies severe malnutrition and is believed to represent a significant risk for sudden death in malnourished children. Compared with WHO-ORS, ReSoMaL therapy corrected hypokalemia in a much greater proportion of children and in a shorter time. This finding provides a convincing rationale to increase the concentration of potassium in a modified ORS such as ReSoMaL for use in these children. Persistence of hyponatremia at 24 and 48 hours was evident in a greater proportion of children in the ReSoMaL than standard ORS group, especially in children with diarrhea of high purging rates caused by V cholerae and enterotoxigenic E coli. Consistent with persistence of hyponatremia, three children in the ReSoMaL group also developed severe hyponatremia by 24 hours after initiating rehydration. Of note, when children with cholera were excluded from analysis, the risk of remaining hyponatremic was similar in both groups.
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Table III. Hyponatremia (serum <130 mmol) in malnourished children with noncholera and cholera diarrhea treated with the different ORSs Non-cholera diarrhea
0h 24 h 48 h
Cholera diarrhea
ReSoMaL n = 47
Standard n = 46
OR (95% CI)
P value
ReSoMaL n = 18
Standard n = 19
OR (95% CI)
P value
13/47 (28) 11/47 (23) 7/47 (15)
11/46 (24) 7/46 (15) 4/46 (9)
1.2 (0.4, 3.5) 1.7 (0.5, 5.8) 1.84 (0.4, 8.2)
.86 .52 .55
12/18 (67) 13/18 (72) 10/11 (56)
9/19 (47) 8/19 (42) 2/19 (11)
2.2 (0.5, 10) 3.6 (0.8, 18) 10.63 (1.6, 92.1)
.65 .09 .01
Data are n (%).
In our experience, moderate hyponatremia (serum sodium >120 to <130 mmol/L) without any specific symptoms (eg, lethargy, alteration of mental status, and so forth) in severely malnourished children has little clinical significance other than indicating a pathophysiologic process during illness. In contrast, severe hyponatremia (<120 mmol/L) associated with symptoms precipitated during treatment of the acute phase has great clinical significance and should be managed with urgent intervention. The single child who developed convulsions, who was in the ReSoMaL-treated group, did not have cholera but had high purging and ORS consumption rates (stool rate, 18 g/kg/h, and ORS intake, 22 mL/kg/h) during the first 24 hours of treatment and exhibited a rapid decline of serum sodium (from 127 mmol/L at 0 hours to Na 108 mmol/L at 24 hours). The convulsion was successfully managed with anticonvulsant therapy and restoration of serum sodium to normal by infusing 3% sodium chloride 12 mL/kg/h over a period of 4 hours. Although we cannot absolutely exclude other possible electrolyte abnormalities as the cause of the seizure, this serious adverse effect should limit the use of ReSoMaL in its current formulation in severely malnourished children with diarrhea, especially those with high purging rates. Based on conventional concepts of the pathophysiology of severe malnutrition and sodium metabolism, the observation of greater and consequential hyponatremia with the use of ReSoMaL was not expected. Severely malnourished children have excess total body and intracellular sodium even in the presence of reduced sodium concentration in the blood, ie, hyponatremia.20 During the acute phase of recovery, a shift of intracellular sodium to the intravascular compartment occurs, accompanied later by excretion of large quantities of sodium in the urine. The results of our study suggest that the rate of urinary sodium excretion surpasses that of intracellular to extracellular shift of sodium in a clinically significant manner. An ORS with sodium concentration reduced to the level contained in ReSoMaL does not seem to be supported by the results of our study. In recent years, there has been growing interest about the use of hypotonic or reduced osmolarity ORS (lower sodium and lower glucose ORS) in the treatment of diarrhea, because some clinical studies have demonstrated better efficacy, especially in reduced need for unscheduled intravenous fluids.21-27 Based on these findings, a WHO/UNICEF expert committee meeting28 recommended a revised formulation of 618
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reduced-osmolarity ORS (Na 75, Cl 65, K 20, citrate 20, glucose 75 mosmol/L, osmolarity 245 mosmol/L) for use in children and adults for all causes of diarrhea, including cholera; however, the issue of the best ORS remains controversial, and criticism persists.29,30 Reduced osmolarity ORS with higher potassium and added micronutrients has never been evaluated in the treatment of severely malnourished children with diarrhea. The rationale for other micronutrients in ReSoMaL including magnesium, zinc, and copper is mainly to replace those micronutrients in which severely malnourished children are known to be deficient and in which deficiency is known to increase risk of adverse outcome.5 These micronutrients (especially zinc) may influence recovery from diarrhea; however, we were unable to evaluate this possibility, because the standard WHO-ORS group also received supplements as part of our routine practice for the treatment of severely malnourished children.15,31 We conclude that ReSoMaL and standard WHO-ORS were similarly efficacious in the rehydration of severely malnourished children with diarrhea and dehydration. Compared with children receiving standard ORS, children receiving ReSoMaL had significantly better potassium status and less hypokalemia but also had a tendency to remain hyponatremic and to develop hyponatremia, including symptomatic hyponatremia in those with high purging. A modified ORS such as ReSoMaL but with a higher sodium concentration (Na 75 mmol/L) than the current formulation would be expected to have meaningful advantages compared with standard ORS in the treatment of severely malnourished children; however, the recommendation for universal use without qualifications of ReSoMaL in its current formulation should be reconsidered. Dr Alam was involved in proposal and protocol development, all phases and management of the study, data analysis, and manuscript preparation. Dr Hamadani was involved in clinical treatment of the study patients and assisted in manuscript preparation. Dr Dewan was involved in proposal and protocol development and clinical care of the study patients. Prof Fuchs was involved in proposal and protocol development, data analysis, and manuscript preparation. ICDDR,B acknowledges with gratitude the commitment of WHO to the Centre’s research efforts. We express our sincere appreciation to Dr Oliver Fontaine, WHO, Geneva, for his review of the protocol and for supplying the ReSoMaL used in the study. We also thank Dr Pippa Simpson for her advice on the statistical analyses. The Journal of Pediatrics November 2003
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17. Hunt JB, Elliot EJ, Fairclough PD, Clark ML, Farthing MJG. Water and salt absorption from hypotonic glucose-electrolyte solutions in human jejunum. Gut 1992;55:479-83. 18. Dutta P, Bhattacharya SK, Dutta D, Mitra U, Bhattacharya MK, Rasaily R, et al. Oral rehydration solution containing 90 mmol sodium is safe and useful in treating diarrhoea in severely malnourished children. J Diarrhoeal Dis Res 1991;9:118-22. 19. Nagpal A, Aneja S. Oral rehydration therapy in severely malnourished children with diarrhoeal dehydration. Ind J Pediatr 1992;59:313-9. 20. Waterlow JC. Electrolytes and major minerals. In: Waterlow JC, editor. Protein energy malnutrition. London: Edward Arnold; 1992. p. 40-53. 21. Faruque ASG, Mahlanabis D, Hamadini JD, Zetterstrom R. Reduced osmolarity oral rehydration salt in cholera. Scand J Infect Dis 1996;28:87-90. 22. Mahalanabis D, Faruque ASG, Hoque SS. Hypotonic oral rehydration solution in acute diarrhoea: a controlled clinical trial. Acta Paediatr 1995;84:289-93. 23. Dutta D, Bhattacharya MK, Dela AK, Sarker D. Evaluation of oral hypo-osmolar glucose based and rice based oral rehydration solutions in the treatment of cholera in children. Acta Paediatr 2000;37:952-60. 24. CHOICE study group. Multicentre, randomized, double blind clinical trial to evaluate the efficacy and safety of a reduced osmolarity oral rehydration salts solution in children with acute watery diarrhea. Pediatrics 2001;107: 613-8. 25. Dutta P, Mitra U, Manna B, Niyogi SK, Roy K, Mondol C, et al. Double blind, randomised controlled clinical trial of hypo-osmolar oral rehydration salt solution in dehydrating acute diarrhoea in severely malnourished (marasmic) children. Arch Dis Child 2001;84:237-40. 26. Sarker SA, Mahalanabis D, Alam NH, Sharmin S, Khan AM, Fuchs GJ. Reduced osmolarity oral rehydration solution for persistent diarrhea in infants: a randomized controlled clinical trial. J Pediatr 2001;138: 532-8. 27. Hahn SK, Kim YJ, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhoea in children: systematic review. BMJ 2001;323:81-5. 28. WHO/UNICEF. Reduced osmolarity oral rehydration salts (ORS) formulation. A report from a meeting of experts jointly organized by UNICEF and WHO, UNICEF House, New York, NY. WHO/FCH/CAH/01.22. 29. Fuchs GJ. A better oral rehydration solution? An important step, but not a leap forward. BMJ 2001;323:59-60. 30. Hirschorn N, Nalin DR, Cash RA, Greenough WB, III Formulation of oral rehydration solution. Lancet 2002;360:340-1. 31. Roy SK, Tomkins AM, Mahalanabis D, Akramuzzaman SM, Haider R, Fuchs GJ. Impact of zinc supplementation on persistent diarrhoea in malnourished Bangladeshi children. Acta Paediatr 1998;87:1235-9.
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