by Ruchika Kumar, 1 Praveen Kumar, 1 S. Aneja, 1 Virendra Kumar, 1 and Harmeet S. Rehan 2

Transcription

1 Journal of Tropical Pediatrics, 2015, 61, doi: /tropej/fmv054 Advance Access Publication Date: 27 August 2015 Original Paper Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children for Treatment of Children with Severe Acute Malnutrition and Diarrhea: A Randomized Controlled Trial by Ruchika Kumar, 1 Praveen Kumar, 1 S. Aneja, 1 Virendra Kumar, 1 and Harmeet S. Rehan 2 1 Department of Pediatrics, Kalawati Saran Children Hospital, New Delhi, India 2 Department of Pharmacology, Lady Hardinge Medical College, New Delhi, India Correspondence: Ruchika Kumar, Department of Pediatrics, Lady Hardinge Medical College & associated Kalawati Saran Children s Hospital, Bangla Sahib Road, New Delhi, India. <ruchika2908@gmail.com> ABSTRACT World Health Organization-recommended rehydration solution for malnourished children (ReSoMal) for rehydrating severe acute malnourished children is not available in India. In present study, 110 consecutive children aged 6 59 months with severely acute malnourishment and acute diarrhea were randomized to low-osmolarity oral rehydration solution (ORS) (osmolarity: 245, sodium: 75) with added potassium (20 mmol/l) or modified ReSoMal (osmolarity: 300, sodium: 45). In all, 15.4% of modified ReSoMal group developed hyponatremia as compared with 1.9% in lowosmolarity ORS, but none developed severe hyponatremia or hypernatremia. Both groups had equal number of successful rehydration (52 each). Both types of ORS were effective in correcting hypokalemia and dehydration, but rehydration was achieved in shorter duration with modified ReSoMal. KEYWORDS: hyponatremia, rehydration, severe acute malnutrition. INTRODUCTION Diarrhea is most common morbidity in severely acute malnourished (SAM) children. Diarrhea in SAM children has greater severity and increases risk of mortality eight to nine times as compared with children with normal nutrition [1, 2]. As a result of the adaptive state of severe acute malnutrition, there is a concern that oral rehydration solution (ORS) containing higher quantities of sodium may result in increase in intracellular sodium and the risk of fluid overload and heart failure [3]. World Health Organization (WHO) has recommended a different ORS known as ReSoMal (rehydration solution for malnourished children) for rehydrating SAM children; however, these recommendations were based on experiences, and no efficacy trial was undertaken [4]. Results of a randomized controlled trial conducted in Bangladesh on children with severe acute malnutrition have raised concerns regarding safety of ReSoMal [5]. WHO and VC The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 435

2 436 Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children UNICEF now recommend low-osmolarity ORS for nonmalnourished children. The newer formulation has lesser sodium (75 mmol/l) as compared with standard ORS (90 mmol/l) used earlier [6]. WHO recommended ReSoMal is also currently not available in India. In view of this, Indian Academy of Pediatrics (IAP) Guidelines for the management of severe acute malnutrition has recommended use of low-osmolarity ORS with added potassium supplements or preparing ReSoMal with low-osmolarity ORS as per WHO recommendation [7]. With this background, we undertook the present study to compare the safety and efficacy of lowosmolarity ORS vs. modified ReSoMal for treatment of children with severe acute malnutrition and diarrhea. We hypothesized that because hyponatremia was more common in modified ReSoMal group, low-osmolarity ORS will have less sodium derangements. METHODS The study was conducted in Kalawati Saran Children s Hospital, Lady Hardinge Medical College, New Delhi, India from November 2011 to March The study protocol was approved by the institutional ethical committee, and trial was registered with clinical trials registry for Indian Council of Medical Research (CTRI No. REF/2013/01/ ). Material and methods Children with severe acute malnutrition as per WHO case definition and diarrhea were eligible for inclusion [8]. Critically ill children with shock, history of not passed urine for 6 h, convulsions and severe dyselectrolytemia requiring intravenous (IV) correction were excluded. Children with known renal, heart disease and history of receiving IV fluid before admission were also excluded. It was an open-labeled, randomized, controlled study. Block randomization sequence was generated using computer-generated random sequence to divide patients into two study arms. Allocation concealment was done using opaque sealed envelopes. Group-A For preparation of low-osmolarity ORS with added potassium supplements, one packet of low-osmolarity ORS was dissolved in 1000 ml of boiled cooled water, and 15 ml of potassium chloride syrup containing 20 meq of potassium was added and mixed thoroughly. Group-B For preparation of modified ReSoMal, mineral solution powder was prepared in department of pharmacology. The amount of powder was made in sachet for 250 ml solution. Modified ReSoMal was made by dissolving one packet of low-osmolarity ORS in 1700 ml of plain water in which 40 g of sugar powder and 35 ml of electrolyte mineral solution were added and mixed thoroughly. Baseline demographic and clinical parameters were noted in a preformed proforma. All enrolled patients were admitted and studied for 48 h. In all children, blood sugar was checked and 2.5 ml of blood sample was collected for serum sodium, potassium, creatinine and blood urea. Serum sodium and potassium were repeated at 12 h, 24 h and 48 h. Serum sodium, potassium, creatinine and blood urea were analyzed by auto analyzer Roche (902). Randomization and intervention Both the groups were given ORS and other treatment as per WHO-recommended guidelines. Starter F 75 was locally prepared diet with milk, sugar and oil as per WHO guideline. The child s progress was monitored every half hour for the first 2 h; then hourly, i.e. every time the child received starter (F-75) diet or ORS by respiratory rate, pulse rate and volume and stool or vomit frequency. ORS was stopped when the child had three or more of the signs of improved hydration status, namely child no longer thirsty, less lethargic, slowing of respiratory and pulse rates from previous high rate, skin pinch less slow and appearance of tears. Primary outcome was the number of children developing hyponatremia. Secondary outcomes were incidence of hypokalemia, treatment failure, stool frequency, ORS consumption and time for achieving complete rehydration.

3 Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children 437 Statistical analysis was performed by the SPSS program for Windows, version 20 (SPSS, Chicago, Illinois). Continuous variables were presented as mean 6 SD, and categorical variables were presented as absolute numbers and percentage. Normally distributed continuous variables were compared using the unpaired t-test, whereas the Mann Whitney U-test was used for those variables that were not normally distributed. Categorical variables were analyzed using either the chi square test or Fisher s exact test. Risk difference and risk ratio with 95% CI was also calculated. RESULTS A total of 110 children were randomly allocated into Group A and Group-B (Fig. 1). Both the groups were comparable for age, gender, degree of dehydration and number of episodes of loose stools/vomiting. Baseline sodium, potassium, urea, creatinine and blood sugar were similar in low-osmolarity ORS group and ReSoMal group (Table 1). Analysis was done by both per protocol and intention to treat methods. Three children in each group had trial deviation in form of IV fluid administration. In group A (low-osmolarity ORS), two children developed shock and one patient developed hypernatremia (serum sodium>150 mmol/l). In group B (ReSoMal), three children developed shock. These children receiving IV fluid were excluded from per protocol analysis. Greater proportion of children developed hyponatremia in ReSoMal compared with low-osmolarity ORS (15.4% vs. 1.9% p ¼ 0.03); however, none had symptomatic or severe hyponatremia (sodium <130 mmol/l). Both groups had equal number of successful rehydration (52 each). Both the groups were similar in terms of median stool frequency (p ¼ 0.87) and incidence of hypokalemia (low-osmolarity ORS vs. ReSoMal, 9.6 vs. 17%, p ¼ 0.25) (Table 2). Trend of serum sodium and potassium are depicted in Figs 2 and 3. Amount of ORS consumed was lower in ReSoMal (76 vs. 83 ml/kg, p ¼ 0.06). Time for achieving rehydration was earlier in ReSoMal (16.1 vs h, p ¼ 0.036). DISCUSSION As a result of the adaptive state of severe acute malnutrition, there is a concern that ORS containing higher quantities of sodium may result in increase in intracellular sodium and the risk of fluid overload and heart failure. WHO has recommended a different ORS known as ReSoMal for rehydrating SAM children; however, these recommendations were based on experiences and no efficacy trial was undertaken [5, 9]. Our study showed that 15.4% of the children who are rehydrated with modified ReSoMal develop mild hyponatremia (serum sodium < 135 meq/l) as compared with 1.9% in low-osmolarity ORS group. The proportion of children developing hyponatremia in our study is much less as compared with study by Alam et al. [5]. They reported hyponatremia in higher proportion of children (29%) at 48 h in modified ReSoMal rehydrated children. Out of these, three children developed severe hyponatremia by 24 h, with one experiencing hyponatremic convulsions (serum sodium, 108 mmol/l). The difference in proportion of children developing hyponatremia in our study and Alam s study could be attributed to difference of pathogens causing diarrhea, i.e. predominance of Vibrio cholerae and rotavirus in their study. In another study by Dutta et al. [10], hypo-osmolar ORS (224 mmol/l; sodium, 60 mmol/l) and standard ORS solution (311 mmol/l; sodium, 90 mmol/l) were compared and reported mean serum sodium within normal range in both the groups. However, in this study, case definition used for recruitment was weight for age and thus in true sense does not represent severe acute malnutrition. Children with severe malnutrition are depleted in potassium owing to an inefficient Naþ/Kþ pump potassium and excess fecal potassium excretion. In our study on admission, 30.8% of children were hypokalemic (serum potassium <3.5 mmol/l) in lowosmolarity ORS group vs. 36.5% in ReSoMal group. In both the groups, there was gradual improvement in serum potassium status, which was slightly better in low-osmolarity ORS as compared with ReSoMal group (Fig. 3). Similar results have been reported by Alam et al. [5]. ReSoMal corrected basal hypokalemia in a greater proportion of children by 24 h compared with standard WHO ORS in this study. In our study, we used low-osmolarity ORS with added potassium supplements (20 mmol/l); thus, the total potassium

4 438 Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children CONSORT FLOW DIAGRAM Assessed for Eligibility ( n 987) Eligible (n 219) EXCLUDED EXCLUSION CRITERIA (n 77) IV fluid before admission -25 Shock -14 H/O convulsions or any life threatening-1 complication Known renal and heart disease -2 Not passed urine > 6 hrs. -20 RANDOMIZATION Electrolyte disturbance requiring IV -15 correction Randomised ( n 110) Refusal of consent -32 ALLOCATION Group 1 Low Osmoraity ORS (n=55) Group 2 ReSoMal (n=55) OBSERVATION Completed 48 hrs of observation (n-52) Treatment Failure (n 3) Completed 48hrs of observation (n-52) Treatment Failure (n 3) ANALYSIS Analysed - per protocol analysis (n 52) Analysed intension to treat analysis (n-55) Analysed -per protocol analysis (n 52) Analysed-intension to treat analysis (n-55) Fig. 1. Consort flow diagram. concentration in low-osmolarity ORS was similar to ReSoMal. Our results are in concordance with IAP and WHO guidelines, which recommend additional potassium supplementation of 20 mmol/l when using low-osmolarity ORS in children with SAM with diarrhea [7, 11]. Our results strongly indicate that lowosmolarity ORS without potassium supplements will be inappropriate for rehydration of SAM children with diarrhea. In our study, the number of children rehydrated successfully was similar in both the groups (95% in each group). Alam et al. reported successful rehydration in 76% and 81% of ReSoMal and WHO ORS groups, respectively. We could not find any child

5 Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children 439 Table 1. Comparison of baseline characteristics of children Parameters Group-A: Low-osmolarity ORS (n-55) Group-B: Modified ReSoMal (n-55) Males, n (%) 33 (60%) 35 (63.6%) Severe dehydration, n (%) 27 (49.1%) 26 (47.3%) Diarrhea duration (days) Median (range) 4 (2 8) 4 (2 10) Stool frequency (episodes/day) Median (range) 10 (8 20) 10 (8 15) Serum sodium (mmol/l) Serum potassium (mmol/l) Serum urea (mg/dl) Serum creatinine (mg/dl) Blood sugar Mean 6 SD Table 2. Comparison of children with hypokalemia at various time points Time points Group-A: Group-B: Low-osmolarity Modified ReSoMal ORS n (%) n (%) p-value 0 h 16 (30.7) 19 (36.5) h 14 (26.9) 19 (36.5) h 12 (23.1) 17 (32.6) h 5 (9.6) 9 (17.3) Resomal Low Osmolarity ORS Mean values At admission 12 hrs 24 hrs 48 hrs Fig. 2. Trend of serum sodium values at various time interval.

6 440 Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children Mean values ReSoMal Low Osmolarity ORS At admission 12 hrs 24 hrs 48 hrs Fig. 3. Trend of serum potassium value at various time interval. with fluid overload. Nagpal et al. reported signs of fluid overload in 25% of children managed with standard WHO ORS [12]. In our study, three children in ReSoMal group could not achieve rehydration and developed shock. Two of these children had high purge rate and one had persistent vomiting. In the low-osmolarity ORS group, two children developed shock owing to high purge rate. As mentioned above, one child developed hypernatremia in low-osmolarity group and had to be given IV correction. In our study, the duration of completion of hydration in hours was less in ReSoMal group as compared with low-osmolarity ORS (16 vs. 19, p-value ¼ 0.036) and the time interval till passage of formed stool in hours was also less in ReSoMal group as compared with low-osmolarity ORS (60 vs. 75, p-value ¼ 0.027). Our study concludes that both ReSoMal and lowosmolarity ORS with added potassium are safe, as we did not observe any signs of fluid overload, symptomatic hyponatremia or symptomatic hypokalemia. Use of ReSoMal in children with SAM has a risk of mild hyponatremia (serum sodium < 135 mmol/l), but there is no risk of severe hyponatremia. ReSoMal and low-osmolarity ORS with added potassium both are effective in correcting basal hypokalemia associated with SAM and diarrhea. Rehydration may be achieved with ReSoMal in a slightly shorter duration. REFERENCES 1. Ahmed T, Ali M, Ullah MM, et al. Mortality in severely malnourished children with diarrhea and use of a standardised management protocol. Lancet 1999;353: Black RE, Morris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003;361: Management of Severe Malnutrition: A Manual for Physicians and Other Senior Health Workers. Geneva: World Health Organisation, Ashworth A, Khanum S, Jackson A, et al. Guidelines for the Inpatient Treatment of Severely Malnourished Children. Geneva: World Health Organization, Alam NH, Hamadani JD, Dewan N, et al. Efficacy and safety of a modified oral rehydration solution (ReSoMaL) in the treatment of severely malnourished children with watery diarrhea. J Pediatr 2003;143: World Health Organization (WHO); United Nations Children s Fund (UNICEF). WHO/UNICEF Joint Statement: Clinical Management of Acute Diarrhoea. Geneva: WHO, Bhatnagar S, Lodha R, Choudhury P, et al. IAP guidelines 2006 on hospital based management of severely malnourished children. Ind Pediatr 2007;44: WHO Child Growth Standards and the Identification of Severe Acute Malnutrition in Infants and Children. A Joint Statement by the World Health Organization and the United Nations Children s Fund. Geneva: World Health Organization, 2009.

7 Safety and Efficacy of Low-osmolarity ORS vs. Modified Rehydration Solution for Malnourished Children Iannotti LL, Trehan I, clitheroe KL, et al. Diagnosis and treatment of severely malnourished children with diarrhea. J Pediatr child Health 2015;51: Dutta P, Mitra U, Manna B, et al. Double blind, randomized controlled clinical trial of hypo-osmolar oral rehydration salt solution in dehydrating acute diarrhea in severely malnourished (marasmic) children. Arch Dis Child 2001;84: WHO. Guideline: Updates on the Management of Severe Acute Malnutrition in Infants and Children. Geneva: World Health Organization, Nagpal A, Aneja S. Oral rehydration therapy in severely malnourished children with diarrheal dehydration. Ind J Pediatr 1992;59:313 9.