Search for the ideal oral rehydration solution: studies in a model of secretory diarrhoea.

In situ perfusion of whole rat small intestine was used to compare the efficacy of five oral rehydration solutions in promoting water and sodium absorption in normal intestine and secreting intestine after exposure to cholera toxin. Solutions varied in their sodium (35-90 mmol/l) and glucose (111-200 mmol/l) concentrations, molar ratio of glucose:sodium (1.2-5.8), and osmolality (281-331 mOsmol/kg), and contained either bicarbonate (18-30 mmol/l) or citrate (10 mmol/l). In normal intestine all solutions promoted net water absorption. Cholera toxin induced reproducible water secretion but all solutions reversed this to absorption. Water absorption was greatest with solutions containing sodium 60 mmol/l and glucose 111 or 140 mmol/l, and with a glucose:sodium ratio approximately 2, in both normal and secreting intestine. All solutions promoted net glucose absorption in both normal and secreting intestine. Net sodium absorption occurred with solutions containing greater than or equal to 60 mmol/l sodium in normal intestine but sodium secretion occurred from all solutions in secreting intestine. Sodium movement was directly related to the sodium concentration of the solution and sodium secretion occurred despite net water and glucose absorption. We consider that these studies may guide future development of oral rehydration solutions.     

Effect of bicarbonate on efficacy of oral rehydration therapy: studies in an experimental model of secretory diarrhoea.

In situ perfusion of rat intestine was used to evaluate the effect of bicarbonate on the efficacy of a low sodium (35 mmol/l) glucose-electrolyte oral rehydration solution in normal and cholera toxin-treated rat small intestine. In normal intestine, absorption of water was greater (108 (8.1) microliters/min/g; p less than 0.01) and sodium secretion less (-4.3 (0.3) mumol/min/g; p less than 0.01) from the oral rehydration solution containing bicarbonate than from the solution in which bicarbonate was replaced by chloride ions (59.5 (7.2) microliters/min/g and -7.8 (0.8) mumol/min/g, respectively). Glucose absorption in normal intestine was similar with both solutions. In the secreting intestine, both oral rehydration solutions reversed net water secretion to absorption, but inclusion of bicarbonate resulted in significantly less net absorption of both water (2.18 (6.9) microliters/min/g; p less than 0.05) and glucose (18.7 (2.1) mumol/min/g; p less than 0.001) compared with bicarbonate free oral rehydration solution (19.4 (3.9) microliters/min/g and 35.8 (3.7) mumol/min/g, respectively). Net sodium secretion occurred in normal and secreting intestine but was significantly less with the bicarbonate containing oral rehydration solution. These findings suggest that the demonstrable advantage of bicarbonate in promoting water absorption from this oral rehydration solution in normal rat intestine does not apply to cholera toxin treated secreting intestine.     

Water and solute absorption from a new hypotonic oral rehydration solution: evaluation in human and animal perfusion models.

Controversy continues regarding the optimal composition of glucose electrolyte oral rehydration solutions for the treatment of acute diarrhoea. Four perfusion models (normal human jejunum, normal rat small intestine, cholera toxin treated secreting rat small intestine and rotavirus infected rat small intestine) have been developed and used to compare the efficacy of a hypotonic oral rehydration solution with standard United Kingdom British National formulary and developing world oral rehydration solutions (WHO). Despite obvious physiological and pathophysiological differences between these models there was general congruence in the water and solute absorption profiles of the different oral rehydration solutions. Hypotonic oral rehydration solution promoted significantly greater water absorption than other oral rehydration solutions in all rat models (p < 0.001) but apparently increased water absorption failed to achieve significance in human jejunum. British National Formulary-oral rehydration solution was unable to reverse net water secretion in both rotavirus and cholera toxin models. Net sodium absorption from hypotonic and WHO-oral rehydration solutions was significantly greater than from the low sodium British National Formulary-oral rehydration solutions (p < 0.001) except in the rotavirus model when absorption was similar to hypotonic-oral rehydration solutions. These findings show that there is agreement in the apparent efficacy of oral rehydration solutions in these animal and human perfusion models, and that improved water absorption with adequate sodium absorption may be achieved by reducing oral rehydration solution osmolality.     

Acetate and citrate stimulate water and sodium absorption in the human jejunum

Using a standard perfusion technique, the organic anions acetate (50 mmol/l) and citrate (5 mmol/l) have been shown to stimulate absorption of water and sodium from the human jejunum. These observations may support further the rationale for including acetate or citrate in oral rehydration solutions for the treatment of acute diarrhoeal disease in humans.     

Effect of bicarbonate or base precursor on water and solute absorption from a glucose-electrolyte solution in the human jejunum

A modified perfusion technique was used to examine the effect on water and solute absorption in the healthy human jejunum of replacing bicarbonate (18 mmol/l) by equivalent amounts of different base precursors in a glucose-electrolyte solution. Acetate, citrate and lactate were absorbed from the perfusion solutions. Absorption of these base precursors appeared to have no effect on water uptake, but greater sodium (p less than 0.05) absorption occurred from solutions containing either acetate or lactate compared with the bicarbonate-containing solution. These data suggest that oral rehydration solutions with base precursors other than bicarbonate are as effective as bicarbonate-containing solutions in promoting absorption of water and electrolytes.     

The effect of bicarbonate and acidification on water and electrolyte absorption by the intestine of normal and infected (Hymenolepis diminuta: Cestoda) rats

The jejunum, proximal, and distal ileum of both uninfected and parasitized rats (Hymenolepis diminuta: Cestoda) were perfusedin vivo with saline solutions differing in hydrogen ion and bicarbonate concentration. In the jejunum and proximal ileum of both the parasitized and uninfected animals the luminal fluid was acidified via a hydrogen-ion secretory mechanism; similarly in the infected distal ileum.Hymenolepis diminuta further acidified the intestinal lumen by secreting hydrogen ions. The presence of bicarbonate stimulated absorption of sodium, bicarbonate, and fluid in the uninfected jejunum, in all the regions of the infected intestine, and also by the parasites. This accelerating effect of bicarbonate was pH-sensitive and it is considered to be of questionable importance in the acidic postprandial proximal intestine. Lowering the pH of the luminal fluid diminished intestinal absorption of salt and water, or caused a net secretion of isotonic fluid; the distal ileum was less sensitive to the pH changes. Water and electrolyte absorption byHymenolepis diminuta was stimulated by low luminal pH, but absorption in all three regions of the infected small intestine was diminished, due either to reduced absorption or enhanced secretion.This work is part of a thesis which will be submitted by the senior author to the University of Toronto in partial fulfillment of the requirements for the degree of Doctor of Philosophy. The award of a National Research Council of Canada Scholarship is gratefully acknowledged. This work was supported by the National Research Council of Canada, through Grant No. A4667 to D.F. Mettrick.     

Absorption of water and solute from glucose-electrolyte solutions in the human jejunum: effect of citrate or betaine

The inclusion in oral rehydration solutions of solutes that are actively co-transported with sodium has been suggested as a means of increasing the effect of glucose on water absorption by the small intestine. Using a modified perfusion system we have examined water and solute absorption in the normal human intestine from two effervescent glucose-electrolyte solutions, containing either citrate or betaine hydrochloride, and compared the absorption rates with those from a commonly used bicarbonate-containing oral rehydration solution. Absorption of citrate (355 +/- 87 mumol/cm/h) and betaine (313 +/- 125 mumol/cm/h) occurred from the respective solutions. The inclusion of 46 mmol/l citrate or 36 mmol/l betaine in effervescent oral rehydration solutions had no effect on water or solute absorption.     

Effect of base precursors on water and electrolyte transport during oral hydration solution perfusion in secreting rat intestine

In situ steady-state, single-pass small intestine perfusions in rats were carried out to compare the effect of the bicarbonate and citrate World Health Organization oral rehydration solutions and a base precursor-free solution on intestinal water and electrolyte transport after inducing intestinal secretion with purified heat-stableEscherichia coli enterotoxin. When toxin was not perfused, the rates of water, sodium, and bicarbonate absorption were significantly greater from the bicarbonate-containing solution than from the citrate or base precursor-free solutions. Chloride absorption was greater from the base precursor-free solution, but this might reflect the higher chloride concentration of the perfusate. When toxin was perfused, there was no significant difference among the solutions in the rates of water, potassium, or chloride absorption. Sodium absorption occurred at significantly greater rates from both the bicarbonate and the base precursorfree solutions than from the citrate solution. Base precursor-containing solutions may not provide any advantage over a base precursor-free solution in stimulating water and sodium absorption in 5-cyclic guanosine monophosphate mediated acute diarrhea.The Wellcome Research Unit is supported by the Wellcome Trust, London, UK, in association with the Christian Medical College Hospital, Vellore.     

Effects of olsalazine and sulphasalazine on jejunal and ileal water and electrolyte absorption in normal human subjects.

The effect of sulphasalazine and olsalazine on jejunal and ileal water and electrolyte absorption was investigated in normal subjects by a steady state intestinal perfusion of a physiological glucose bicarbonate electrolyte solution in the absence and presence of increasing concentrations of each drug. (Olsalazine 0.25 g/l, 1.0 g/l, jejunum; 0.5 g/l, 1.0 g/l, ileum; sulphasalazine 0.25 g/l, 0.5 g/l, 2.0 g/l jejunum; 1.0 g/l, 2.0 g/l, ileum.) In the jejunum olsalazine at 1.0 g/l significantly inhibited water, sodium, chloride, and potassium absorption (p less than 0.05). In the ileum olsalazine at 0.5 and 1 g/l significantly inhibited glucose uptake (p less than 0.04) and water absorption (p less than 0.03). In the jejunum sulphasalazine had a dose related and significant inhibitory effect on water, bicarbonate, and sodium absorption and at 2.0 g/l an inhibitory effect on chloride, potassium (p less than 0.005), and glucose (p less than 0.05) absorption. In the ileum sulphasalazine had no significant effect on water and electrolyte absorption. All inhibitory effects were rapidly reversible. These data show that unexplained diarrhoea in patients with ulcerative colitis treated with olsalazine may occur as a consequence of inhibition of water and electrolyte absorption in the small intestine and that the mechanisms of inhibition of sulphasalazine and olsalazine are different.     

Evidence of a dominant role for low osmolality in the efficacy of cereal based oral rehydration solutions: studies in a model of secretory diarrhoea.

Clinical trials suggest that including naturally occurring complex carbohydrate in oral rehydration solutions (ORS) in place of glucose increases water absorption and reduces stool volume during acute diarrhoea. The mechanisms for this greater clinical efficacy has not been established. This study examined the ability of two hypotonic rice based ORS, RS-ORS (137 mOsm/kg) and RP-ORS (143 mOsm/kg), and HYPO-ORS (240 mOsm/kg) a glucose equivalent ORS, to effect water absorption by in vivo perfusion of normal and secreting rat small intestine. The results were compared with those for two widely used conventional hypertonic ORS, WHO-ORS (331 mOsm/kg) and UK-ORS (310 mOsm/kg). In the normal intestine, water absorption was similar from WHO-ORS (87.4 (45.1-124.6) microliters/min/g; median and interquartile range) and UK-ORS (57.6 (41.5-87)) but less than from the hypotonic solutions (p < 0.02); water absorption from RS-ORS (181.8 (168.5-193.8)) and RP-ORS (195.7 (179.3-207.9)) was similar but less than from HYPO-ORS (241.3 (230.6-279.7); p < 0.005). In the secreting intestine, all ORS reversed net secretion of fluid to net absorption; the hypotonic solutions, HYPO-ORS (105.2 (95.2-111)), RS-ORS (127.7 (118.3-169.4)) and RP-ORS (133.7 (122.1-174.5)), produced more water absorption (p < 0.005) than the hypertonic solutions WHO-ORS (47.1 (29-75.9)) and UK-ORS (24.9 (18.4-29.4)). The rice based ions promoted most water absorption in secreting intestine (p < 0.007). These data indicate that low osmolality is of primary importance in mediating the increased water absorption from cereal based ORS.     

Comparative effects of oral rehydratation solutions in experimental cholera in the rat

The composition of the World Health Organisation (WHO) solution in oral rehydration therapy has remained controversial because of its total osmolarity (303 mosm/L) and higher sodium concentration (90 mEq/L), increasing the risk of hypernatraemia. AIM OF THE STUDY: To compare the efficacy of two reduced-osmolarity oral rehydration solutions (S1: 268 mosm/L and 50 mEq/L Na(+); S2: 240 mosm/L and 60 mEq/L Na(+) ) with the WHO recommended formula taken as the reference solution. Water, electrolytes and glucose fluxes were directly measured in vivo, in isolated ligated loops of rat jejunum (n=12). Intestinal secretion was induced by exposing jejunum to cholera toxin (CT=20 microg/loop). RESULTS: All three test solutions similarly reversed cholera toxin-induced net water absorption (3.37 +/- 1.35; 3.31 +/- 0.43 and 3.13 +/- 0.66 microL/min.cm(2) for S1, S2 and WHO solutions respectively). However, net Na secretion induced by cholera toxin was observed with S1 and S2 while Na absorption occurred with the WHO solution. CONCLUSION: For a same amount of water absorbed, Na absorption from reduced - osmolarity rehydration solutions is lower than with the WHO solution. Our data may contribute to a better rationale for the use of orally administered hydration solutions in man.     

Acetate absorption in the normal and secreting rat jejunum.

Acetate absorption was studied in rat jejunum using steady state perfusion in vivo. Absorption conformed to apparent saturation kinetics and was similar in magnitude to glucose absorption. When compared with normal saline, acetate perfusion was associated with luminal alkalinisation. There was no difference in total CO2 secretion when similar rates of acetate and glucose absorption were compared, suggesting that total CO2 secretion was the result of mucosal metabolism. Absorption of acetate and propionate were mutually inhibitory. Acetate absorption was also inhibited by Tris-Hepes pH 7.0. When the gut was pretreated with cholera toxin to induce a secretory state, acetate absorption was reduced by 41.9%. This effect could be reproduced if similar water secretion was osmotically induced by the addition of mannitol. These data suggest that acetate is absorbed, at least, partially by non-ionic diffusion in the rat jejunum and that its absorption is reduced in the secreting intestine by solvent drag.     

Response to jejunal acidification in man. I. Changes in composition of perfusate.

The jejunal disposal of perfused acid was studied in 11 control subjects and 12 patients with duodenal ulcer. It was found that the capacity to dispose of acid was saturable and was less than control in patients with duodenal ulcer. When the load of acid was small, all the acid disappeared from the jejunum and sodium bicarbonate could be aspirated. During acid perfusion there was secretion of water and electrolytes into the jejunum if the load of acid exceeded the dissipative capacity. Superimposed intravenous infusion of secretin and cholecystokinin increased acid disposal, particularly in patients with duodenal ulcer, and increased the associated rate of secretion of water and electrolytes or changed net absorption to net secretion. We conclude, firstly, that acid is removed from the jejunum by secreted bicarbonate, and secondly that the whole of the upper small intestine of patients with duodenal ulcer is functionally abnormal.     

L-arginine in low concentration improves rat intestinal water and sodium absorption from oral rehydration solutions.

BACKGROUND: The nitric oxide (NO) precursor L-arginine has been shown to produce variable effects on intestinal absorptive function, including ion transport. AIMS: To determine whether there is an optimal concentration of L-arginine, promoting proabsorptive effects from oral rehydration solutions (ORS) with 90 or 60 mM sodium. SUBJECTS AND METHODS: In vivo perfusion of rat jejunum with determination of net water absorption, unidirectional fluid exchanges, sodium and calcium transport, and glucose absorption. RESULTS: L-Arginine (1 mM) added to the 90 mM sodium ORS increased intestinal absorption of both sodium and water. Higher concentrations of L-arginine (2 to 10 mM) lacked this stimulatory effect. At 20 mM, L-arginine decreased sodium absorption below baseline. With a 60 mM sodium ORS, 2 mM L-arginine had a maximal fluid and electrolyte proabsorptive effect. At 20 mM L-arginine, net water absorption was indistinguishable from that obtained in the absence of L-arginine, and lower than with 2 mM L-arginine. Sodium absorption remained raised above baseline in perfusions with 10 and 20 mM L-arginine. Morphologically, villi from perfusions with increased absorption showed a large expansion of intercellular and lamina propria intercellular spaces. CONCLUSIONS: Low concentrations of L-arginine seem to stimulate water and electrolyte absorption by the small intestine. This effect is consistent with NO induced vasodilation, may be vaso-constrictive and thereby reverse fluid and electrolyte transport.     

Effect of two new antisecretory drugs on fluid and electrolyte transport in a patient with secretory diarrhoea.

The effect of oral lidamidine hydrochloride and subcutaneous long acting somatostatin analogue, SMS 201-995, on stool output and salt and water transport in the small intestine was investigated in a patient with gross secretory diarrhoea caused by a vasoactive intestinal polypeptide (VIP) secreting tumour in the liver. Transport in the jejunum and ileum were assessed by steady state perfusion techniques. Under basal conditions, the patient was absorbing fluid and electrolytes from the jejunum and ileum, but at rates that were abnormally low. Lidamidine had no effect on either intestinal transport or stool frequency and output. SMS 201-995 increased intestinal absorption in the jejunum and ileum, reduced plasma VIP concentrations, daily stool frequency and weight, and enabled the patient to resume a normal diet without oral or intravenous fluid and electrolyte supplements. After two months of treatment, medical control was becoming increasingly difficult and stool output had risen again to 2 litres per day. Surgical resection, fortunately, was possible and led to resolution of symptoms and normal plasma VIP concentrations.     

Evaluation of the efficacy of oral rehydration solutions using human whole gut perfusion.

Whole gut perfusion in humans was used to compare the effect on intestinal water and electrolyte transport of the World Health Organisation oral rehydration solution (solution II, composition in mmol/l: glucose 111, sodium 90, bicarbonate 30, potassium 20; 308 mOsm/kg); a hypertonic commercial oral rehydration solution (solution III, glucose 188, sodium 50, bicarbonate 20, potassium 20 mmol/l; 335 mOsm/kg); and three experimental bicarbonate free, hypotonic oral rehydration solutions: solution IV (glucose 111, sodium 60, potassium 20 mmol/l; 260 mOsm/kg), solution V (glucose 80, sodium 60, potassium 20 mmol/l; 219 mOsm/kg), and solution VI (glucose 80, sodium 30, potassium 20 mmol/l; 177 mOsm/kg). Perfusion of the intestine with a standard cleansing solution (solution I, sodium 125, potassium 10, bicarbonate 20, sulphate 40, mannitol 80 mmol/l; 275 mOsm/kg) confirmed published data on minimal water and sodium absorption. Experimental solution VI produced maximum water absorption (mean (SE) +1660.0 (29.8) ml/h) significantly greater than solution II (+1195.3 (79.5) ml/h), III (+534.7 (140.3) ml/h), IV (+1498.0 (42.7) ml/h), and V (+1327.7 (24.4) ml/h; p less than 0.05). Sodium absorption was significantly greater with solution II (+97.4 (7.9) mmol/h) compared to VI (+43.3 (7.8) mmol/h; p less than 0.01) but not compared to IV (+67.2 (13.0) mmol/h). A hypotonic oral rehydration solution such as solution VI may provide optimal replacement treatment for patients with acute diarrhoea.     

The effects of different bile salts on the absorption of fluid, electrolytes, and monosaccharides in the small intestine of the rat in vivo

The effects of different bile salts on the absorption of fluid, electrolytes, and monosaccharides have been investigated in the rat small intestine in vivo. In the jejunum, deoxycholate (1 mM) impaired absorption of water and potassium, but not of sodium or glucose; at higher concentrations (2.5 and 5 mM) secretion of fluid and electrolytes occurred, and glucose and fructose absorption was impaired. By contrast, in the ileum, 1 mM deoxycholate failed to inhibit fluid and electrolyte absorption, and a concentration of 10 mM was required completely to inhibit absorption; secretion was not observed in the ileum.Chenodeoxycholate (5 mM) produced a similar effect to deoxycholate on fluid and electrolyte absorption in both jejunum and ileum, but taurocholate (5 mM) and taurodeoxycholate (5 mM) were ineffective.In jejunum, cholate, taurocholate, and taurodeoxycholate, each at a concentration of 5 mM, were less effective inhibitors of glucose transport than deoxycholate; chenodeoxycholate failed to inhibit glucose absorption.Deoxycholate produced histological damage at 5 mM, but not at lower concentrations. The functional and structural abnormalities were shown to be reversible phenomena.These findings may be relevant to the pathogenesis of diarrhoea in patients with bacterial overgrowth in the small intestine.     

Effect of total colectomy and mucosal proctectomy on intestinal absorptive capacity in dogs

Changes in intestinal absorptive capacity for water and electrolytes were investigated in dogs after total colectomy and mucosal proctectomy reconstructed with interposing jejunum into the anorectal area. Rate of abosorption of water and sodium from the ileum increased significantly at 29 weeks postoperatively. The absorption of water, sodium, and chloride in the jejunum was significantly higher than in the neorectum. The net secretion rate of potassium increased significantly in the ileum and neorectum. The authors suggest that intestinal adaptation achieved after proctocolectomy is enhanced in the jejunum and ileum rather than in the neorectum.     

Immunodeficiency, malabsorption and secretory diarrhea. A new syndrome.

Described here is a patient with severe watery diarrhea associated with common variable immunodeficiency. Malabsorption for fat, bile acids, vitamin B12 and xylose was demonstrated, but the patient failed to respond to all the usual therapeutic maneuvers. The diarrhea responded only to high dose steroid therapy. Intestinal perfusion studies showed a hitherto undescribed, presumably acquired, glucose-stimulated water, sodium and chloride secretion in the jejunum and ileum, whereas normal fluid and electrolyte transport occurred from bicarbonate and mannitol solutions. Glucose absorption itself was normal and no hormonal, morphologic or biochemical defect was demonstrated to account for the phenomenon. The patient was also interesting when compared with other patients with common variable immunodeficiency in having normal plasma cells in the intestinal mucosa and an extensive family involvement.     

Human intestinal ion transport in vitro.

The transport of sodium and chloride across human jejunal and ileal mucosa was studied using an in vitro technique. Specimens of mucosa removed at operation were stripped of muscle coats, mounted in specially designed Perspex flux chambers and bathed in warmed oxygenated and stirred buffer solutions. Evidence was obtained for the active transport of sodium in both jejunum and ileum and of chloride in the ileum. Sodium absorption was enhanced by glucose in both regions of the gut but net chloride transport was unaffected. Glucose had a greater effect on sodium transport in the ileum than the jejunum. The electrical potential difference and resistance was greater and undirectional ion fluxes smaller in jejunal than ileal mucosa. Many of these results with human intestine are similar to results reported with in vitro animal intestine. Apparent discrepancies between the behavior in vivo of human intestine and in vitro of animal intestine are thus likely to be due predominantly to technical rather species differences.