Enhancing clinical efficacy of oral rehydration therapy: Is low osmolality the key?

doi:10.1016/S0016-5085(98)70647-X

Gastroenterology

Volume 114, Issue 1, January 1998, Pages 197-210

https://doi.org/10.1016/S0016-5085(98)70647-X Get rights and content

Abstract

Many empirical clinical trials have used complex carbohydrate as substrate in oral rehydration solutions (ORSs) instead of glucose and have shown a number of important clinical benefits. Foremost among these are reduced stool volumes, shorter duration of diarrheal illness, and lower ORS intake. The underlying mechanisms to explain this clinical advantage have not been fully established, but a number of possible factors have been proposed: (1) increased substrate availability, (2) a “kinetic advantage” for glucose absorption by glucose polymer, (3) differential handling of glucose monomer and polymer by the small intestine, (4) low osmolality, (5) a separate effect of peptides and amino acids on solute-linked sodium absorption, (6) an antisecretory moiety in rice, and (6) enhanced mucosal repair and regeneration by luminal nutrients. In this report, we assess the relative contribution of these factors using evidence from laboratory-based studies, mainly in disease-related intestinal perfusion systems in animals and humans, and the relevant clinical studies available to date. We advance the hypothesis that of all the possible mechanisms proposed to underlie the enhanced clinical efficacy of complex carbohydrate ORSs, their hypotonicity plays the dominant role. If confirmed, this concept could guide future development of glucose and complex carbohydrate-based ORSs.

GASTROENTEROLOGY 1998;114:197-210

Section snippets

Background physiology

This review does not provide an exhaustive discussion of digestive processes and transport mechanisms in the small intestine, but a brief mention of the salient aspects may help put the focus of this review in its proper physiological perspective.

Toward a super-ORS

During the last 15 years, many clinical trials have been performed using ORSs containing complex carbohydrate as substrate in place of glucose to treat acute diarrhea of diverse etiology.55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 These trials were performed on the basis that inclusion of complex carbohydrate would allow more substrate to be made available for cotransport without incurring an osmotic penalty.67, 68 These cereal-based ORSs, using various carbohydrate staples such as

Increased substrate availability?

Diarrhea is associated, at least temporarily, with nutritional deficits. Hence, the concept of developing energy-dense ORSs to provide “extra” calories during the fluid therapy of diarrheal disease was one of the concepts providing the impetus for the use of complex carbohydrate in ORT.⁷² Clinical investigators have tested the maximum quantity of rice that could be made into a drinkable ORS.⁵⁶ Another reason complex carbohydrate was ever considered stems from the osmotic penalty incurred by

Kinetic advantage?

Many human and animal studies have shown that glucose oligomers may be associated with rapid glucose absorption from the small intestine compared with glucose monomer. This has been proposed as the rationale for using glucose polymer mixtures derived from starch hydrolysis as substrate in ORS. The concept of kinetic advantage was first proposed by Crane⁷⁸ who, on the basis of in vitro studies, postulated sodium-independent, hydrolase-related glucose transport in which some, but not all, mucosal

Differences in small intestinal handling of glucose polymer?

Differential small intestinal handling of glucose presented as polymer compared with monomer is another possible mechanism for the enhanced efficacy of ORSs containing complex carbohydrate. Studies of starch digestion have shown that even infants and young children can absorb and digest large amounts of rice starch.⁹⁰ The digestion of starch to glucose is thought to occur slowly, thereby reducing the risk of osmotic diarrhea and malabsorption.⁹¹ It has been suggested that this slow digestion of

Low osmolality?

Table 2 shows the composition of currently available ORSs in the United Kingdom and United States as well as two experimental polymeric ORSs.

. Composition of some currently available and experimental ORS

ORS	Na⁺ (mmol/L)	K⁺ (mmol/L)	Cl⁻ (mmol/L)	HCO₃⁻ (mmol/L)	Citrate (mmol/L)	Glucose (mmol/L)	Rice derivative or glucose polymer	Osmolality (mOsm/kg)
WHO (formula C)^a	90	20	80	—	10	111	—	311
WHO (formula B)^a	90	20	80	30	—	111	—	331
BP 1993^b	90	20	80	—	10	111	—	311
USP 23^c	90	20	80	—	10	111	—	311
Diocalm Junior^d (SmithKline Beecham,

Role of peptides and amino acids as substrate in ORT

The protein content of rice can be in the order of 11% and comprises important amino acids such as glycine (30-36 mg/100 g), lysine (30-40 mg/100 g), leucine and isoleucine (30-40 mg/100 g), and various oligopeptides.¹¹¹ Oligopeptides and amino acids can promote sodium absorption independently of glucose by specific sodium-linked carrier mechanisms as discussed earlier. The protein content of wheat and other major cereal grains can be even higher than that of rice. Therefore, some of the

Luminal nutrients and epithelial recovery

In addition to the reduced stool volumes and ORS intake, some studies have shown that ORSs containing complex carbohydrate, particularly those based on rice, can also shorten the duration of the diarrheal illness and can be associated with improved growth and weight gain in affected children.¹²² In particular, the improvement in anthropometric indices is an important clinical outcome and may be related to an improved rate of intestinal recovery in acute diarrhea.

The exact role of specific

An intrinsic antisecretory property for rice?

Some clinical investigators have suggested on the basis of recent in vitro experiments that the decrease in stool output after treatment with rice ORS may be accounted for by a hydrophobic, nonpeptide, nonglycoprotein, low-molecular-weight (<1.5-kilodalton) moiety that may be a chloride channel blocker.⁷¹ A fraction extracted from rice inhibited cell shrinkage and chloride efflux in fresh suspended guinea pig crypt cells by inhibiting adenosine 5'-cyclic monophosphate. This effect has not yet

Hypothesis

We consider therefore that among the putative mechanisms said to underlie the enhanced clinical efficacy of ORSs containing complex carbohydrate, their low osmolality is preeminent. Recent clinical trials showing improved efficacy of hypotonic glucose monomer ORSs may indicate that it is unnecessary to decrease osmolality further by using polymers, although experimental studies in animal models would suggest that this is not the case. The final proof of the hypotonicity hypothesis, and the

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^☆: Address requests for reprints to: Michael J.G. Farthing, M.D., Digestive Diseases Research Centre, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Turner Street, Whitechapel, London E1 2AD, England. Fax: (44) 171-295-7192.

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Viewpoints in Digestive DiseasesEnhancing clinical efficacy of oral rehydration therapy: Is low osmolality the key?☆

Abstract

Section snippets

Background physiology

Toward a super-ORS

Increased substrate availability?

Kinetic advantage?

Differences in small intestinal handling of glucose polymer?

Low osmolality?

Role of peptides and amino acids as substrate in ORT

Luminal nutrients and epithelial recovery

An intrinsic antisecretory property for rice?

Hypothesis

Pharmacol Ther

Biophys J

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Lancet

Lancet

J Pediatr

Gastroenterology

Gastroenterology

J Pediatr

The magnitude of the global problem of acute diarrheal disease: a review of active surveillance data

Bull World Health Organ

Diarrheal deaths in the United States, 1979 through 1987

JAMA

Water with sugar and salt

Lancet

High sugar worse than high sodium in oral rehydration solutions

Acta Paediatr Scand

Rice water solution in diarrhoeal dehydration

Indian J Pediatr

Ion transport across mammalian small intestine

Ion transport across the large intestine

Glucose movements across the wall of the rat small intestine

J Physiol (Paris)

The absorption of water and of some small solute molecules from the isolated small intestine of the rat

J Physiol Lond

Effects of cations on sugar absorption by isolated surviving guinea pig intestine

Can J Biochem

Significance of sodium ions in active intestinal transport of non-electrolytes

Am J Physiol

Hypothesis for mechanism of intestinal active transport of sugars

Fed Proc

Solute and water absorption by human small intestine

Nature

Expression cloning and cDNA sequencing of the Na+/glucose co-transporter

Nature

Membrane transport mechanisms for hexoses and amino acids in the small intestine

Intestinal transport of bile acids

Am J Physiol

History and rationale of oral rehydration and recent developments in formulating an optimal solution

Drugs

Digestion and absorption of carbohydrate and protein

Is intestinal peptide transport energised by a proton gradient?

Am J Physiol

Intestinal transport of amino acids and peptides

The kinetics of water absorption in the human intestine

Trans Assoc Am Physicians

The mechanisms of sodium absorption in the human small intestine

J Clin Invest

Ion and water fluxes in the ileum of rats

J Gen Physiol

Short-circuit current and solute transfer by rat jejunum

J Physiol Lond

Electrolyte, urea and water movements across canine intestinal mucosa

Am J Physiol

Permeability characteristics of the human small intestine

J Clin Invest

Ionic conductances of extracellular shunt pathway in rabbit ileum

J Gen Physiol

Passive movement of water and sodium across the human small intestinal mucosa

J Appl Physiol

Viewpoints in Digestive Diseases
Enhancing clinical efficacy of oral rehydration therapy: Is low osmolality the key?☆

Expression cloning and cDNA sequencing of the Na⁺/glucose co-transporter