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Invited Review

Oral Rehydration: Toward a Real Solution

Guarino, Alfredo*; Albano, Fabio*; Guandalini, Stefano Working Group on Acute Gastroenteritis

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Journal of Pediatric Gastroenterology and Nutrition: October 2001 - Volume 33 - Issue - p S2-S12
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Infectious diarrhea is a leading cause of childhood death. Although in 1980, it accounted for as many as 5 million deaths, the last estimate in 1999 was 2.2 million deaths of adults and children. Such a spectacular decrease in mortality rate is largely because of the increasing use of oral rehydration solution (ORS) (1). However, acute gastroenteritis is a major problem worldwide, with two distinct patterns. In the so-called developing countries, acute gastroenteritis is a dramatic, often catastrophic, condition that may have an epidemic pattern and is associated with a high mortality rate, particularly in younger and malnourished infants. It therefore requires a combined effort to decrease the mortality rate and to prevent the spread of infectious agents, namely Vibrio cholerae. In developed countries, death of gastroenteritis is almost nonexistent, but gastroenteritis is associated with enormous costs either directly (medical expenses) or indirectly (loss of working days by the parents of sick children) because of the frequency of the disease (2).

The widespread use of ORS in diarrheal diseases has saved the lives of millions of adults and children with diarrhea. Oral rehydration solution has been called “the most important advance in this century”(3), and this remains so for the turn of the century. However, the ideal composition of ORS is a matter of controversy and heated debate. To gain a wider perspective on the “ideal” ORS, this review will briefly discuss the current understanding of pathophysiologic processes responsible for water and electrolyte absorption from the intestine and their modifications in diarrheal disease. It will then review available options and possible new developments.

PATHOPHYSIOLOGIC BASIS FOR USING ORS

Water and Electrolyte Absorption

The intestine absorbs large quantities of sodium, chloride, and bicarbonate. It also secretes H + ions and, to a lesser extent, bicarbonate. The intestine is capable of absorption and secretion of electrolytes and water, which passively follow the solute net transport. Thus, the net absorption of water, sodium, chloride, and potassium is the result of two opposing unidirectional fluxes of ions, one absorptive and the other secretory. The two processes are probably anatomically separated: absorption takes place mainly in the mature epithelial cells, whereas secretion seems to occur in the crypts.

Most absorbed water crosses the intestinal epithelium between the cells, following the osmotic gradient generated by the transcellular transport of nutrients and electrolytes. Electrolytes are transported paracellularly and transcellularly. The paracellular transport across the tight junctions is always passive (or “diffusional”), in response to the electrochemical gradient. In contrast, electrolyte transport through the epithelial cells may be either active or passive. The most important ion in handling intestinal absorption of water and nutrients is sodium. Three different processes of sodium absorption, all driven by sodium, potassium, adenosine triphosphatase, have been described (Fig. 1):

FIG. 1.
FIG. 1.:
Intestinal absorptive/secretory processes for electrolytes. In the villous cell (top panel), sodium, K adenosine triphosphatase (ATPase) maintains a low intracellular sodium concentration, thus allowing the “downhill” entry of sodium-coupled Cl and nutrients. In the crypt cell (bottom panel), the low sodium cell concentration maintained by sodium, potassium, adenosine triphosphatase builds a sodium gradient between the extracellular compartment and the cell. Energized by such a gradient, a carrier in the basolateral membrane (lower part of the figure) couples the flow of one Na, two Cl, and one K from the serosal compartment into the crypt cell. As a result, Cl accumulates above its electrochemical equilibrium and under physiologic circumstances leaks into the lumen across a semipermeable apical membrane. As the absorptive activity going on in the villous cell quantitatively far exceeds the minor secretion arising from the crypts (as suggested in the figure by the arrows' sizes), the net result is absorption of electrolytes and nutrients. Water absorption then passively follows, mainly through the intercellular tight junctions. Secretory changes induced by second messengers. Cyclic AMP, cyclic GMP and Ca ++ /protein kinase C have similar effects. In the mature villous cell (above), they inhibit the coupled influx of sodium and Cl. In the undifferentiated crypt cell, cyclic AMP, cyclic GMP and Ca ++ /protein kinase C act by opening Cl channels (mainly CFTR) in the luminal membrane. As a consequence, Cl leaves the cell moving down its electrochemical gradient. Because the epithelium cannot secrete only anions, cations (Na) flow across the paracellular pathway, driven by the electrical gradient created by the secretory transport of Cl. Thus, antiabsorptive (in the villous cell) and prosecretory (in the crypt cell) forces combine to shift ions, and with them water, from absorption to secretion. The molecular identity of the transporters involved is illustrated in the figure. AMP = adenosine monophosphate, GMP, guanosine monophosphate, CFTR, cystic fibrosis transmembrane regulator.
  • “Neutral” NaCl absorption: This transport process operates throughout the small intestine, but predominantly in the ileum. The transport is mediated by two coupled antiports; one exchanges Na + /H + (cation exchanger), and the other exchanges Cl /HCO 3 (anion exchanger). The Na + /H + antiport maintains intracellular pH, increasing it in the presence of extracellular sodium.
  • Sodium absorption coupled to the absorption of organic solutes: Operative throughout the small intestine. Entry of glucose and most amino acids is coupled to sodium. The existence of the sodium-coupled glucose absorption and its integrity during most acute diarrheal disorders (see herein) is the pathophysiologic cornerstone of the evidence for using ORS for children and adults with diarrhea.
  • “Electrogenic” sodium absorption: Sodium enters the cell downhill of its electrochemical gradient, through selective channels, uncoupled to other substrates. This process has been demonstrated both in the ileum and in the whole colon, where it is predominant.

Regulatory Mechanisms of Electrolyte Transport

A variety of factors, mainly hormones and neurotransmitters, acting either as paracrine agents or at nerve endings, can affect intestinal electrolyte transport in either the absorptive or the secretory direction. Most of these agents are mediators of the enteric nervous system, which plays a crucial role in regulating water and electrolyte transport. The intracellular mediators of secretion responsible for regulating transepithelial ion transport mechanisms in response to such agents, and to exogenous agents, such as bacterial toxins, are cyclic adenosine monophosphate (AMP), cyclic guanosine monophosphate (GMP), and Ca ++ . These are generated in response to different cascades of metabolic pathways and eventually act on different protein kinases, resulting in changes of functional proteins (such as the Cl channel cystic fibrosis transmembrane regulator) and ultimately affecting ion transport.

Nutrient Absorption in Diarrheal States

In normal circumstances, absorptive processes for water and electrolytes prevail over secretory processes and, as a net result, water is absorbed. Diarrhea ensues when there is a derangement in the absorptive–secretory processes (briefly outlined previously herein). The reversal of the normal net absorptive status to secretion can either be the result of an osmotic force acting in the lumen that drives water across the dynamic tight junctions from the serosal to the luminal compartment (osmolar diarrhea, as typically observed in lactose malabsorption) or the result of an active secretory state induced in the crypt cell compartment (secretory diarrhea, best exemplified by enterotoxin-induced diarrhea). In many cases, both mechanisms coexist. For example, in rotavirus enteritis, a serious disruption of absorptive functions occurs as a result of the selective invasion of the mature enterocytes by organisms. In this circumstance, osmolar diarrhea ensues. However, the reduction of absorptive cells in the gut lining also unmasks the secretion in the crypts, and a secretory component is superimposed. The secretory nature of rotaviral diarrhea is further augmented by a recently described enterotoxin, the rotavirus nonstructural protein NSP4 that acts as a viral enterotoxin to induce diarrhea and causes Ca ++ -dependent transepithelial Cl secretion (4,5).

It is now well established that diarrhea induced by classic enterotoxigenic bacteria such as Vibrio cholerae or enterotoxigenic Escherichia coli leaves intact small intestinal mucosal morphology and absorptive functions. Such a demonstration, obtained almost 30 years ago in relation to cholera toxin and cyclic AMP-induced secretion in several in vitro and in vivo systems, was later confirmed in cyclic GMP-induced diarrhea (6) and has been fundamental in providing the pathophysiologic basis for the worldwide use of ORS.

In fact, as previously outlined, the coupling between sodium and glucose entry allows ongoing absorption of these substances, even during active fluid secretion caused by stimulated Cl secretion. Thus, the enhanced fluid absorption allows rehydration despite the large fluid loss seen in enterotoxic diarrhea.

Increased intracellular levels of cyclic AMP and cyclic GMP leave intact the uptake not only of glucose, but also of amino acids and low-molecular-weight peptides, providing a basis for the potential use of other nutrients to produce a more effective fluid-promoting ORS. However, despite several promising laboratory studies of a `super' ORS, solutions based on a mixture of glucose and individual amino acids have never proven to be superior to traditional ORS in the field.

DEVELOPMENT OF ORS

Table 1 summarizes the historic background of ORS, which resulted in 1975 in the formulation of the solution currently recommended by WHO/UNICEF.

TABLE 1
TABLE 1:
Oral rehydration solution: historical perspective in 2001

Subsequently, it became clear that the composition of WHO solution (Table 2) was not ideal for children in industrialized countries. The concentration of sodium, estimated to replace the losses of adults with cholera, was too high for well-nourished children with mild to moderate noncholera diarrhea, as indicated by the reported risk of hypernatremia (7). Scientific societies in the United States and in Europe proposed modifications of ORS composition that eventually led to a change in the universal ORS approach. The American Academy of Pediatrics recommended an ORS with reduced sodium concentration for maintenance, after initial rehydration was accomplished with the WHO solution (8). The European Society of Pediatric Gastroenterology and Nutrition (ESPGAN) proposed a single solution, with reduced sodium concentration (9).

TABLE 2
TABLE 2:
Composition of WHO/UNICEF oral rehydration solution (mmol/L)

Meanwhile, ORS was challenged in developing countries that perceived it as a medicine, but one that did not work as quickly as a drug is expected to work. In addition, even in its packaged form, its cost could be prohibitive in more undeveloped countries. Scientists working at the International Centre for Diarrheal Disease Research in Bangladesh started to explore, with good results, the use of rice instead of glucose (10). The rationale was to provide more calories while keeping a low osmolal load and to obtain an evident change in the frequency and fluidity of stools, at the same time taking into account local traditions.

Thus, a gap opened between the treatment of diarrhea in developed and undeveloped countries. Adopting different strategies that originated from completely different cultural backgrounds, both worked toward an ORS with reduced osmolality.

Today a number of different ORSs are available. These solutions have different electrolyte concentrations, with or without the addition of alkaline compounds, and qualitatively and quantitatively different sources of carbohydrates. Other strategies, including the addition of novel compounds, are being explored to increase the antidiarrheal effectiveness of ORS.

Although the classic WHO/UNICEF solution rightly remains the standard in most countries, increasing evidence suggests that its formulation may not be ideal for treating all children with acute gastroenteritis of differing causes and geographic locations. Other milestones in treating acute gastroenteritis have occurred since the WHO solution was made available, including less use of so-called intestinal rest, an unfortunately common practice worldwide because of WHO recommendations to resume feeding promptly after initial rehydration (11). Implementing early feeding in childhood gastroenteritis is strongly endorsed by ESPGHAN, based on collaborative studies (12) that resulted in a specific medical position article (13). The need for trials of ORS and early feeding has been stressed in a previous work, which concluded that when providing early feeding rather than intestinal rest, there is no advantage to an ORS other than the WHO solution (14).

Therefore, early studies of ORS, performed in settings and with procedures and protocols substantially different from those currently recommended, should be regarded cautiously.

In addition to the need to assess optimal composition, ORS remains underused in both developing and developed countries (15–17). Underuse of ORS leads to unnecessary hospitalizations, clinic visits, and admissions to emergency departments, resulting in >$1 billion in direct medical costs in the United States each year (15). There is no controlled information about the consequences of not using ORS in developing countries. However, because in most developing countries the systematic use of ORS has had a dramatic impact on the morbidity and mortality of diarrheal disease (17), not using it could have catastrophic consequences.

The WHO solution was made available approximately 30 years ago. Since then, substantial progresses have been made in understanding the pathophysiology of diarrhea. In the meantime, the epidemiology of intestinal infections has substantially changed, and infrastructures of developing countries are (unfortunately slowly) being improved. Although resources have increased in less developed countries, careful evaluation of cost/benefit ratio is necessary.

There is little doubt of the advantage of having a single ORS that could meet the needs of people independent of age, cause of diarrhea, phase of the disease, or geographic and even seasonal factors. Such a universal solution would have immense advantage in simplicity of use, cost-effectiveness, ease of training doctors, and educating user candidates (virtually every person in the world), and would increase prescription rate and adherence (18). This review will consider options for ORS composition and strategies to improve its use.

ORS COMPOSITION

The most used solutions include the WHO/UNICEF solution, rice-based ORS, hypoosmolar ORS, rice-based hypotonic ORS, (Table 3), and those recommended by ESPGHAN and the American Academy of Pediatrics. The major differences in these solutions are related to sodium concentration and to the source of carbohydrates. Variations in ORS solute content imply changes in osmolality.

TABLE 3
TABLE 3:
Composition of WHO–ORS, rice–ORS, hypoosmolar–ORS, rice hypoosmolar–ORS, ESPGHAN ORS, AAP ORS

As discussed in a recent review (19), in vitro and in vivo data suggest that low osmolality may be the key for enhancing ORS clinical effectiveness (Table 4). Decreased osmolality may be obtained through two major modifications of ORS formulation: the decrease in sodium concentration and the use of a carbohydrate source more complex than glucose.

TABLE 4
TABLE 4:
Putative mechanisms for the efficacy of low-osmolality ORS

Sodium Concentration

The initial composition of ORS contained from 100 to 120 mmol/L Na, estimated to replace fecal losses of patients (adults) with diarrhea (cholera). The current formulation of WHO/UNICEF solution resulted from a consensus meeting held in 1975.

The report of hypernatremia in well-nourished children with diarrhea who received the classic WHO/UNICEF solution raised questions about the ideal concentration of sodium (7,20). In 1985, the American Academy of Pediatrics recommended the use of 75 to 90 mmol/L Na for initial rehydration, followed by 40 to 60 mmol/L Na ORS for maintenance (8). Subsequently, a trial performed in infants with mild-to-moderate diarrhea who were rehydrated with maintenance ORS showed the safety and effectiveness of low-sodium ORS (21), leading to a statement by the American Academy of Pediatrics that these patients could be successfully treated with low-sodium (45 mmol/L) ORS (22).

In 1988, an ad hoc ESPGAN workshop observed that the etiology and clinical consequences of acute diarrhea generally observed in European children are often different from that of children in developing countries, because cholera was not a likely cause. Fecal sodium concentration in well-nourished children with mild-to-moderate diarrhea is much lower than that associated with cholera (23). In addition, in vitro experiments showed that water absorption is increased in the presence of hypotonic solutions when compared with isotonic solutions with plasma (24,25). The workshop resulted in a recommendation for a specific composition of ORS for the children of Europe, published in 1992 (9), with an optimal sodium concentration equal to 60 mmol/L. The use of low-sodium ORS compared with the standard WHO solution resulted in decreased stool volumes and reduced hospital stay in a Finnish population (26). Similar results were reported in Egypt, where an ORS with 75 mmol/L Na was more effective than the classic ORS (27).

To further assess the effectiveness of hypotonic ORS, a multinational evaluation study was performed in four developing countries (India, Brazil, Mexico, and Peru) to compare the safety and effectiveness of classic ORS with an ORS of reduced osmolality (60 mmol/L Na and 84 mmol/L glucose) in children with acute noncholera diarrhea (28). The study found that both ORSs were equally safe, but the latter was associated with lower stool volumes and with significant reduction of the duration of diarrhea (Fig. 2). The authors, while supporting the use of hypotonic ORS for noncholera diarrhea in developing countries, called for specific studies in children with cholera because of the risk that increased sodium fecal losses may not be balanced by low-sodium ORS.

FIG. 2.
FIG. 2.:
Efficacy on total stool output and duration of diarrhea of World Health Organization oral rehydration solution (ORS) and of low-sodium ORS in children with noncholera (left panel) and cholera (right panel) diarrhea. Children with noncholera diarrhea received a reduced-osmolarity ORS containing 60 mmol/L Na, 84 mmol/L glucose (25). Children with cholera received a reduced-osmolarity ORS containing 70 mmol/L Na and 90 mmol/L glucose (27). Data are expressed as percentage of results obtained with WHO ORS.

Evidence of effectiveness of low-sodium ORS in cholera was reported in adults (29) and, finally, in children. Dutta et al. (30) recently performed a comparative trial in Bangladeshi children, showing that hypoosmolar, (70 mmol/L Na) was associated with reduced stool volume, ORS consumption, and duration of diarrhea comparable with either WHO ORS or glucose-based hypoosmolar ORS. However, all outcome variables also improved with glucose hypotonic (70 mmol/L Na, reduced glucose) ORS compared with WHO ORS (Fig. 2).

This article (30), while highlighting important perspectives, has two major limitations: the first, all patients were initially rehydrated with intravenous Ringer lactate solution for 6 to 8 hours, after which they were randomized to treatment groups. Therefore, the population features may be not representative of children with cholera, who have no access to or do not need parenteral rehydration in the hospital. The second limitation is that low-sodium rice ORS, which was also included in the comparative trial, was also superior to glucose-based low-sodium ORS, raising the possibility that rice, rather than low sodium, could have made the difference. Of note, the same hypotonic ORS has been successfully compared with WHO ORS in a population of severely malnourished children with dehydrating diarrhea (31). Overall, consistent data indicate the opportunity for decreasing osmolality and sodium content in ORS. The optimal concentration, however, is still debated. A panel of experts has reviewed studies on low-osmolality ORS that were performed in a double-blind fashion and concluded that low-osmolality ORS has an advantage over classic WHO ORS in reducing stool outputs and the need for unscheduled intravenous therapy. On this basis, a double-blind, randomized, controlled clinical study was performed in five developing countries (Bangladesh, Brazil, India, Peru, and Vietnam) and compared the WHO ORS with a low-sodium (75 mmol/L), equimolar, glucose ORS (32). Although several outcome measures were the same (stool volumes, proportion of vomiting children in the first 24 hours, and duration of diarrhea), the proportion of children who needed unscheduled intravenous therapy was reduced in the group receiving low-osmolal ORS. In addition, unlike what has been reported in adults, there was no additional risk of hyponatremia in children receiving low-sodium ORS (33). The study concludes that hypoosmolar ORS may be effective in children, but that trials in adults with cholera are necessary if a single ORS formulation is to be used for cholera and noncholera patients. Therefore, the major problem in reducing sodium composition—if a universal ORS is to be developed—is the risk of hyponatremia in adults with cholera, whereas it is hypernatremia in children with diarrhea other than cholera receiving the standard WHO-ORS.

Source of Carbohydrates

The other measure for decreasing osmolality is using glucose polymers rather than monomers as a carbohydrate source. The putative mechanisms for increased effectiveness of low-osmolal ORS are summarized in Table 4 and are supported by a number of in vitro and clinical studies. A meta-analysis of clinical trials of cereal-based ORS, commissioned by the WHO (34), showed clearcut superiority of cereal solutions over glucose-based ORS in adults with cholera (36% reduction in stool volume in the first 24 hours) and in children with cholera (32% reduction). In children with acute gastroenteritis from causes other than cholera, the volume reduction was 18%, a result considered as limited. However, even a limited effect could be important in light of the magnitude of the problem and of cost effectiveness. Duration of diarrhea was also reduced with cereal-based ORS (34).

Molla et al. (35) have summarized a number of studies performed with ORS with glucose or with rice and other cereals in several undeveloped countries. Their analysis concludes that cereal-based ORS are effective in significantly reducing purging rates in both adults and children with cholera and noncholera diarrhea. Of interest, the amount of vomitus was also reduced, although the mechanism of this effect is unclear. Field trials were also performed in various countries, including Bangladesh, Kenya, and Afghanistan, with a uniform study design but using different cereals on the basis of local traditions (rice in Bangladesh, maize in Kenya, and wheat in Afghanistan). The results were similar in all settings and indicated significantly better outcome with cereal-based ORS in terms of cumulative recovery rate, median duration of diarrhea, and gain of body weight (Table 5). The comparative evaluation of the differences in children with watery and dysentery diarrhea showed greater benefit in the latter form (35).

TABLE 5
TABLE 5:
Comparison of efficacy of WHO–ORS and cereal-based oral rehydration solutions in diarrhea in three countries

Data obtained in children with cholera provided substantial support for using rice ORS (Fig. 3). The comparative evaluation of WHO ORS, hypoosmolar (70 mmol/L Na) ORS, and hypoosmolar rice ORS showed that the hypoosmolar glucose ORS was associated with a better outcome than was WHO ORS, but the best results were obtained with rice-based ORS (30).

FIG. 3.
FIG. 3.:
Comparative effects of World Health Organization oral rehydration solution (ORS), hypoosmolar glucose-based ORS, and rice-based ORS solutions on total stool output and total duration of diarrhea in children with cholera (27). Data are expressed as percentage of results obtained with ORS.

A meta-analysis compared the use of glucose-based with cereal-based ORS (36). Twenty-two different trials were examined, which included a substantial pediatric component. Rice-based ORS was associated with significant reduction of stool volume compared with glucose ORS in patients with cholera. In contrast, a marginal and not significant reduction was observed in noncholera patients. This study is highly relevant because a large number of data were analyzed under the stringent criteria of evidence-based medicine. However, comparative trials must be regarded in their global aspect. A large trial was performed in Egypt, comparing the effectiveness of glucose and rice-based ORS in children receiving rice and vegetables in an early phase of diarrhea soon after full rehydration (4–12 hours). There were no differences between the groups in the rehydration phase. In contrast, the data collected after initiation of feeding showed that glucose ORS was associated with reduced stool output, ORS intake, and duration of diarrhea compared with rice ORS (14). Evaluating a global approach to diarrhea with focus on all related aspects such as settings, features of enrolled subjects, and comprehensive therapeutic strategies (including early feeding), is crucial because it may reverse the outcomes of testing strategies.

However, there are several problems with cereal-based ORS, starting with the lack of uniform criteria for what cereal-based ORS is. Several types of cereals have been used in clinical trials, and sometimes food other than cereals, such as potatoes, have been tested, at different concentrations and prepared in different ways. Perhaps it would be more appropriate to refer to starch-based ORS with different degrees of hydrolysis and processing (35). The hypothesis also was raised that cereal administration might produce only a cosmetic effect, because of the presence of undigested fibers in the stools, rather than a real reduction of purging rates. However, compelling evidence indicated that reduction of diarrhea was not simply the result of modified stool appearance. But a cosmetic effect is desirable because it may increase the use of ORS and induce mothers to continue feeding children in the presence of less liquid stools (35).

Although cereals other than rice have been used with good results, in the light of the widespread availability and acceptability of rice and based also on the evidence that rice contains a yet unidentified antisecretory moiety (37), there seems to be little reason to consider other carbohydrates for a universal ORS. However, rice should not be considered as a single cereal, because genetics, use of pesticides, and agricultural procedures used in different settings result in different products. In this respect, glucose has a clearcut advantage over rice in terms of homogeneity and stability, which should be carefully considered.

To have a simple-to-prepare and largely available product, practical problems need to be addressed in the carbohydrate source. The WHO ORS is contained in a single packet and it is stable and may be prepared in an easy and standard manner, i.e., dissolving it in 1 liter of water. Replacing glucose with rice may not be an easy task because several steps are needed to obtain the final solution.

Risks have been reported for homemade ORS (38). To make rice ORS liquid enough to drink requires an amount of water sufficient to prevent the risk of higher sodium concentrations (39).

Overall, many problems, beyond chemical composition of ORS, must be considered (40), including the need for collaboration with the pharmaceutical industry and other agencies to select the ingredients, evaluate stability, simplify preparation procedures, ensure global distribution, and examine the cost/effectiveness ratio before making such a major modification of a product that is already effective in more than 90% of cases.

Need for Base Precursor

Bicarbonate was included in the original ORS formulation to help correct acidosis. After 1975, bicarbonate was replaced by citrate to improve stability with similar effectiveness (41). The qualitative and quantitative presence of base precursors has not been addressed in detail. In vitro studies cast doubts on including base precursors in the ORS, because they may actually decrease water absorption (9). In a population of children hospitalized with acute diarrhea, two equimolal ORS, one containing citrate and one not, were equally effective in correcting dehydration. Duration of diarrhea was similar but correction of acidosis was accomplished earlier with citrate-containing ORS (42). Studies are needed to specifically address this potentially important problem, and they should include evaluation of base precursor effects on the stability of the mix.

The possibility of partially replacing chloride with citrate has been considered. This would improve the low palatability of ORS, which largely depends on chloride. This hypothesis should be tested under appropriate conditions. However, it is preliminarily important to check the essential role of base precursors in ORS on more direct clinical outcomes.

Is There a Super-ORS?

Substrates and substances other than rice or cereals have been added to ORS to enhance clinical effectiveness (Table 6). The theoretical background for this includes the following:

TABLE 6
TABLE 6:
Additional components to electrolyte and carbohydrates considered for Super ORS
  • to reduce osmolality, while providing increased calories. This has been done with rice as well as with glucose polymers (43).
  • to use substrates that enhance sodium uptake by coupled transport. This has been done with peptides and amino acids (44).
  • to use substances capable of liberating short-chain fatty acids, such as an amylase-resistant starch derived from corn (45) or guar gum (46), capable of increasing salt and water colonic absorption. This novel approach is based on the knowledge that the colon possesses a peculiar butyrate/bicarbonate antiport coupled with sodium/proton antiport that may be upregulated to increase fluid salvaging during diarrhea (47).
  • to include in ORS therapeutic agents against enteric pathogens. This has been done with the probiotic Lactobacillus GG (48) and with diosmectite (49), a clay that reduces the duration of symptoms of acute gastroenteritis (50). The administration of selected probiotics for which there is solid evidence of effectiveness, has been included for the first time in the guidelines released by the Italian Society of Pediatric Gastroenterology and Nutrition for treatment of children with diarrhea of mild to moderate degree (51).

These strategies, although attractive, are associated with several problems, including costs, stability, and availability of additional compounds (40). Currently, they cannot be considered a priority in the formulation of a universal ORS. However, many of these innovative approaches are promising and should not be dismissed.

USE OF ORS AROUND THE WORLD

The rate of ORS use is relatively low in developed and developing countries. A WHO report estimates that less than 50% of acute diarrheal episodes are treated with ORS (52). A recent ESPGHAN survey reported that one in six doctors in Europe would not prescribe ORS (53). Other papers have estimated the risks and consequences of ORS underuse in undeveloped and developed countries (15–17). Underuse is probably of at least equal importance as the clinical effectiveness of ORS, in relation to its clinical composition, and should be considered in any modification of oral rehydration therapy.

Barriers to ORS Use

There are several barriers to ORS (Table 7), as suggested by surveys of doctors' cultural backgrounds and clinical practices (54), anthropologic surveys (55), opinions of experts (56) and, to a minor extent, by case controlled studies (57,58). The reasons for poor adherence to oral rehydration are complex and largely depend on local conditions.

TABLE 7
TABLE 7:
Barriers against the use of ORS

In developed countries, an excess of hospital admissions results in unnecessary intravenous rehydration. A study performed in Australia showed that the average body weight of a population of children hospitalized for diarrhea and receiving prolonged intravenous rehydration increased by approximately 10 g at discharge, compared with the admission (pre-rehydration) weight, indicating that patients were not dehydrated and there was probably little need for intravenous fluids (59). Preliminary data obtained in Italy indicated an excess of hospital admissions for acute gastroenteritis: hospitalizations because of diarrhea doubled on weekends when family pediatricians were not on duty and children were brought to the emergency department (M. Fontana et al, personal communication, 2000). The paradox is that after being admitted, with little clinical reason, the patients is treated very aggressively, as if really requiring hospitalization.

A study performed in the United States showed that several barriers exist among pediatricians to the use of oral rehydration, including its lack of convenience, the need for additional training of support staff, and the question of reimbursement for intravenous versus oral rehydration (54). This study underlined the need for expanding education on oral rehydration therapy beyond physician education and asked for solutions to counteract financial constraints. These recommendations have been fully endorsed in a symposium on oral rehydration therapy held at the Johns Hopkins University School of Hygiene and Public Health in Baltimore on the twenty-fifth anniversary of WHO ORS (16), and revised codes for oral rehydration and reimbursement by third-party payers also were suggested (16).

The situation is apparently different in developing countries, where parents rather than doctors tend to refuse ORS. A sociologic study, conducted in five countries in Africa and Asia, evaluated the causes of poor adherence to oral rehydration, analyzing the most common reasons for poor adherence either by families or by doctors. The authors reported that diarrhea was considered a normal event, even a lucky one, in several settings. However, parents of affected children made a clearcut difference between mild and severe episodes and, in the latter case, ORS was considered inadequate to induce prompt remission of symptoms and was therefore palliative, for which parents had a negative perception. This was reflected by doctors' prescriptions, which often included a number of unnecessary drugs (55). The authors concluded that effective drugs are needed that promptly (and evidently) reduce the symptoms of enteric infections, as well as a need for careful consideration of the constraints imposed on physicians in their practice that have relevance for their professional careers (55).

Thus, the U.S. study, performed by physicians investigating the barriers to oral rehydration (54), and the study performed by sociologists in Asia and Africa (55) led to surprisingly similar conclusions. Both studies recognized that doctors should be encouraged to prescribe oral rehydration and this should not negatively affect their practices. This indicates, again, the universal nature of the problem, calling for a unique approach.

However, one major barrier to ORS, as suggested by several authors, is that it is not perceived as effective in reducing the volume or the frequency of stools, or the duration of diarrheal episodes. Ironically, the majority of users and doctors share this view. However, the WHO/UNICEF ORS is effective as the current therapeutic standard and reduces both symptoms and duration of diarrhea. But this is difficult to prove (the appropriate control for such a study would be a “not rehydrated population” or maybe a population of children with diarrhea treated with tap water). It is also true that other formulations of ORS more rapidly reduced duration of symptoms and were thus superior to the classic ORS in selected populations. However any forthcoming ORS would probably be challenged with the same disappointing observation, i.e., giving some salt and sugar is not enough! Can this problem be solved?

There are two options. The first is to add something that is universally appropriate and matches all the requirements that have been discussed. Is there any drug or compound that can be added to ORS to improve its effectiveness? Currently, the answer is no. However changing ORS formulation may provide a partial response.

The other option is to promote a cultural campaign to explain what exactly diarrhea is and how to deal with it. A strategy would be to teach the mothers how to give ORS before their children have diarrhea (56). International experts from developing and industrialized countries endorse preventive education of mothers at early well-child visits about acute diarrhea and ORS (56). Doctors should anticipate that oral rehydration be given soon at the onset of symptoms, in light of the high probability of acute gastroenteritis and the associated risk of dehydration.

Efforts in this direction are worth combined professional approach from sociologists, psychologists, experts in media communication, and strong support (and coordination) from scientific societies.

Costs of ORS

Another major problem relates to cost-effectiveness. Indeed, one of the reasons for underuse of ORS in developed countries, particular by poor people, is its relatively high cost (60). A U.S. survey revealed that in as many as 16 states there was no coverage for ORS, thus showing that access to ORS may be limited when it is required most (61). In a recent study, free ORS along with written instructions directly provided to mothers of children with acute gastroenteritis was effective in significantly increasing the use of ORS, thereby reducing the need for unscheduled follow-up visits, compared with controls receiving written instructions only (62).

Similar considerations apply to more undeveloped countries. Estimates of the economic advantages of rice ORS in Bangladesh indicate that it may be possible to save as much as US$305 million per year by treating pediatric diarrhea with rice-based ORS (35). These estimates derive from local rates and do not apply to other settings. Furthermore, this study did not take into account the additional costs for more expensive rice ORS compared with glucose ORS.

We believe that these issues require substantial attention from experts in financing, industry, and logistics, working together with health agencies. However substantial savings may be expected with improved ORS and its extended use. This money could be used for improving infrastructures, thereby triggering a virtuous circle against diarrhea.

Other Variables for Universal ORS

When considering a universal ORS, every aspect becomes potentially crucial including practical aspects (Table 8). Palatability is a major factor for ORS success. If a child does not accept ORS, it is usually because the child is not, or is only slightly, dehydrated. However, a prospective controlled crossover study showed better acceptance of frozen ORS compared to liquid ORS (63), whereas another study showed that flavored glucose-based ORS did not result in increased intake of rehydrating solution (64). Commercially available products may be used to change the flavor of ORS without substantially modifying its chemical composition, but their effectiveness needs to be carefully evaluated. However, neither freezing nor adding flavoring compounds are feasible options for a universal ORS. The use of cereal-based ORS could partially solve the problem; its acceptance has reportedly been good (35).

TABLE 8
TABLE 8:
Practical problems to be considered for universal ORS

Other problems relate to industrial preparation, distribution, and storage (Table 8), for which close collaboration with other professionals again is strongly recommended.

Finally proper presentation of the product along with training for doctors and social workers is essential to increase ORS use.

STRATEGIES FOR REACHING THE GOAL

The goal of having a universal ORS is ambitious and requires collaborative strategies. Scientific societies have the main responsibility for reaching the goal and they should work together.

The first step is to put together a panel of experts to rank problems and set up possible solutions. The Federation of the Societies of Pediatric Gastroenterology and Nutrition with its working group on infectious diarrhea offers a suitable environment to accomplish this for of at least two reasons: 1) it operates worldwide and 2) it has already produced a document that addresses the major issues in investigating and implementing practical suggestions for oral rehydration (65).

An ad hoc committee of this group could work in close cooperation with the WHO and should also include experts in media communications to promote worldwide adherence to oral rehydration.

Changing ORS is ambitious and challenging. The WHO/UNICEF ORS has immense merits and has saved millions of human lives, especially in children and in undeveloped countries. We need to be cautious in undertaking a change. Nevertheless, 30 years after the formulation of the WHO solution, there are several reasons for reconsidering not only its composition but also the global approach to the problem of rehydration in acute diarrhea, taking advantage from the lessons learned with the WHO-ORS.

This task should be approached with a positive, optimistic view because an improved global approach to oral rehydration has the potential of

  • reducing stool volume and duration of diarrhea
  • preventing pathogen spread
  • reducing hospital admissions
  • preventing nutritional consequences of acute and persistent diarrhea
  • increasing prescription by physicians
  • improving compliance of patients and their families
  • cutting the enormous expenses related to the problem
  • raising funds for health improvement, particularly in more undeveloped countries

A global, worldwide approach could be dramatically effective, save resources, allow deeper understanding of the problems of each country, and expand local, successful strategies to worldwide scale.

Is this the time for a change? We think so. Today we have better knowledge not only of ORS chemical composition, but also of the various aspects and problems of its use.

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