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Polymer-based oral rehydration solution for treating acute watery diarrhoea
Germana V Gregorio,
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. email@example.com.
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.
To compare polymer-based ORS with glucose-based ORS for treating acute watery diarrhoea.
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.
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.
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.
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.
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.
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: கா.அழகு மூர்த்தி மற்றும் சி.இ.பி.என்.அர் குழு
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).
To compare polymer-based oral rehydration solution (ORS) with glucose-based ORS for treating acute watery diarrhoea.
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
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.
Unscheduled intravenous fluid therapy.
Cases of vomiting.
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).
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.
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.
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.
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.
Description of studies
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.
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.
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).
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).
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).
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.
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.
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.
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.
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.
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.
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.
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
Sources of support
Effective Health Care Research Programme Consortium, UK.
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]