Polymer-based oral rehydration solution for treating acute watery diarrhoea

  • Review
  • Intervention

Authors

  • Germana V Gregorio,

    Corresponding author
    1. College of Medicine-Philippine General Hospital, University of the Philippines, Department of Pediatrics, Manila, National Capital Region, Philippines
    • Germana V Gregorio, Department of Pediatrics, College of Medicine-Philippine General Hospital, University of the Philippines, Taft Avenue, Manila, National Capital Region, 1000, Philippines. germana1@hotmail.com.

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  • Maria Liza M Gonzales,

    1. College of Medicine-Philippine General Hospital, University of the Philippines, Department of Pediatrics, Manila, National Capital Region, Philippines
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  • Leonila F Dans,

    1. Philippine General Hospital, University of the Philippines, Departments of Pediatrics and Clinical Epidemiology, Manila, National Capital Region, Philippines
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  • Elizabeth G Martinez

    1. College of Medicine-Philippine General Hospital, University of the Philippines, Department of Pediatrics, Manila, National Capital Region, Philippines
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Abstract

Background

Acute diarrhoea is one of the principal causes of morbidity and mortality among children in low-income countries. Glucose-based ORS helps replace fluid and prevent further dehydration from acute diarrhoea. Since 2004, the World Health Organization has recommended the osmolarity < 270 mOsm/L (ORS ≤ 270 ) over the > 310 mOsm/L formulation (ORS ≥ 310). Glucose polymer-based ORS (eg prepared using rice or wheat) slowly releases glucose and may be superior.

Objectives

To compare polymer-based ORS with glucose-based ORS for treating acute watery diarrhoea.

Search methods

In September 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also contacted researchers, organizations, and pharmaceutical companies, and searched reference lists.

Selection criteria

Randomized controlled trials of people with acute watery diarrhoea (cholera and non-cholera associated) comparing polymer-based and glucose-based ORS (with identical electrolyte contents).

Data collection and analysis

Two authors independently assessed the search results and risk of bias, and extracted data. In multiple treatment arms with two or more treatment groups, we combined outcomes as appropriate and compared collectively with the control group.

Main results

Thirty-four trials involving 4214 participants met the inclusion criteria: 27 in children, five in adults and two in both. Twelve trials used adequate methods to conceal allocation. Most compared polymer-based ORS with ORS ≥ 310. There were fewer unscheduled intravenous infusions in the polymer-based ORS group compared with glucose-based ORS (ORS ≥ 310 and ≤ 270 groups combined) (RR 0.75, 95% CI 0.59 to 0.95; 2235 participants, 19 trials). Adults positive for Vibrio cholerae had a shorter duration of diarrhoea with polymer-based ORS than with ORS ≤ 270 (MD -7.11 hours, SD -11.91 to -2.32; 228 participants, 4 trials). Wheat-based ORS resulted in lower total stool output in the first 24 hours compared with ORS ≤ 270 (MD -119.85 g/kg, SD -114.73 to -124.97; 129 participants, 2 trials). Adverse effects were similar for polymer-based ORS and glucose-based ORS.

Authors' conclusions

Polymer-based ORS shows some advantages compared to ORS ≥ 310 for treating all-cause diarrhoea, and in diarrhoea caused by cholera. Comparisons favoured the polymer-based ORS over ORS ≤ 270, but the analysis was underpowered. If specialists consider a potential role for polymer-based ORS, further trials against the current standard (ORS ≤ 270) will be required.

摘要

背景

使用聚合物為基礎的口服補充液治療急性水樣腹瀉

急性腹瀉是低收入國家的兒童主要的罹病和死亡原因之一。葡萄糖的口服補充液在急性腹瀉時可以有效補充水分,防止進一步的脫水。世界衛生組織自2004年以後已建議使用滲透壓小於270 mOsm/L(ORS&≤ 270)優於滲透壓大於310 mOsm/L的配方(ORS &≥ 310)。葡萄糖聚合物為基礎的口服補充液(如製備由米飯或小麥製成者)可以緩慢釋放葡萄糖,可能是較佳的。

目標

比較使用聚合物為基礎的口服補充液或葡萄糖為基礎的口服補充液治療急性水樣腹瀉之差異。

搜尋策略

我們搜尋了自2008年九月以後Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT等資料庫。我們也聯繫了研究者、研究組織、製藥公司和搜尋參考資料。

選擇標準

納入研究急性水樣腹瀉之隨機對照試驗(包括霍亂和非霍亂),比較使用聚合物或葡萄糖的口服補充液之不同(電解質具有相同成份)。

資料收集與分析

由兩位獨立審查者來搜尋結果、偏見風險、並擷取數據。如有兩個或更多治療,我們適當的合併治療組之結果與對照組來比較。

主要結論

共有34個臨床試驗,有4214受試者符合納入標準:27個試驗是針對兒童,5個試驗是針對成人和2個試驗是包含成人以及小孩。 12個臨床試驗使用適當的方法做盲分配,試驗中多是以口服補充液ORS &≥ 310和聚合物比較。使用聚合物為基礎的口服補充液與葡萄糖的口服補充液(ORS &≥ 310 and &≤;包括270組,RR 0.75,95% CI 0.59 – 0.95; 2235名受試者; 19個臨床試驗)相比,較少需要臨時的靜脈營養。成人霍亂弧菌患者使用聚合物為基礎的口服補充液和ORS &≤ 270組相比,腹瀉持續時間較短。(MD −7.11 小時, SD −11.91 to −2.32; 228個受試者,4個臨床試驗)。小麥為基礎的口服補充液和ORS &≤270組相比,在24小時內排便量較少(MD −119.85g/kg, SD −114.73 to −124.97;129個受試者,2個臨床試驗)。聚合物為基礎的口服補充液和葡萄糖的口服補充液之副作用相似。

作者結論

治療各種原因所引起的腹瀉(包括霍亂造成的),使用聚合物為基礎的口服補充液較ORS &≥ 310有效。聚合物為基礎的口服補充液較ORS &≤ 270為佳,但證據仍不夠強。如果專家學者認為,以聚合物為基礎的口服補充液,有其一定的治療角色,未來應進一步設計臨床試驗比較目前的治療準則(ORS &≤270)和聚合物為基礎的口服補充液之差異。

翻譯人

本摘要由三軍總醫院吳宜穎翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

原文為Plain language summary,非總結。

Plain language summary

Polymer-based oral rehydration solution (ORS) ORS for acute diarrhoea

Acute diarrhoea is a common cause of death and illness in developing countries. Oral rehydration solutions (ORS) have had a massive impact worldwide in reducing the number of deaths related to diarrhoea.

Most ORS is in the form of a sugar–salt solution, but over the years people have tried adding a variety of compounds ('glucose polymers') such as whole rice, wheat, sorghum, and maize. The aim is to slowly release glucose into the gut and improve the absorption of the water and salt in the solution. This review updates and expands on a 1998 Cochrane Review of rice-based ORS, and assesses the available evidence on the use of polymer-based ORS (both rice and non-rice based) in comparison with the glucose-based ORS.

The original ORS was based on glucose and had an osmolarity of ≥ 310 mOsm/L (ORS ≥ 310). Glucose-based ORS with a lower osmolarity was later introduced in attempts to improve efficacy, and is considered better at reducing the amount and duration of diarrhoea.

Thirty-four trials involving 4214 participants met the inclusion criteria: 27 in children; five in adults; and two in both. Most trials compared polymer-based ORS with a sugar–salt ORS with a particular strength (ORS ≥ 310), which is slightly more salty than the currently agreed best formula (≤ 270 mOsm/L). The trials' methodological quality was variable.

Fewer people in the polymer-based ORS group needed a drip to be rehydrated compared with those in the glucose-based ORS group. Adverse events were similar for polymer-based ORS and glucose-based ORS.

The authors conclude that polymer-based ORS show some advantages compared to glucose-based ORS for treating diarrhoea of any cause and in diarrhoea caused by cholera. Limited evidence favoured the polymer-based ORS over ORS ≤ 270. 

Further trials should compare the efficiency of ORS ≤ 270 with a polymer-based ORS.

எளியமொழிச் சுருக்கம்

தீவிர வயிற்று போக்கிற்கு பலபடி (polymer) சார்ந்த வாய்வழி அளிக்கப்படும் நீரேற்றல் கரைசல்கள் (ORS)

கடுமையான வயிற்றுப் போக்கு வளரும் நாடுகளில் இறப்பு மற்றும் சுகவீனத்திற்கும் ஒரு பொதுவான காரணமாக உள்ளது. வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) உலகெங்கிலும் வயிற்றுப்போக்கு தொடர்பான இறப்பு எண்ணிக்கை குறைப்பதில் பெரிய தாக்கத்தை ஏற்படுத்தியுள்ளது.

பெரும்பாலான ORS கரைசல்கள் சர்க்கரை-உப்பு கரைசலாக உள்ளது.ஆனால் நாளடைவில் முழு அரிசி, கோதுமை,சோளம், மற்றும் மக்காச்சோளம் ஆகியவற்றை சேர்த்து விதவிதமான கரைசல்களை உபயோகபடுத்தினார்கள். அதனுடைய நோக்கம் குடலில் குளுகோஸை மெதுவாக விடுத்து மற்றும் கரைசலில் உள்ள தண்ணீர் மற்றும் உப்பை உறிஞ்சுதலை அதிகப்படுத்துதலுமாகும். இந்த ஆய்வு 1998 இன் காக்ரேனின் அரிசி சார்ந்த ஆய்வை விரிவுபடுத்தப்பட்டது மற்றும் மேம்படுத்தப்பட்டதாகும் மற்றும் குளுகோஸ் சார்ந்த ORS உடன் ஒப்பிடுகையில் (polymer) பலபடி சார்ந்த ORS ஐ உபயோகப்படுத்துவதற்கு (அரிசி சார்ந்த மற்றும் அரிசி சாராத) கிடைக்கின்ற சான்றுகளை மதிப்பீடு செய்கிறது.

ஆரம்பகால வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) குளுகோஸ் (இனிகம் ) சார்ந்தது மற்றும் ஊடமைச் செறிவு (osmolarity) 310 mOsm /L வரை அல்ல்து அதைவிட அதிகமானதாகவும் இருந்த்தது. பிற்காலத்தில் திறனை அதிகபடுத்தும் நோக்கில் குறைந்த ஊடமைச் செறிவு (osmolarity) கொண்ட குளுகோஸ் (இனிகம்) சார்ந்த வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) அறிமுகப்படுத்தப்பட்டன். அவைகள் வயிற்றுப் போக்கின் அளவு மற்றும் கால அளவை குறைப்பதில் சிறந்ததாக கருதப்பட்டன.

4214 பங்கேற்பாளர்களைக் கொண்ட, 27 ஆராய்ச்சிகள் குழந்தைகளிலும் ஐந்து ஆராய்ச்சிகள் பெரியவர்களிடமும் இரண்டு ஆராய்ச்சிகள் பெரியவர்கள் மற்றும் குழந்தைகளிலுமாக மொத்தம் 34 ஆராய்ச்சிகள் எங்களது திறனாய்வில் சேர்ப்பதற்கான அடிப்படை தகுதியை பெற்றிருந்த்ன. பெரும்பாலான ஆராய்ச்சிகள் பலபடி(polymer) சார்ந்த வாய்வழி நீரேற்றல் கரைசல்களை (ORS) குறிப்பிட்ட அடர்த்தியுள்ள சர்க்கரை - உப்பு கரைசலுடன் (ORS ≥ 310)ஒப்பிட்டுள்ளன. அவை தற்போது ஏற்றுக்கொள்ளப்பட்ட சிறந்த சூத்திரத்தைக்காட்டிலும் (≤ 270 mOsm/L) சிறிது உவர்ப்பானது. ஆராய்ச்சிகளின் வழிமுறைகள் தரத்தில் வேறுபட்டவையாக இருந்தது.

குளுக்கோஸ் (இனிகம் ) சார்ந்த வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) குழுவில் இருந்தவர்களுடன் ஒப்பிடுகையில் (polymer) பலபடி சார்ந்த வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) குழுவில் சில பங்கேற்பாளர்களுக்கே மீள் நீரேற்றம் (rehydrated) செய்ய ட்ரிப்ஸ் தேவைப்பட்டது. எதிர்மறை விளைவுகள் இரண்டு குழுவில் உள்ளவர்களுக்கும் ஒரே மாதிரியாக இருந்தது.

காலராவால் (வாந்தி பேதி) வரும் வயிற்று போக்கிற்கு மற்றும் எந்த ஒரு காரணங்களாலும் வரும் வயிற்று போக்கிற்கு குளுக்கோஸ் (இனிகம் ) சார்ந்த வாய்வழி நீரேற்றல் கரைசல்களைக்காட்டிலும் (ORS) (polymer) பலபடி சார்ந்த வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) சிறந்தது என்னும் முடிவுக்கு ஆய்வாளர்கள் வந்துள்ளனர். ≤ 270 கொண்ட ORS யை விட (polymer) பலபடி சார்ந்த வாய்வழி நீரேற்றல் கரைசல்கள் (ORS) சிரந்தது என்று தெரிவிக்கும் ஆதாரங்கள் குறைவு. 

வருங்கால ஆராய்ச்சிகள் வாய்வழி நீரேற்றல் கரைசளின் ORS ≤ 270 திறனை (polymer) பலபடி-சார்ந்த கரைசல்களுடன் ORS ஒப்பிடவேண்டும்.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: கா.அழகு மூர்த்தி மற்றும் சி.இ.பி.என்.அர் குழு

Background

Acute diarrhoea, which is defined as three or more loose bowel movements in a 24-hour period (WHO/ICDDRB 1995), is one of the principal causes of morbidity and mortality among children in low-income countries. A 2003 review of 27 prospective studies from 20 countries published from 1990 to 2000 estimated the incidence of diarrhoea as 3.8 episodes per child per year for children less than 11 months of age and 2.1 episodes per child per year for children aged one to four years (Kosek 2003). It has a negative impact on quality of life and can result in considerable healthcare costs. Most of these diarrhoeal illnesses occur in low-income countries and are largely caused by infection. The cause is mainly viral in children aged less than five years, while both bacterial and viral pathogens are implicated in adults (Casburn-Jones 2004). Other causes of acute diarrhoea are disordered motility, such as irritable bowel syndrome, intake of certain drugs, or ileal bile acid malabsorption.

Since the 1980s, efforts to decrease the number of deaths from diarrhoea have been based on several interventions, including the improvement of water quality and sanitation, promotion of breastfeeding, and the introduction of treatment programmes that include oral rehydration therapy (Claeson 1990). Oral rehydration solution (ORS) was introduced in 1979 by the World Health Organization (WHO), and it rapidly became the cornerstone of programmes for the control of diarrhoeal diseases (Claeson 1990). The osmolarity of the original formulation is 310 mOsm/L (referred to as ORS ≥ 310) and consists of glucose (111 mmol/L), sodium (90 mmol/L), potassium (20 mmol/L), chloride (80 mmol/L), and citrate (10 mmol/L) or bicarbonate (30 mmol/L). The ORS was shown to improve signs of dehydration, including thirst, sunken eyeballs, sunken fontanelles, poor skin turgor, or a decreased or absence of urine output (WHO/ICDDRB 1995). It is considered as both safe and effective (Santosham 1991), and, since its introduction, it has been considered to be mainly responsible for the decrease in case-fatality rates from acute dehydrating diarrhoea (Victora 2000).

The physiological basis for the use of ORS ≥ 310 was the co-transport of glucose and sodium across the intestinal membrane (Santosham 1991). While this glucose-based ORS is effective in replacing the fluid from acute diarrhoea thus preventing further dehydration, it neither reduces stool loss nor shortens the duration of illness (Santosham 1991). Increasing the glucose concentration to greater than 111 mmol/L increases the osmotic load of the solution, which may further aggravate the fluid loss and induce hypernatraemia (Hunt 1992). In 2004, the WHO recommended a different formulation in which the glucose and sodium content were each reduced to 75 mmol/L to give a total osmolarity of 245 mOsm/L (referred to as ORS ≤ 270) (WHO 2004). ORS ≤ 270 reduces stool volume, shortens the duration of diarrhoea, and decreases the need for unscheduled intravenous therapy compared with ORS ≥ 310 (Hahn 2002).

New ORS formulations have been evaluated in attempts to improve the efficacy of ORS ≥ 310. Glucose polymer-based ORS (referred to as polymer-based ORS) may contain whole rice (amylopectins), as in rice-based ORS or rice syrups (maltodextrins). The difference is that the latter contains only a small amount of amino acids and protein. Other sources of polymers are wheat, sorghum, and maize (high amylase-resistant starch). In these polymer-based solutions, the glucose is slowly released after digestion and is absorbed in the small bowel, enhancing the reabsorption of water and electrolyte secreted into the bowel lumen during diarrhoea (Carpenter 1988; Pizarro 1991). Although ORS ≥ 310 is no longer recommended it remains unknown whether a polymer-based ORS is indeed more effective than a glucose-based ORS (ie ORS ≥ 310 or ORS ≤ 270).

A 1998 Cochrane Review of rice-based ORS for treating diarrhoea concluded that it significantly reduced the mean 24-hour stool output in adults and children with cholera or cholera-like diarrhoea, but results were inconclusive for infants and children with non-cholera diarrhoea (Fontaine 1998). Our Cochrane Review has updated the evidence on the use of polymer-based ORS (both rice and non-rice based) and expanded the primary outcome measures to include the number of participants who required unscheduled use of intravenous fluid therapy. Other primary outcome measures focus on the duration of diarrhoea and the stool output in the first 24 hours since these are considered crucial in the management of these patients and the first 24 hours is the period of greatest stool loss. Our Cochrane Review also aims to provide more insights into whether polymer-based ORS is more effective than glucose-based ORS, and to inform future research.

Patients are dehydrated during the first six to eight hours, but once rehydrated, feeding is initiated and stool losses are replaced volume per volume with the ORS. The effect of feeding a rice-based or starch-based food as soon as the participants are rehydrated could confound the effects of glucose polymer-based ORS (Alam 1992).

Objectives

To compare polymer-based oral rehydration solution (ORS) with glucose-based ORS for treating acute watery diarrhoea.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Types of participants

Infants, children, and adults with acute watery diarrhoea (cholera and non-cholera associated) and mild, moderate, or severe dehydration, as defined by trial authors.

We excluded trials enrolling patients who were unable to drink or take in oral fluids, those in shock, and those with bloody diarrhoea or dysentery.

Types of interventions

Intervention: polymer-based ORS

ORS in which glucose was replaced by a commercial or a local preparation of a polymer (eg rice, wheat, maltodextrins, maize, sorghum, or corn), the electrolyte composition remaining unchanged between the two solutions.

Control: glucose-based ORS

ORS that contains glucose as a carbohydrate source with either 90 or 60 to 75 mmol/L of sodium.

Types of outcome measures

Primary
  • Total stool output (g/kg) during the first 24 hours after randomization.

  • Total stool output (g/kg) from randomization to cessation of diarrhoea.

  • Duration of diarrhoea (hours) from randomization until cessation of diarrhoea.

Secondary
  • Unscheduled intravenous fluid therapy.

  • Cases of vomiting.

Adverse events
  • All adverse events including hyponatraemia (serum sodium level ≤130 mmol/L) (low sodium), hypokalaemia (≤ 3 mol/L) (low potassium), and development of persistent diarrhoea.

Search methods for identification of studies

All relevant trials regardless of language or publication status (published, unpublished, in press, and ongoing).

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (September 2008); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2008, Issue 2); MEDLINE (1966 to September 2008); EMBASE (1974 to September 2008); and LILACS (1982 to September 2008). We also searched the metaRegister of Controlled Trials (mRCT) using 'diarrhoea' and 'oral rehydration solution' as search terms.

Researchers, organizations, and pharmaceutical companies

To help identify unpublished and ongoing trials, we conducted a communications or website search (May 2006 to September 2008) with individual researchers working in the field of general paediatrics and gastroenterology, and the following organizations who may be funding a similar study: WHO – Dr. Kevin Palmer, Regional Adviser, Waterborne and Parasitic Diseases, WHO Regional Office for the Western Pacific, Manila, Philippines; INCLEN (www.inclen.org); USAID (www.usaid.gov); Asian Development Bank (www.adb.org); and World Bank (www.worldbank.org). We also searched United Laboratories Philippines (www.unilab.com.ph) and Abbott International (www.abbott.com.ph) (pharmaceutical companies who manufacture oral rehydration solution) for any unpublished or ongoing trials.

Reference lists

We checked the reference lists of all studies identified by the above methods.

Data collection and analysis

Selection of studies

Two authors (GV Gregorio and LF Dans) independently assessed the results of the literature search to determine whether the title or abstract cited a randomized controlled trial. We retrieved the full reports of clinical trials considered by one or both authors to be potentially relevant as well as trials with unclear treatment allocation. We independently assessed the inclusion criteria of these trials using a standard eligibility form. We resolved any disagreements through discussion, or if this failed, by consulting another author (MLM Gonzales). We scrutinized trial reports to ensure multiple publication would be detected. We listed the excluded studies and the reasons for the exclusion.

Data extraction and management

Two authors (GV Gregorio and EG Martinez or MLM Gonzales) independently extracted the data from the trials using pre-tested data extraction forms. We extracted the number of participants who were randomized and the number analysed for all outcomes for each treatment arm in each trial to determine loss to follow up, whether loss was comparable across treatments, and to determine the type of analysis used. Since the primary outcome measures were continuous, we extracted arithmetic means and standard deviations for each treatment group and noted the number of participants in each group. In trials with multiple interventions (two or more different polymer-based ORS that were used as treatment groups) we pooled the means and standard deviations of the different polymer-based ORS across the treatment arms.

For dichotomous outcome measures, we recorded the number(s) experiencing the event and the numbers analysed in each treatment group. In the meta-analysis, for multiple treatment arms, we combined the numbers experiencing the outcome in two or more experimental interventions as appropriate and compared collectively with the control group.

We resolved any disagreements about data extracted by referring to the trial report and through discussion, or, if that failed, by consulting with another author. Where data were insufficient or missing, we attempted to contact the trial authors. GV Gregorio entered the data into Review Manager 5.

Assessment of risk of bias in included studies

Two authors (GV Gregorio and LF Dans or MLM Gonzales) independently assessed the risk of bias (methodological quality) of each trial using a prepared assessment form. We assessed the generation of allocation sequence and allocation concealment as adequate, inadequate, or unclear according to Jüni 2001. We also noted who was blinded, such as the trial participants, care providers, or outcome assessors, and classified the inclusion of randomized participants in the analysis as adequate if greater than 90% or inadequate if 90% or less. We used the results of the assessment to perform a sensitivity analysis. In the case of unclear or missing information, we made attempts to contact the authors. We resolved disagreements by discussion between review authors.

Assessment of reporting biases

We assessed the presence of publication bias by looking for asymmetry in the funnel plots. We also assessed asymmetry of the funnel plots using StatsDirect and considered a P value < 0.05 on Egger's bias test as significant.

Data synthesis

GV Gregorio analysed the data using Review Manager 5 and presented the results with 95% confidence intervals (CI). We determined and reported the percentage lost to follow up for all trials from the numbers randomized and the numbers analysed in each treatment group. Analyses were based on a complete-case approach. For the participants who did not adhere to the study protocol, their outcome was based on what was reported by the author (if an intention-to-treat analysis was done) or on data sought from the trial authors (if there was no intention-to-treat analysis).

We presented risk ratios (RR) for dichotomous outcomes. We determined continuous outcomes summarized as arithmetic means and standard deviations data using the mean difference (MD).

We checked the normality of the data by calculating the ratio of the mean over the standard deviation. If the ratio (mean/SD) was less than two, then it was likely that the data were skewed and therefore were not combined in the meta-analysis.

Subgroup analysis and investigation of heterogeneity

We evaluated the presence of statistical heterogeneity among the interventions by inspecting the forest plot and by performing a Chi2 test for heterogeneity using a P value of 0.10 to determine statistical significance. Also, we used a I2 value of 50% as an indication of moderate heterogeneity. If there was statistically significant heterogeneity, we used the random-effects model (DerSimonian and Laird method) to combine data, otherwise we applied a fixed-effect model.

We investigated heterogeneity using subgroup analyses. We subgrouped trials according to the osmolarity of glucose ORS (ORS ≥ 310 or ORS ≤ 270) and type of polymer (rice, wheat, maltodextrins, and sorghum). We also evaluated the effect of the participant age (< 19 years (paediatric) and ≥ 19 years (adult)) and of cholera as a pathogen. When there was substantial statistical heterogeneity (ie I2 = 100%), we did not combine the trials in the meta-analysis.

Sensitivity analysis

We performed sensitivity analyses to assess the robustness of the meta-analysis by excluding trials of a low methodological quality, that is, those that used an inadequate method of randomization, unconcealed treatment allocation, and inadequate inclusion of randomized participants in the analysis.

Results

Description of studies

Search results

Of the 212 clinical trials included in the primary search until 26 September 2008, 69 were assessed for inclusion in the review (none were multiple publications). Thirty-five trials met the inclusion criteria (see 'Characteristics of included studies'). We excluded the remaining 35 trials for the following reasons (see also 'Characteristics of excluded studies'): electrolyte composition of the intervention and the control group were not identical or not known (11); composition of treatment group was either unknown or not a polymer (eight); not a clinical trial on ORS but on the use of drugs in acute diarrhoea (four); control group used an oral saline solution (one) or an ORS that did not contain either a 90 or a 60 to 75 mmol/L of sodium (three); not a randomized controlled trial (one); no control group (one); not an efficacy but an effectiveness study (two); patients with persistent and not acute diarrhoea (two); and in two clinical trials, the primary or secondary outcome of interest of this review was not reported. Communication with researchers, an organization, and pharmaceutical companies yielded no further information with regards to unpublished or ongoing clinical trials on polymer-based ORS.

Setting

Most trials were conducted in India (10) and Bangladesh (nine). Other study centres were in Egypt (three) (El-Mougi 1988; Fayad 1993; El-Mougi 1996), Chile (two) (Guiraldes 1995a; Guiraldes 1995b), Mexico (two) (Maulen-Radovan 1994; Maulen-Radovan 2004), and one trial each was done in Australia (Wall 1997), Colombia (Bernal 2005), Madagascar (Razafindrakoto 1993), Malaysia (Iyngkaran 1998), Pakistan (Islam 1994), Philippines (Santos Ocampo 1993), Romania (Nanulescu 1999), and Sudan (Mustafa 1995). Only two trials were not done in a hospital setting. One was done in a paediatric clinic (Nanulescu 1999) and one in a rural treatment centre (Zaman 2007).

Participants

The 34 eligible trials included 4214 participants: 2269 used polymer-based ORS and 1945 used glucose-based ORS. In the individual trials, there was no statistically significant difference in the baseline characteristics between the two groups.

Age

Twenty-seven trials included children only (26 in children < five years old), five included adults only (Alam 1992; Bhattacharya 1998; Ramakrishna 2000; Hossain 2003), and two included both adults and children (Molla 1985; Dutta 1998). The two trials that included both adults and children randomized and reported the outcomes separately for each group.

Pathogen

In terms of the aetiology of diarrhoea, only eight trials randomized exclusively Vibrio cholerae positive patients (Molla 1989a; Alam 1992; Bhattacharya 1998; Dutta 1998; Dutta 2000; Ramakrishna 2000; Zaman 2001; Hossain 2003), while 21 included participants with mixed pathogens (both cholera and non-cholera), and five did not report the pathogen (El-Mougi 1988; Molla 1989b; Fayad 1993; Mustafa 1995; Sharma 1998).

Interventions

Twenty-eight trials compared two interventions (polymer versus glucose-based ORS), five trials compared three interventions (rice ORS versus non-rice ORS versus glucose-based ORS) (Alam 1987; Dutta 1988; Mustafa 1995; Ramakrishna 2000), and one trial≤ (Molla 1989b) compared six interventions (rice, millet, maize, potatoes, sorghum, and wheat ORS versus glucose-based ORS). Only five trials used an ORS ≤ 270 mOsm/L (Bhattacharya 1998; Iyngkaran 1998; Nanulescu 1999; Dutta 2000; Maulen-Radovan 2004), while 29 used ORS ≥ 310 mOsm/L.

Twenty-five trials used a variety of rice (uncooked, cooked, powdered, and pop rice) as a source of polymer, three utilized maltodextrins (Akbar 1991; Santos Ocampo 1993; El-Mougi 1996), two trials used amylase-resistant starch (Ramakrishna 2000; Ramakrishna 2008), and one trial each employed plain flour (Bernal 2005), mung beans (Bhan 1987) (with another arm of the trial using pop rice), and wheat (Alam 1987) (another arm using rice). One trial compared the efficacy of glucose ORS with several polymers in the form of wheat, millet, maize, rice, sorghum, and potatoes (Molla 1989b).

The polymer was prepared locally in 23 trials and obtained commercially in eight trials (Santos Ocampo 1993; Maulen-Radovan 1994; Guiraldes 1995a; Guiraldes 1995b; El-Mougi 1996; Faruque 1997; Zaman 2001; Maulen-Radovan 2004). The source was not reported in three trials (Akbar 1991; Nanulescu 1999; Hossain 2003).

Only one trial withheld feeding in the first 24 hours (Molla 1989b). In another trial (Alam 1992), the patients were randomized into the rice- and glucose-based ORS and further stratified as with and without food intake (Alam 1992). In this, only the data on participants with food intake were used in the review. Feeding was immediately started after hydration in 25 trials, while in seven the onset of refeeding was unclear (Patra 1982; Molla 1985; Bhattacharya 1998; Dutta 1998; Iyngkaran 1998; Dutta 2000; Ramakrishna 2000).

Outcomes reported

Most of the 34 trials reported the total stool output in the first 24 hours (25), total stool output from randomization to discharge (18), duration of diarrhoea (26), and unscheduled use of intravenous fluid (19). However, some of these outcomes were measured and reported in different units by the different studies and therefore not all the data could be used in the meta-analysis. Furthermore, we did not include the data in the meta-analyses if they were skewed: data for total stool output in 24 hours (Molla 1989a; Santos Ocampo 1993; Maulen-Radovan 2004; Bernal 2005); data on duration of diarrhoea (Santos Ocampo 1993; Mustafa 1995; Wall 1997); and data on total stool output from randomization to discharge (Santos Ocampo 1993).

There were a few trials that reported the number of participants with vomiting (nine) (Patra 1982; Bhan 1987; El-Mougi 1988; Mohan 1988; Alam 1992; Islam 1994; Mustafa 1995; Dutta 1998; Iyngkaran 1998), hyponatraemia (six) (Dutta 1988; Guiraldes 1995a; Bhattacharya 1998; Dutta 2000; Zaman 2001; Ramakrishna 2008), hypokalaemia (two) (Bhan 1987; Zaman 2007), and development of persistent diarrhoea (two) (Fayad 1993; Faruque 1997).

Risk of bias in included studies

See Appendix 2 for a summary of the assessment and the 'Characteristics of included studies' for details of each trial's methods.

Of the 34 trials, the methods used to generate the allocation sequence were adequate (computer-generated or random-numbers table) in 24 trials and unclear in the remaining 10 trials (Patra 1982; Bhan 1987; Mohan 1988; Molla 1989a; Razafindrakoto 1993; Mustafa 1995; Faruque 1997; Sharma 1998; Iyngkaran 1998; Nanulescu 1999).

Less than half of the trials (12) used an adequate method to conceal allocation. The method was unclear in the other 22 trials.

Blinding of the participants, providers, and assessors was only done in three trials (Akbar 1991; Santos Ocampo 1993; El-Mougi 1996). Blinding was difficult or impossible in most trials because of the difference in the appearance of the ORS formulation after reconstitution.

All but two trials included an adequate (> 90%) number of randomized participants in the analysis. The number was assessed as inadequate in two trials (Akbar 1991; Nanulescu 1999).

Effects of interventions

There were two trials that reported the effects on adults and children separately (Molla 1985; Dutta 1998). Thus, in the following results, there are some analyses that have more comparison groups than the number of trials reported.

Type of glucose ORS

Five trials compared polymer-based ORS with ORS ≤ 270, and 30 trials with ORS ≥ 310. Overall, the stool volume during the first 24 hours was lower in the polymer-based ORS group (1375 participants, 12 trials, Analysis 1.1). There was substantial, significant heterogeneity (Chi2 test P < 0.00001, I2 = 100%). One trial with ORS ≤ 270 also showed lower stool volume (99 participants, Nanulescu 1999, Analysis 1.1). The duration of diarrhoea varied from 30 to 81 and 34 to 91 hours in the polymer-based ORS and glucose-based ORS groups, respectively.

For ORS ≥ 310, overall duration was shorter in the polymer-based ORS group (977 participants, 12 trials, Analysis 1.2) (Chi2 test P < 0.00001, I2 = 100%). For ORS ≤ 270, there was a similar difference (MD -5.98 g/kg, 95% CI -2.08 to -9.89; 194 participants, 3 trials, Analysis 1.2), but we observed significant heterogeneity when we excluded Nanulescu 1999, the one trial with incomplete outcome data (Chi2 test P < 0.10, I2 = 63%).

There was a trend toward slightly fewer unscheduled intravenous infusions in the polymer-based ORS group compared with both the ORS ≥ 310 and ≤ 270 groups; neither was significant, but when both ORS groups were combined the difference was significant in favour of the polymer-based ORS (RR 0.75, 95% CI 0.59 to 0.95; 2235 participants, 19 trials, Analysis 1.3, Figure 1). There was no statistically significant difference between the polymer-based and glucose-based ORS groups in the number of participants with vomiting (Analysis 1.4), hyponatraemia (Analysis 1.5), hypokalaemia (Analysis 1.6), and development of persistent diarrhoea (Analysis 1.7).

Figure 1.

Any polymer-based ORS vs glucose-based ORS: unscheduled use of intravenous fluid.

Type of polymer

Stratification by types of polymer showed that participants in the rice-based ORS group had a lower stool output (1262 participants, 12 trials, Analysis 2.1: subgroup 1) and duration of diarrhoea (1097 participants, 15 trials, Analysis 2.2: subgroup 1) (Chi2 test P < 0.00001, I2 = 100%). Results with wheat-based ORS were consistent with this (MD -119.85 g/kg, 95% CI -114.73 to -124.97; 129 participants, 2 trials; Analysis 2.1; subgroup 2). For sorghum (1 trial) and maltodextrin ORS (1 trial) the data were clearly skewed (mean/SD > 2) so the results are difficult to interpret. A sensitivity analysis showed similar results.

There was a decrease in the number of participants requiring intravenous fluid for those given rice-based ORS (RR 0.75, 95% CI 0.58 to 0.98; 1962 participants, 16 trials, Analysis 2.3), but not for those given wheat-based ORS and maltodextrin-based ORS.

Effects of age and pathogen

The effects of age and type of pathogen were evaluated using trials that compared rice-based ORS with glucose-based ORS. In children, there was a significant decrease in the total stool output (Analysis 3.1) and duration of diarrhoea (Analysis 3.2) (Chi2 test, P < 0.00001, I2 = 100%). Among the adults, there was a significant decrease in the duration of diarrhoea (MD -7.11 hours, 95% CI -2.32 to -11.91; 228 participants, 4 trials, Analysis 3.2: subgroup 2, Figure 2). All four trials were conducted with participants positive for V. cholerae.

Figure 2.

Rice-based ORS vs glucose-based ORS: duration of diarrhoea, by age group.

Participants positive for V. cholerae had a lower stool output (Analysis 3.3) when given a rice-based ORS. These effects were not seen among participants with non-cholera diarrhoea (Chi2 test P < 0.00001, I2 = 100%). The duration of diarrhoea was significantly shorter among those given rice-based ORS, regardless of the pathogen (Analysis 3.4) (Chi2 test P < 0.00001, I2 = 100%). Sensitivity analysis of the above outcomes showed similar results.

Publication bias

We observed substantial, significant heterogeneity in the primary outcomes and therefore we decided to use a funnel plot for the secondary outcome, where the data were homogenous. We constructed a funnel plot of 19 trials comparing polymer-based ORS, and glucose-based ORS and measuring the outcome of unscheduled use of intravenous fluid (Figure 3). The funnel plot is asymmetric due to the absence of smaller trials at the base and to the right of the pooled estimate. This was confirmed by the test for funnel plot asymmetry, which indicated significant asymmetry (Egger: bias = -0.856208 (95% = -1.699023 to -0.013393, P = 0.0469)). Asymmetry in the funnel plot could result from possible selection bias where smaller studies reporting greater treatment benefit for the experimental group were published (publication bias). The gap in the bottom corner of the graph suggests that smaller studies without statistically significant effects remain unpublished. Differences in inclusion criteria (eg cholera positive versus any pathogen) and method of assessment of unscheduled use of intravenous fluid may also account for the asymmetry.

Figure 3.

Funnel plot on the trials of polymer-based ORS vs glucose-based ORS, measuring the outcome of unscheduled use of intravenous fluid.

Discussion

The biochemical basis for the use of a polymer-based ORS is the presence of starch in rice, wheat, sorghum, and some fruits and vegetables (Carpenter 1988; Pizarro 1991). Even during diarrhoea, the digesting enzyme (amylase) is present in large amounts in the small intestine, so this starch is slowly broken down into glucose molecules. This glucose in turn provides the carrier molecules for co-transport of sodium and water across the intestinal epithelium, without the corresponding osmotic penalty that results if the quantity of glucose is further increased by the use of ORS ≥310.

There are three significant findings in this systematic review of 34 randomized controlled trials. First, there was a decrease in the need for unscheduled intravenous fluid among the participants given polymer-based ORS and in the subgroup of participants who were given rice-based ORS as compared with a glucose-based ORS. This indicates a decrease in the failure rate of oral rehydration when patients are given a polymer-based as compared to a glucose-based oral rehydration therapy. These results remained significant when a sensitivity analysis was carried out. However, the risk difference between the two ORS formulations is only 3%, with 34 patients needing treatment with a polymer-based ORS to prevent one episode of oral rehydration therapy failure. Is this result clinically important? While the use of polymers, such as rice, wheat, maize or potatoes, may be more acceptable as a treatment for diarrhoea, being foods that are familiar and readily available in the household, the preparation of the solution is more tedious. Polymers from local sources require cooking and have to be consumed within eight hours, especially in humid countries, to prevent bacterial growth and contamination. This is in contrast to the glucose-based ORS whose preparation only requires mixing the sachet of glucose and electrolytes in boiled water, and the solution may be consumed up to 12 hours in room temperature. It also has to be borne in mind that the clinical trials that were included in this meta-analysis do not allow one to conclude whether polymer-based ORS is indeed physiologically better than glucose-based ORS, as most of the trials immediately re-fed the patients after hydration. Patients with diarrhoea are dehydrated during the first six to eight hours, but once rehydrated, feeding is initiated. The effect of feeding a rice-based or starch-based food as soon as the participants are rehydrated could confound the effects of polymer-based ORS (Alam 1992) and may have led to an underestimate of the effect of glucose-based ORS (Molla 1989a). In a large multicentre trial, the use of a reduced osmolarity ORS (ORS ≤ 270) compared to a glucose-based ORS (ORS ≥ 310) was shown to decrease the need for unscheduled use of intravenous fluid by 33% (Choice 2001). In this review, most of the included clinical trials used ORS ≥ 310 compared to the newer ORS ≤ 270, which has a lower osmolarity. Whether polymer-based ORS is as effective as, or more effective than the reduced osmolarity ORS, which is presently recommended, remains a subject for investigation.

A second observation of this meta-analysis is the decrease in the duration of diarrhoea among V. cholerae positive adults who were given polymer-based ORS, which was not seen when the analysis was limited to participants with non-cholerae or mixed pathogens. This positive result was not demonstrated in children. The efficacy of rice-based ORS has previously been reported to decrease the stool output in the first 24 hours among V. cholerae positive patients, in both adults and children (Fontaine 1998). These findings, however, were not confirmed in the present review, possibly due to the marked heterogeneity of the pooled data. Moreover, in some of the trials, the data were skewed and could not be used in the meta-analysis. Nonetheless, the efficacy of polymer-based ORS in reducing the duration of diarrhoea among cholera-positive patients but not in patients with other types of pathogens maybe due to the difference in the diarrhoeal mechanisms between the two groups (Casburn-Jones 2004). In cholera, which is an enterotoxin-mediated diarrhoea, intestinal secretory processes are activated by the bacteria, leading to massive fluid and electrolyte losses, without any macro- or micro-damage to the intestinal mucosa. On the other hand, commonly encountered enteric pathogens in childhood diarrhoea, such as rotavirus, Salmonella spp, and Shigella spp cause injury to the intestinal mucosae leading to a decrease in intestinal absorption of fluid, electrolytes, and nutrients.

Lastly, an interesting finding of this meta-analysis is the decrease in the total stool output during the first 24 hours in patients given wheat-based ORS who were enrolled in two trials (Alam 1987, wheat; Molla 1989b, wheat). Apart from its carbohydrate content, the proteins present in wheat may also help in the transport of salt and water across the intestinal mucosa, further decreasing the stool output and duration of diarrhoea (Dagher 1996). The available data in this review, however, are only derived from two trials. The chemical quality and digestibility of wheat-based ORS, as well as its clinical efficacy and safety, warrants further research. The ultimate goal is to find an ORS that is cheap, readily available, acceptable, and effective in all types of diarrhoea.

A major limitation of this review is the substantial heterogeneity in the clinical trials, despite statistically significant results in the primary outcomes. Heterogeneity in the treatment effect may have been affected by the way the outcomes have been measured (methodological diversity). Ideally, measurement of stool output should be made by taking the difference in the weight of the diaper before and after use. In some studies in which both males and females were included (especially in the paediatric group) the urine output may have been inadvertently mixed with the stool, giving an erroneously higher stool output. In adults, three trials used a cholera cot to measure stool output (Bhattacharya 1998; Dutta 2000; Ramakrishna 2000), while one trial did not state the measurement method used (Alam 1992). The cholera cot has a bucket underneath to measure the stool output more accurately. It was also unclear in most of the trials whether the duration of diarrhoea was measured from the initial onset of the disease, before admission to the study, or only from admission up to the time of discharge. Different trials may also have used different criteria to define patients who warrant an unscheduled use of intravenous fluid. Despite these limitations, however, sensitivity analyses did not change the results when trials with unclear randomization, unclear allocation, and inadequate numbers of patients analysed were excluded, suggesting that the results of this review are robust.

Authors' conclusions

Implications for practice

Polymer-based ORS decreases the duration of diarrhoea among adults positive for V. cholerae and lowers the risk of unscheduled use of intravenous fluid, compared with a glucose-based ORS ≥ 310. Trial participants who were given a wheat-based ORS were also shown to have a decrease in total stool output in the first 24 hours; however, the data on wheat ORS were only derived from two trials. Glucose-based ORS, when accompanied by early feeding, may be just as effective.

Implications for research

The rationale for the use of polymer-based ORS is the slow release of glucose from starch, which provides the carrier molecules for sodium without the osmotic penalty that results if the quantity of glucose is increased by the use of ORS ≥ 310. Since the ORS presently recommended already has a reduced osmolarity (ORS ≤ 270), it will be of interest to compare the efficacy of ORS ≤ 270 with a polymer-based ORS in reducing the total stool output, the total volume of ORS intake, the duration of diarrhoea, and the risk of unscheduled intravenous fluid therapy. There is also a need for more trials on the efficacy of wheat-based ORS.

Acknowledgements

This document is an output from a project funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID.

Data and analyses

Download statistical data

Comparison 1. Type of glucose ORS: any polymer-based ORS vs glucose-based ORS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total stool output: during first 24 hours13 Mean Difference (IV, Random, 95% CI)Totals not selected
1.1 ORS ≥31012 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
1.2 ORS ≤ 2701 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2 Duration of diarrhoea15 Mean Difference (IV, Random, 95% CI)Totals not selected
2.1 ORS ≥ 31012 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2.2 ORS ≤ 2703 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3 Unscheduled use of intravenous fluid212235Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.59, 0.95]
3.1 ORS ≥ 310181909Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.60, 1.01]
3.2 ORS ≤ 2703326Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.36, 1.08]
4 Vomiting (no. participants)10617Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.65, 1.05]
4.1 ORS ≥ 3109554Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.68, 1.11]
4.2 ORS ≤ 270163Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.24, 1.34]
5 Hyponatraemia (no. participants)6480Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.52, 2.01]
5.1 ORS ≥ 3103335Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.34, 14.92]
5.2 ORS ≤ 2703145Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.43, 1.82]
6 Hypokalaemia (no. participants)2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 ORS ≥ 3102260Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.74, 2.25]
7 Developed persistent diarrhoea (no. participants)2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 ORS ≥ 3102885Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.68, 2.41]
Analysis 1.1.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 1 Total stool output: during first 24 hours.

Analysis 1.2.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 2 Duration of diarrhoea.

Analysis 1.3.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 3 Unscheduled use of intravenous fluid.

Analysis 1.4.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 4 Vomiting (no. participants).

Analysis 1.5.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 5 Hyponatraemia (no. participants).

Analysis 1.6.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 6 Hypokalaemia (no. participants).

Analysis 1.7.

Comparison 1 Type of glucose ORS: any polymer-based ORS vs glucose-based ORS, Outcome 7 Developed persistent diarrhoea (no. participants).

Comparison 2. Type of polymer: polymer-based ORS vs glucose-based ORS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total stool output during the first 24 hours17 Mean Difference (IV, Random, 95% CI)Totals not selected
1.1 Rice-based ORS13 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Wheat-based ORS2 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Sorghum-based ORS1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
1.4 Maltodextrin-based ORS1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2 Duration of diarrhoea18 Mean Difference (IV, Random, 95% CI)Totals not selected
2.1 Rice-based ORS15 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2.2 Wheat-based ORS1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Sorghum-based ORS1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2.4 Maltodextrin-based ORS1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3 Unscheduled use of intravenous fluid212168Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.59, 0.97]
3.1 Rice-based ORS181962Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.58, 0.98]
3.2 Wheat-based ORS148Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.53]
3.3 Maltodextrin-based ORS2158Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.31, 2.02]
Analysis 2.1.

Comparison 2 Type of polymer: polymer-based ORS vs glucose-based ORS, Outcome 1 Total stool output during the first 24 hours.

Analysis 2.2.

Comparison 2 Type of polymer: polymer-based ORS vs glucose-based ORS, Outcome 2 Duration of diarrhoea.

Analysis 2.3.

Comparison 2 Type of polymer: polymer-based ORS vs glucose-based ORS, Outcome 3 Unscheduled use of intravenous fluid.

Comparison 3. Effects of age and pathogen: rice-based ORS vs glucose-based ORS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total stool output during the first 24 hours, by age group13 Mean Difference (IV, Random, 95% CI)Totals not selected
1.1 Paediatric11 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Adults2 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2 Duration of diarrhoea, by age group15998Mean Difference (IV, Random, 95% CI)-7.19 [-11.80, -2.58]
2.1 Paediatrics11770Mean Difference (IV, Random, 95% CI)-6.81 [-12.10, -1.52]
2.2 Adults4228Mean Difference (IV, Random, 95% CI)-7.11 [-11.91, -2.32]
3 Total stool output during the first 24 hours, by pathogen11 Mean Difference (IV, Random, 95% CI)Totals not selected
3.1 Cholera3 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Non-cholera4 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Mixed pathogens5 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
4 Duration of diarrhoea, by type of pathogen12 Mean Difference (IV, Random, 95% CI)Totals not selected
4.1 Cholera7 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
4.2 Non-cholera3 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Mixed pathogens2 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Effects of age and pathogen: rice-based ORS vs glucose-based ORS, Outcome 1 Total stool output during the first 24 hours, by age group.

Analysis 3.2.

Comparison 3 Effects of age and pathogen: rice-based ORS vs glucose-based ORS, Outcome 2 Duration of diarrhoea, by age group.

Analysis 3.3.

Comparison 3 Effects of age and pathogen: rice-based ORS vs glucose-based ORS, Outcome 3 Total stool output during the first 24 hours, by pathogen.

Analysis 3.4.

Comparison 3 Effects of age and pathogen: rice-based ORS vs glucose-based ORS, Outcome 4 Duration of diarrhoea, by type of pathogen.

Appendices

Appendix 1. Search methods: detailed search strategies

Search setMEDLINEbEMBASEbOTHERb
1REHYDRATION SOLUTIONSFLUID THERAPYoral rehydration
2FLUID THERAPYORAL REHYDRATION THERAPYfluid therapy
3oral rehydration solutionoral rehydration solutionORS
4ORSORS1 or 2 or 3
51 or 2 or 3 or 41 or 2 or 3 or 4glucose
6STARCHGLUCOSE-POLYMERrice
7glucoseSTARCHamylase
8riceglucoseamylopectin
9amylasericecorn
10amylopectinsamylasesorghum
11cornamylopectinsmaize
12sorghumcorn6-11/or
13maizesorghum4 and 12
146-13/ormaize
155 and 146-14
16Limit 15 to human5 and 15
17Limit 16 to human

aSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2008); upper case: MeSH or EMTREE heading; lower case: free text term.
bUsed for Cochrane Infectious Diseases Group Specialized Register, CENTRAL, and LILACS.

Appendix 2. Risk of bias assessment

TrialAllocation sequenceAllocation concealmentBlindingInclusion of randomized participants in analysis
Akbar 1991         AdequateAdequateParticipants, providers, outcome assessorsInadequate
Alam 1987  AdequateUnclearNoneAdequate
Alam 1992AdequateUnclearNoneAdequate
Bernal 2005AdequateAdequateUnclearAdequate
Bhan 1987UnclearUnclearNoneAdequate
Bhattacharya 1998  AdequateUnclearNoneAdequate
Dutta 1988AdequateUnclearUnclearAdequate
Dutta 1998AdequateUnclearNoneAdequate
Dutta 2000AdequateUnclearNoneAdequate
El-Mougi 1988AdequateUnclearNoneAdequate
El-Mougi 1996  AdequateAdequateParticipants, providers, outcome assessorsAdequate
Faruque 1997  UnclearUnclearNoneAdequate
Fayad 1993AdequateAdequateUnclearAdequate
Guiraldes 1995a  AdequateAdequateNoneAdequate
Guiraldes 1995b  AdequateAdequateNoneAdequate
Hossain 2003  AdequateAdequateNoneAdequate
Islam 1994  AdequateUnclearNoneAdequate
Iyngkaran 1998  UnclearUnclearNoneAdequate
Maulen-Radovan 1994  AdequateAdequateNoneAdequate
Maulen-Radovan 2004AdequateAdequateNoneAdequate
Mohan 1988UnclearUnclearNoneAdequate
Molla 1985  AdequateUnclearNoneAdequate
Molla 1989a  UnclearUnclearUnclearAdequate
Molla 1989bAdequateUnclearParticipants and providers not blinded; outcome assessors unclearAdequate
Mustafa 1995  UnclearUnclearUnclearAdequate
Nanulescu 1999  UnclearUnclearNoneInadequate
Patra 1982UnclearAdequateNoneAdequate
Ramakrishna 2000  AdequateUnclearParticipants and providers partially blinded; outcome assessors unclearAdequate
Ramakrishna 2008  AdequateAdequateAssessors but not the participants or providers were blinded because of the nature of the studyAdequate
Razafindrakoto 1993UnclearUnclearNoneAdequate
Santos Ocampo 1993AdequateAdequateParticipants, providers, outcome assessorsAdequate
Sharma 1998  UnclearUnclearNoneAdequate
Wall 1997  AdequateUnclearParticipants and providers not blinded; outcome assessors unclearAdequate
Zaman 2001AdequateUnclearNoneAdequate

Contributions of authors

GV Gregorio was the principal investigator, wrote the protocol, carried out the risk of bias (methodological quality) assessment, data extraction and analysis, and wrote the final manuscript.

MLM Gonzales helped in writing the protocol, carried out the risk of bias (methodological quality) assessment and data extraction, and commented on the final manuscript.

LF Dans carried out the risk of bias (methodological quality) assessment.

EG Martinez carried out the data extraction and commented on the final manuscript.

Declarations of interest

None known.

Sources of support

Internal sources

  • Effective Health Care Research Programme Consortium, UK.

External sources

  • Department for International Development (DFID), UK.

Differences between protocol and review

  • Change in title: The title was changed to highlight the fact that this is a review of polymer-based ORS (not glucose-based ORS).

  • New author: EG Martinez joined the author team after the protocol was published.

  • Data extraction: We originally planned to extract count data by determining the total number of episodes in each group (if the episode is rare) or the number of person years in each group for each treatment arm (if the episode is common). However, during the assessment of the trials, the trials reported the number of participants with unscheduled use of intravenous fluid, and thus it was considered to be a dichotomous rather than a count outcome. Similarly, in the data extraction for number of episodes of vomiting, there were only four trials that reported this outcome, while nine clinical trials reported the number of participants with vomiting. It was decided that the latter would be reported. Other adverse effects that were reported in the trials, including number of participants with hypokalaemia (low potassium levels) and those with development of persistent diarrhoea (diarrhoea of more than 10 days' duration from onset), were also included in the review.

  • Data analysis: In multiple treatment arms with two or more polymer-based ORS as treatment groups, the outcomes were combined as appropriate and compared collectively with the control group. Most of the trials included both cholera and non-cholera cases, and this group was collectively termed as having mixed pathogens rather than non-cholera related diarrhoea.

  • Subgroup analyses: These were limited to the osmolarity of the glucose ORS, the type of polymer, and the effects of participant's age and pathogen. The source of the polymer and the effect of feeding were no longer evaluated as most of the polymers were locally prepared and all but two trials withheld feeding after hydration.

  • Publication bias: The presence of publication bias was confirmed with StatsDirect, a statistical software program.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Akbar 1991

Methods

Randomized controlled trial

Generation of allocation sequence: block randomization

Allocation concealment: code broken at the end of the study

Blinding: participants, providers, outcome assessors

Inclusion of participants in analysis: 81% (maltodextrin group 33/43, 77%; glucose group 36/43, 84%)

Duration: 20 months, from January 1987 to August 1988

Participants

Number: 86 enrolled

Inclusion criteria: male; 4 to 36 months; diarrhoea < 3 days; mild to moderate dehydration

Exclusion criteria: bloody diarrhoea; antibiotic treatment in the last 3 days; severe malnutrition; presence of systemic illness

Interventions
  1. Glucose oral rehydration solution (ORS): 43 participants

  2. Maltodextrin ORS: 43 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

  4. Number with unscheduled use of intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

Notes

Alam 1987

Methods

Randomized controlled trial

Generation of allocation sequence: permuted block design

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 13 months, from April 1983 to April 1984

Participants

Number: 72 enrolled

Inclusion criteria: age 1 to 8 years; watery diarrhoea < 3 days; presence of moderate to severe dehydration

Exclusion criteria: antibiotic treatment before admission; severe malnutrition; presence of systemic illness

Interventions
  1. Glucose oral rehydration solution (ORS): 24 participants

  2. Wheat ORS: 24 participants

  3. Rice ORS: 24 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled use of intravenous fluid

  4. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

NotesParticipants who were given rice ORS were less dehydrated compared to those given glucose ORS, but the difference was not statistically significant

Alam 1987, rice

MethodsRice arm of Alam 1987
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 30 participants

  2. Rice ORS: 30 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Alam 1987, wheat

MethodsWheat arm of Alam 1987
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 30 participants

  2. Wheat ORS: 30 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Alam 1992

Methods

Randomized controlled trial

Generation of allocation sequence: random numbers

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 30 months, from July 1986 to December 1988

Participants

Number: 182 enrolled

Inclusion criteria: age 15 to 60 years; acute watery diarrhoea; presence of dehydration; positive for Vibrio cholerae

Exclusion criteria: history of antidiarrhoeal or antimicrobial intake before admission

Interventions
  1. Glucose oral rehydration solution (ORS) with no food intake: 47 participants

  2. Rice ORS with no food intake: 46 participants

  3. Glucose ORS with food intake: 42 participants

  4. Rice ORS with food intake: 47 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

  4. Number of participants with unscheduled use of intravenous fluid

  5. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

NotesAnalysed separately with or without food intake

Bernal 2005

Methods

Randomized controlled trial

Generation of allocation sequence: permuted blocks of variable length

Allocation concealment: sealed, opaque envelopes

Blinding: unclear

Inclusion of participants in analysis: > 90%

Duration: 17 months, from March 2001 to July 2002

Participants

Number: 101 enrolled

Inclusion criteria: age 1 to 48 months; acute watery diarrhoea < 7 days; presence of dehydration but without hypovolaemic shock

Exclusion criteria: malnourished, kwashiorkor type; presence of paralytic ileus

Interventions
  1. Glucose oral rehydration solution (ORS): 54 participants

  2. Plain flour ORS: 47 participants≥

Outcomes
  1. Total stool output in first 24 hours

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Medellin, Colombia

NotesData on total stool output in first 24 hours are skewed

Bhan 1987

Methods

Randomized controlled trial

Generation of allocation sequence: randomly assigned using sealed envelopes

Allocation concealment: sealed envelopes

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not specified; only stated that trial was done for 10 consecutive months

Participants

Number: 93 enrolled

Inclusion criteria: males; age 3 months to 5 years; watery diarrhoea < 5 days; presence of dehydration; weight for height > 70% of 50th centile of reference standard

Exclusion criteria: female; persistent vomiting; bloody diarrhoea; temperature > 39 °C; other associated medical illness; intake of antibiotics during illness

Interventions
  1. Glucose oral rehydration solution (ORS): 33 participants

  2. Pop rice ORS: 31 participants

  3. Mung bean ORS: 29 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

  4. Number of participants with unscheduled use of intravenous fluid

  5. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: New Delhi, India

NotesParticipants who were given glucose ORS were more malnourished as compared to the treatment groups, but the difference was not statistically significant

Bhan 1987, mung bean

MethodsMung bean ORS arm of Bhan 1987
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 33 participants

  2. Mung bean ORS: 29 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Bhan 1987, rice

MethodsPop rice ORS arm of Bhan 1987
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 33 participants

  2. Pop rice ORS: 31 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Bhattacharya 1998

Methods

Randomized controlled trial

Generation of allocation sequence: permuted block of random numbers

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 32 months, from August 1993 to March 1996

Participants

Number: 123 enrolled

Inclusion criteria: adult males; acute watery diarrhoea; presence of severe dehydration; no antibiotic or intravenous fluid intake; no systemic illness

Exclusion criteria: presence of systemic illness; use of intravenous fluid before admission

Interventions
  1. Glucose oral rehydration solution (ORS) ≥ 310: 30 participants

  2. Glucose ORS ≤ 270: 33 participants

  3. Rice ORS with electrolytes as glucose ORS ≥ 310: 27 participants

  4. Rice ORS with electrolytes as glucose ORS ≤ 270: 33 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

Glucose-based ORS osmolarity≥ 310 mOsm/L and ≤ 270 mOsm/L
Setting

Hospital-based trial

Location: Calcutta, India

Notes

Dutta 1988

Methods

Randomized controlled trial

Generation of allocation sequence: random-numbers table

Allocation concealment: not reported

Blinding: unclear

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 105 enrolled

Inclusion criteria: age 4 months to 4 years; males; acute watery diarrhoea; presence of severe dehydration

Exclusion criteria: presence of systemic illness; antibiotic intake before admission

Interventions
  1. Glucose oral rehydration solution (ORS): 33 participants

  2. Rice ORS: 35 participants

  3. Pop rice ORS: 37 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

  4. Number of participants with hypo- and hypernatraemia

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Calcutta, India

NotesResults of rice ORS and pop rice ORS were combined both for the continuous and dichotomous outcomes, and compared with glucose ORS. These were all reported as rice-based ORS

Dutta 1998

Methods

Randomized controlled trial

Generation of allocation sequence: permuted block of random numbers

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 14 months, from May 1995 to June 1996

Participants

Number: 50 adults and 20 children enrolled

Inclusion criteria: age 3 to 12 years for children, and 18 to 55 years for adults; acute watery diarrhoea; severe dehydration

Exclusion criteria: presence of systemic illness; with intake of drug or intravenous fluid before admission

Interventions

Adults:

  1. Glucose oral rehydration solution (ORS): 25 participants

  2. Rice ORS: 25 participants

Children:

  1. Glucose ORS: 10 participants

  2. Rice ORS: 10 participants

Outcomes
  1. Total stool output from randomization to discharge

  2. Duration of diarrhoea

  3. Number of participants with unscheduled use of intravenous fluid

  4. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Calcutta, India

NotesChildren and adults were randomized separately

Dutta 1998, adults

MethodsAdult arm of Dutta 1998
Participants
  1. Glucose oral rehydration solution (ORS): 25 participants

  2. Rice ORS: 25 participants

Interventions
Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Dutta 1998, children

MethodsChildren arm of Dutta 1998
Participants
  1. Glucose oral rehydration solution (ORS): 10 participants

  2. Rice ORS: 10 participants

Interventions
Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Dutta 2000

Methods

Randomized controlled trial

Generation of allocation sequence: permuted blocks of random numbers

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 34 months, from August 1995 to May 1998

Participants

Number: 58 enrolled

Inclusion criteria: age 2 to 10 years; acute watery diarrhoea; presence of severe dehydration; positive for Vibrio cholerae

Exclusion criteria: presence of systemic illness; with intake of drug or intravenous fluid before admission

Interventions
  1. Glucose oral rehydration solution (ORS) ORS ≥ 310: 20 participants

  2. Glucose ORS ≤ 270: 19 participants

  3. Rice ORS with electrolyte content of glucose ORS ≤ 270: 19 participants

Outcomes
  1. Total stool output from randomization to discharge

  2. Duration of diarrhoea

  3. Number of participants with hypo- or hypernatraemia

Glucose-based ORS osmolarity≥ 310 mOsm/L and ≤ 270 mOsm/L
Setting

Hospital-based trial

Location: Calcutta, India

NotesOnly the data on glucose ORS ≤ 270 were used as this is the one with same electrolyte composition as the rice ORS

El-Mougi 1988

Methods

Randomized controlled trial

Generation of allocation sequence: random permuted blocks

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90% of randomized participants included in the final analysis

Duration: not stated

Participants

Number: 60 enrolled

Inclusion criteria: age 4 months to 4 years; males; acute watery diarrhoea; presence of moderate to severe dehydration; on milk formula intake

Exclusion criteria: presence of bloody diarrhoea; severe dehydration; febrile (temperature > 38.5 °C); marasmic-kwashiorkor malnutrition

Interventions
  1. Glucose oral rehydration solution (ORS): 30 participants

  2. Rice ORS: 30 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with vomiting

  4. Number of episodes of vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Cairo, Egypt

Notes

El-Mougi 1996

Methods

Randomized controlled trial

Generation of allocation sequence: random blocks of fixed length

Allocation concealment: serially numbered identical oral rehydration solution (ORS) packets

Blinding: participants, providers, outcome assessors

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 89 enrolled

Inclusion criteria: age 3 to 24 months; acute watery diarrhoea; presence of mild to moderate dehydration; non-cholera diarrhoea

Exclusion criteria: presence of bloody diarrhoea; severe malnutrition; with no or severe dehydration

Interventions
  1. Glucose ORS: 44 participants

  2. Maltodextrin ORS: 45 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Cairo, Egypt

Notes

Faruque 1997

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 17 months, from August 1990 to December 1991

Participants

Number: 471 enrolled

Inclusion criteria: age 3 to 35 months; acute watery diarrhoea; presence of mild and moderate dehydration

Exclusion criteria: presence of severe dehydration; severe malnutrition; intercurrent illness or chronic disease

Interventions
  1. Glucose oral rehydration solution (ORS): 235 participants

  2. Rice ORS: 236 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of episodes of vomiting

  4. Number of participants who developed persistent diarrhoea

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

Notes

Fayad 1993

Methods

Randomized controlled trial

Generation of allocation sequence: random permuted blocks of variable length

Allocation concealment: sealed, serially numbered envelopes

Blinding: unclear

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 441 enrolled

Inclusion criteria: age 3 to 18 months, acute watery diarrhoea < 7 days; presence of dehydration

Exclusion criteria: bloody diarrhoea; severe malnutrition; presence of systemic illness; exclusively or mostly breastfed

Interventions
  1. Glucose oral rehydration solution (ORS): 222 participants

  2. Rice ORS: 219 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea during the maintenance phase (not from the time of admission)

  3. Number of participants with unscheduled use of intravenous fluid

  4. Number of participants with diarrhoea > 7 days

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Cairo, Egypt

Notes

Guiraldes 1995a

Methods

Randomized controlled trial

Generation of allocation sequence: permuted block randomization

Allocation concealment: code was kept

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 100 enrolled

Inclusion criteria: age 3 to 18 months; acute watery diarrhoea; presence of moderate dehydration; non-breastfed

Exclusion criteria: presence of systemic illness; presence of moderate to severe malnutrition

Interventions
  1. Glucose oral rehydration solution (ORS): 49 participants

  2. Rice ORS: 51 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

  4. Number of participants with unscheduled use of intravenous fluid

  5. Number of participants with hypo- or hypernatraemia

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Santiago, Chile

Notes

Guiraldes 1995b

Methods

Randomized controlled trial

Generation of allocation sequence: block randomization

Allocation concealment: code was kept until end of trial

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 48 enrolled

Inclusion criteria: age 3 to 24 months; acute watery diarrhoea; presence of moderate dehydration; non-breastfed

Exclusion criteria: presence of systemic illness; moderate to severe malnutrition

Interventions
  1. Glucose oral rehydration solution (ORS): 24 participants

  2. Rice ORS: 24 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled use of intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Santiago, Chile

Notes

Hossain 2003

Methods

Randomized controlled trial

Generation of allocation sequence: computer-generated randomization

Allocation concealment: sealed envelopes

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 113 enrolled

Inclusion criteria: adult males 18 to 60 years old; acute watery diarrhoea; presence of severe dehydration; positive for Vibrio cholerae

Exclusion criteria: presence of concomitant illness; received antibiotic and oral rehydration solution (ORS) before admission

Interventions
  1. Glucose ORS: 56 participants

  2. Rice ORS: 57 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled use of intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

NotesData for primary outcomes reported as median (range)

Islam 1994

Methods

Randomized controlled trial

Generation of allocation sequence: permuted block randomization

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 14 months, from March 1989 to April 1990

Participants

Number: 52 enrolled

Inclusion criteria: age < 6 months; acute watery diarrhoea; presence of mild to moderate dehydration; weight for height > 75% of 50th centile

Exclusion criteria: presence of bloody diarrhoea; systemic illness; unable to take oral rehydration solution (ORS); intake of antibiotic

Interventions
  1. Glucose ORS: 25 participants

  2. Rice ORS: 27 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea (but only in those who were successfully treated)

  3. Number of participants with unscheduled use of intravenous fluid, number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial (diarrhoea training unit)

Location: Karachi, Pakistan

NotesParticipants who were given rice ORS were younger compared to those given glucose ORS, but the difference is not statistically significant

Iyngkaran 1998

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 63 enrolled

Inclusion criteria: age < 6 months; loose stools < 7 days' duration

Exclusion criteria: presence of systemic illness; intake of antibiotic/anti-diarrhoeal before admission; severe dehydration

Interventions
  1. Glucose oral rehydration solution (ORS): 32 participants

  2. Rice ORS: 31 participants

Outcomes
  1. Duration of diarrhoea

  2. Number of episodes of vomiting

Glucose-based ORS osmolarity≤ 270 mOsm/L
Setting

Hospital-based trial

Location: Kuala Lumpur, Malaysia

Notes

Maulen-Radovan 1994

Methods

Randomized controlled trial

Generation of allocation sequence: randomly assigned permuted blocks

Allocation concealment: serially numbered sealed envelopes

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 97 enrolled

Inclusion criteria: age 1 to 6 months; acute watery diarrhoea < 5 days; presence of mild to moderate dehydration

Exclusion criteria: presence of bloody diarrhoea; systemic illness; severe malnutrition; history of diarrhoea in the last 2 weeks

Interventions
  1. Glucose oral rehydration solution (ORS): 48 participants

  2. Rice ORS: 49 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial (emergency department)

Location: Mexico City, Mexico

NotesResults for primary outcome skewed

Maulen-Radovan 2004

Methods

Randomized controlled trial

Generation of allocation sequence: block randomization

Allocation concealment: serially numbered sealed envelopes

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 189 enrolled

Inclusion criteria: age 3 to 24 months; males; acute watery diarrhoea; presence dehydration

Exclusion criteria: presence of bloody diarrhoea; systemic illness; severe malnutrition

Interventions
  1. Glucose oral rehydration solution (ORS): 92 participants

  2. Rice ORS: 97 participants

Outcomes
  1. Total stool output in first 24 hours during the maintenance phase only

  2. Duration of diarrhoea

  3. Number of participants with unscheduled use of intravenous fluid

Glucose-based ORS osmolarity≤ 270 mOsm/L
Setting

Hospital-based trial

Location: Mexico City, Mexico

Notes

Mohan 1988

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 50 enrolled

Inclusion criteria: age 3 to 36 months, acute watery diarrhoea, presence of dehydration

Exclusion criteria: none reported

Interventions
  1. Glucose oral rehydration solution (ORS): 23 participants

  2. Rice ORS: 23 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Number of participants with unscheduled use of intravenous fluid

  3. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: New Delhi, India

Notes

Molla 1985

Methods

Randomized controlled trial

Generation of allocation sequence: predetermined random numbers

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 4 months, from December 1982 to March 1983

Participants

Number: 342 enrolled

Inclusion criteria: children aged < 10 years and adults; acute watery diarrhoea; presence of moderate and severe dehydration

Exclusion criteria: presence of systemic illness; intake of antibiotics and oral rehydration solution (ORS) before admission

Interventions

Adults:

  1. Glucose ORS: 72 participants

  2. Rice ORS: 85 participants

Children:

  1. Glucose ORS: 101 participants

  2. Rice ORS: 84 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Number of participants with unscheduled use of intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

NotesSeparate analysis for children and adults

Molla 1985, adults

MethodsAdult arm of Molla 1985
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 72 participants

  2. Rice ORS: 85 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Molla 1985, children

MethodsChildren arm of Molla 1985
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 101 participants

  2. Rice ORS: 84 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Molla 1989a

Methods

Randomized controlled trial

Generation of allocation sequence: randomly assigned

Allocation concealment: not reported

Blinding: unclear

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 93 enrolled

Inclusion criteria: children aged < 5 years; acute watery diarrhoea; presence of moderate and severe dehydration; positive for Vibrio cholerae

Exclusion criteria: breastfed; those with previous treatment

Interventions
  1. Glucose oral rehydration solution (ORS): 46 participants

  2. Rice ORS: 47 participants

Outcomes
  1. Total stool output in first 24 hours

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

NotesData on total stool output in first 24 hours are skewed

Molla 1989b

Methods

Randomized controlled trial

Generation of allocation sequence: permuted block design

Allocation concealment: not reported

Blinding: participants and providers not blinded; outcome assessors unclear

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 276 enrolled

Inclusion criteria: age 1 to 5 years; acute watery diarrhoea < 48 hours; presence of moderate to severe dehydration; no complications

Exclusion criteria: none reported

Interventions
  1. Glucose oral rehydration solution (ORS): 42 participants

  2. Rice ORS: 37 participants

  3. Maize ORS: 38 participants

  4. Sorghuma ORS: 35 participants

  5. Millet ORS: 39 participants

  6. Wheat ORS: 39 participants

  7. Potatoes ORS: 36 participants

Outcomes
  1. Total stool output in first 24 hours

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Dhaka, Bangladesh

NotesStudy with 6 treatment groups vs 1 control group

Molla 1989b, rice

MethodsRice arm of Molla 1989b
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 42 participants

  2. Rice ORS: 37 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Molla 1989b, sorghum

MethodsSorghum arm of Molla 1989b
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 42 participants

  2. Sorghum ORS: 35 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Molla 1989b, wheat

MethodsWheat arm of Molla 1989b
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 42 participants

  2. Wheat ORS: 39 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Mustafa 1995

Methods

Randomized controlled trial

Generation of allocation sequence: randomly assigned

Allocation concealment: not reported

Blinding: unclear

Inclusion of participants in analysis: > 90%

Duration: 9 months, from April to December 1990

Participants

Number: 96 enrolled

Inclusion criteria: males aged < 5 years; acute watery diarrhoea; presence of moderate and severe dehydration

Exclusion criteria: presence of bloody diarrhoea; no systemic illness

Interventions
  1. Glucose oral rehydration solution (ORS): 30 participants

  2. Rice ORS: 32 participants

  3. Sorghum ORS: 34 participants

Outcomes
  1. Duration of diarrhoea

  2. Number of episodes of vomiting

  3. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Khartoum, Sudan

NotesStudy with 3 treatment arms: 2 polymer-based ORS vs 1 control group. Data on duration of diarrhoea are skewed

Mustafa 1995, rice

MethodsRice arm of Mustafa 1995
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 30 participants

  2. Rice ORS: 32 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Mustafa 1995, sorghum

MethodsSorghum arm of Mustafa 1995
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 30 participants

  2. Sorghum ORS: 34 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Nanulescu 1999

Methods

Randomized controlled trial

Generation of allocation sequence: randomly assigned

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: 88% (rice group, 48/56, 86%; glucose group, 51/57, 89%)

Duration: 12 months, from 1 May 1995 to 1 May 1996

Participants

Number: 113 enrolled

Inclusion criteria: age 1 to 12 months; acute watery diarrhoea; presence of mild or moderate dehydration; weight for age > 80% of 50th centile

Exclusion criteria: newborn; presence of bloody diarrhoea; systemic illness; intake of antibiotics; severe dehydration; moderate to severe malnutrition

Interventions
  1. Glucose oral rehydration solution (ORS): 48 participants

  2. Rice ORS: 51 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled use of intravenous fluid

Glucose-based ORS osmolarity≤ 270 mOsm/L
Setting

Paediatric clinic

Location: Ciuj-Napoca, Romania

Notes

Patra 1982

Methods

Randomized controlled trial

Generation of allocation sequence: randomly assigned

Allocation concealment: sealed envelopes

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 52 participants

Inclusion criteria: age 3 months to 5 years; acute watery diarrhoea; presence of moderate to severe dehydration

Exclusion criteria: none reported

Interventions
  1. Glucose oral rehydration solution (ORS): 24 participants

  2. Rice ORS: 24 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled intravenous fluid

  4. Number of participants with vomiting

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Calcutta, India

Notes

Ramakrishna 2000

Methods

Randomized controlled trial

Generation of allocation sequence: block randomization

Allocation concealment: not reported

Blinding: participants and providers partially blinded; outcome assessors unclear

Inclusion of participants in analysis: > 90%

Duration: 27 months, from May 1994 to July 1996

Participants

Number: 48 enrolled

Inclusion criteria: age 14 to 58 years old; acute watery diarrhoea < 72 hours; positive for Vibrio cholerae

Exclusion criteria: presence of systemic illness; intake of antibiotics

Interventions
  1. Glucose oral rehydration solution (ORS): 16 participants

  2. Rice ORS: 16 participants

  3. Amylase-resistant starch ORS: 16 participants

Outcomes
  1. Total stool output in first 24 hours (measured in g and not in g/kg), duration of diarrhoea

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Vellore, India

NotesStudy with 3 treatment arms: 2 polymer-based ORS vs glucose ORS

Ramakrishna 2000, amylase

MethodsAmylase arm of Ramakrishna 2000
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 16 participants

  2. Amylase-resistant starch ORS: 16 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Ramakrishna 2000, rice

MethodsRice arm of Ramakrishna 2000
Participants
Interventions
  1. Glucose oral rehydration solution (ORS): 16 participants

  2. Rice ORS: 16 participants

Outcomes
Glucose-based ORS osmolarity
Setting
Notes

Ramakrishna 2008

Methods

Randomized controlled trial

Generation of allocation sequence: table of random numbers

Allocation concealment: serially numbered oral rehydration solution (ORS) packages

Blinding: assessors but not the participants or providers were blinded because of the nature of the study

Inclusion of participants in analysis: 100%

Duration: not stated

Participants

Number: 50 enrolled

Inclusion criteria: males; 18 to 65 years old; acute watery diarrhoea

Exclusion criteria: presence of bloody diarrhoea; presence of systemic illness

Interventions
  1. Glucose ORS: 25 participants

  2. High amylose maize starch ORS: 25 participants

Outcomes
  1. Total stool output (g) in first 24 hours

  2. Duration of diarrhoea

  3. Unscheduled use of intravenous fluid

  4. Number of participants with hyponatraemia

Glucose-based ORS osmolarity≤ 270 mOsm/L
Setting

Hospital-based trial

Location: Vellore, India

Notes

Razafindrakoto 1993

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: 27 months, from January 1988 to March 1990

Participants

Number: 150 enrolled

Inclusion criteria: age 6 to 36 months; males; acute watery diarrhoea; mild to moderate dehydration; severe malnutrition < 70% of reference standard

Exclusion criteria: presence of bloody diarrhoea; presence of systemic illness; patients in shock

Interventions
  1. Glucose oral rehydration solution (ORS): 68 participants

  2. Rice ORS: 82 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Antanarivo, Madagascar

Notes

Santos Ocampo 1993

Methods

Randomized controlled trial

Generation of allocation sequence: table of random numbers

Allocation concealment: code was kept until the end of trial

Blinding: participants, providers, outcome assessors

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 120 enrolled

Inclusion criteria: age 3 to 36 months; males; acute diarrhoea < 5 days; mild to moderate dehydration

Exclusion criteria: presence of bloody diarrhoea; systemic illness; intake of antibiotics; severe dehydration; severe malnutrition; history of diarrhoea in the last 2 weeks

Interventions
  1. Glucose oral rehydration solution (ORS): 60 participants

  2. Maltodextrin ORS: 60 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Total stool output from randomization to discharge

  3. Duration of diarrhoea

Glucose-based ORS osmolarity≥ 310 mOsml/L
Setting

Hospital-based trial

Location: Manila, Philippines

NotesResults of total stool output in first 24 hours, total stool output from randomization to discharge, and duration of diarrhoea are skewed

Sharma 1998

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Allocation concealment: not reported

Blinding: none

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 100 enrolled

Inclusion criteria: age 7 to 36 months; acute diarrhoea; some dehydration; non-cholerae; weight > 80% of reference standard

Exclusion criteria: presence of bloody diarrhoea; presence of systemic illness; severe dehydration; malnutrition; abdominal distension

Interventions
  1. Glucose oral rehydration solution (ORS): 50 participants

  2. Rice ORS: 50 participants

Outcomes
  1. Total stool output (g, not in g/kg) in first 24 hours

  2. Duration of diarrhoea

  3. Number of participants with unscheduled intravenous fluid

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Rohtak, India

Notes

Wall 1997

Methods

Randomized controlled trial

Generation of allocation sequence: table of random numbers

Allocation concealment: not reported

Blinding: participants and providers not blinded; outcome assessors unclear

Inclusion of participants in analysis: > 90%

Duration: not stated

Participants

Number: 100 enrolled

Inclusion criteria: age 4 weeks to 5 years old; acute diarrhoea; mild to moderate dehydration

Exclusion criteria: presence of systemic illness; intake of antibiotics/antidiarrhoeals; severe dehydration; previous surgery

Interventions
  1. Glucose oral rehydration solution (ORS): 50 participants

  2. Rice ORS: 50 participants

Outcomes
  1. Duration of diarrhoea

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Hospital-based trial

Location: Brisbane, Australia

NotesData on duration of diarrhoea are skewed

Zaman 2001

Methods

Randomized controlled trial

Generation of allocation sequence: table of random numbers

Allocation concealment: not specified whether envelope is opaque and sealed

Blinding: none

Inclusion of participants in analysis: > 90% of randomized participants included in the final analysis

Duration: September 1996 to May 1997

Participants

Number: 167 enrolled

Inclusion criteria: age 5 to 15 years; acute diarrhoea; moderate to severe dehydration; purging rate > 2 mL/kg/hour

Exclusion criteria: presence of bloody diarrhoea; systemic illness; intake of antibiotics; malnutrition < 65% weight for age

Interventions
  1. Glucose oral rehydration solution (ORS): 82 participants

  2. Rice ORS: 85 participants

Outcomes
  1. Total stool output in first 24 hours

  2. Duration of diarrhoea

  3. Number of unscheduled use of intravenous fluid

  4. Number of participants with hyponatraemia and hypokalaemia

Glucose-based ORS osmolarity≥ 310 mOsm/L
Setting

Rural treatment centre

Location: Matlab, Bangladesh

Notes

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Agustina 2007Not a clinical trial on oral rehydration solution
Alam 2008Guar gum, a soluble fibre and not a polymer, was added to the oral rehydration solution
Ansaldi 1990Different electrolyte composition of the 2 groups
Barclay 1995Different electrolyte composition of the 2 groups
Barragan-Guzman 1998Control group given oral saline solution, not oral rehydration solution
Bhandari 2008Not a clinical trial on oral rehydration solution
Cohen 1995Different electrolyte composition of the 2 groups
Gutierrez 2007L-glutamine, an amino acid and not a polymer was added in the oral rehydration solution
Hoekstra 2004Investigated the use of non-digestible carbohydrates, which are not polymers
Jirapinyo 1996Different electrolyte composition of the 2 groups
Kassaye 1994Composition of home-made oral rehydration solution is not known
Kenya 1989The 2 groups have different sources of bicarbonate: polymer-based oral rehydration solution used sodium bicarbonate and glucose oral rehydration solution, trisodium citrate dihydrate
Lebenthal 1995Polymer-based oral rehydration solution has an additional amino acid
Molina 1995Glucose-based oral rehydration solution contained 50 mmol/L sodium. The inclusion criteria of the review specified 90 or 60 to 75 mmol/L of sodium
Molla 1982Used a sucrose and not a glucose-based oral rehydration solution as a control group
Molla 2000Not an efficacy study. The study compared the biochemical analysis of home-made rice oral rehydration solution vs glucose-based oral rehydration solution
Mota-Hernandez 1991Different electrolyte composition of the 2 groups
Murphy 1996Unknown electrolyte composition of the wheat-based oral rehydration solution
Patra 1984Treatment group used an amino acid-based oral rehydration solution, not a polymer-based oral rehydration solution
Pelleboer 1990Not a randomized trial, alternate allocation of participants in the 2 interventions was done
Pizarro 1991Different electrolyte composition of the 2 groups
Prasad 1993The primary outcome of interest relevant to the study was not evaluated
Rabbani 2005Study has no control group that uses glucose-based oral rehydration solution. The control group contains L-histidine, an amino acid
Raghupathy 2006Polymer was not used in place of glucose. Instead, the amylase-resistant starch was added to the glucose-based oral rehydration solution
Roslund 2008Not a clinical trial on oral rehydration solution
Sabchareon 1992Different electrolyte content of rice oral rehydration solution and glucose-based oral rehydration solution
Sarker 2001Participants with persistent diarrhoea (> 14 days)
Sirivichayakul 2000Different electrolyte composition of the 2 groups
Teferedegn 1993Not an efficacy but an effectiveness study
Yang 2007A clinical trial on the use of reduced osmolarity oral rehydration solution in acute diarrhoea. Not a clinical trial on the use of polymer-based oral rehydration solution
Yartev 1995Different electrolyte composition of the 2 groups
Yurdakok 1995Patients were only observed during the rehydration phase. The primary outcome of interest relevant to the study was not evaluated
Zaman 2007Not a clinical trial on oral rehydration solution
Zavaleta 2007Different electrolyte composition of the 2 groups

Ancillary