PRACTICAL THERAPEUTICS
Drugs 44 (I): 57-64, 1992 0012-6667/92/0007-0057/$04.00/0 © Adis International Limited. All rights reserved. DRUll64
Management of Gastroenteritis in Early Childhood Anne Davies and Huw R. Jenkins Department of Child Health, Cardiff Royal Infirmary, Cardiff, Wales
Contents 57 58 58 59 60 60 60 61 61 61 61 62 62 63 63
Summary
Summary I. Oral Rehydration Solutions 1.1 Sodium 1.2 Potassium 1.3 Base 1.4 Carbohydrate Source 1.5 Amino Acids 1.6 Rice and Starch 2. Intravenous Auid Replacement 3. Drug Therapy 3.1 Antibiotics 3.2 Antidiarrhoeal Agents 4. Feeding Following Acute Gastroenteritis 4.1 Breast-Fed Infants 4.2 Formula-Fed Infants
The most important aspect of modem management of acute diarrhoeal illness in children is that of oral rehydration therapy, and drug therapy is very rarely indicated. Despite the dramatic decline in mortality and morbidity in recent years, there is still the need for continuing education in the appropriate use of oral rehydration solutions. The constitution of oral rehydration solutions and policies of feeding practices during illness continue to be controversial, mainly because of wide variation in the aetiology ofthe diarrhoea, the nutrition of the child, and the economic and public health factors involved in any particular community. The priority of all healthcare workers is to provide simple guidelines in the use of a safe oral rehydration solution while discouraging unsafe treatments.
Drugs 44 (1) 1992
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Acute gastroenteritis remains a major clinical problem, both in the developing world and in industrialised nations. With the widespread introduction of glucose-electrolyte oral rehydration solutions childhood mortality in developing countries has fallen dramatically, yet the appropriate use of oral rehydration in developed countries, where young children may experience approximately one diarrhoeal episode per year, is often neglected despite access to a primary healthcare system (Jenkins & Ansari 1990). However, there is continuing controversy regarding not only the nutritional management of the illness, but also the composition of the oral rehydration itself. Such controversy is compounded by many variables: the premorbid nutritional state of the child; the contributions of public sanitation and personal hygiene; the pathogen involved; and the availability of healthcare. Nevertheless, broad, safe guidelines are needed, based on existing data and experience.
1. Oral Rehydration Solutions There is no dotibt that the development of oral rehydration therapy has been of paramount importance in the reduction of morbidity and mortality from acute diarrhoeal states throughout the world. However, several aspects of controversy regarding its constitution still remain, and it is debatable whether one single solution would be applicable for worldwide use. In developed countries where diarrhoeal illness may be mild, juices or commercial carbonated drinks are often administered to children as 'rehydration' solutions. This is ill-advised, since they vary widely in osmolality and electrolyte composition, often being low in sodium and hyperosmolar (e.g. the sodium composition of 'Coca-Cola' is 3 mmol/L with an osmolality of 469 mOsm/kg). l.l Sodium
The inclusion of sodium in oral rehydration solutions is necessary to replace stool sodium losses and to promote water absorption. Ion exchange processes across the apical brush border of the en-
terocyte (whereby sodium is exchanged for hydrogen, and chloride is exchanged for bicarbonate) account for some sodium chloride absorption, but the sodium/hydrogen exchange process may be inhibited during intestinal secretion which occurs in diarrhoeal states (Semrad & Chang 1987) [fig. I]. Of greater implication for the formulation of oral rehydration solutions is the glucose- or amino acidcoupled sodium absorption process, which is unaffected by intestinal secretion. This depends on the maintenance of a low intracellular sodium concentration, so that sodium, linked to glucose, enters the cell across its apical membrane. The sodium/potassium ATPase (or sodium pump) at the basolateral membrane is responsible for maintaining the low intracellular sodium, and this is unaffected by a secretory state. The sodium content of oral rehydration solutions recommended by the World Health Organization (WHO) [90 mmol/L] was set to approximate the sodium losses in stools of cholera cases, yet the common pathogens responsible for diarrhoeal cases in Europe cause much lower sodium losses (e.g. 40 mmol/L in rotavirus diarrhoea, and 50 to 60 mmol/L for the invasive pathogens Shigella, Salmonella and Campylobacter). All clinical trials of oral rehydration solutions with lower sodium concentrations of 30 to 65 mmol/L have shown this constitution to be safe and effective for rehydration of mild, moderate and severe dehydration, with complications of little clinical relevance (e.g. asymptomatic hyponatraemia, periorbital oedema) reported in less than one-third of the trials (da Cunha Ferreira 1989). Furthermore, extensive clinical practice with the use of lower sodium oral rehydration solutions has lent further support to these findings (Walker-Smith 1988). Therefore, the use of WHO oral rehydration solution for children with diarrhoea caused by pathogens common to developed countries can only be recommended if it offers significant advantages over lower sodium oral rehydration solutions. The high sodium load of WHO oral rehydration solutions carries a risk of harmful retention of sodium and water, particularly in young infants who have higher insensible losses (e.g. through the skin), or
Childhood Gastroenteritis
I Lumen I
59
--------.
..
-----..Na+-... ------------' ....
ISerosal
I Individual enterocyte Fig. 1. Diagrammatic representation of sodium (Na+) and chloride (CI-) absorption in the small intestine.
in mildly dehydrated children who may have only low faecal sodium losses from a viral-induced diarrhoea. Some would advocate the use of WHO oral rehydration solutions alternating with free water for clinical rehydration, and thereafter changing to a lower sodium oral rehydration solution for maintenance (Finberg 1980), but this regimen is more complicated for outpatient settings, and more likely to lead to errors of constitution and potentially dangerous hypernatraemia. Hypernatraemic dehydration was a significant cause of mortality and morbidity in the developed world during the 1970s. Some hypernatraemic episodes have been described following the improper use of oral rehydration solutions (without free water), but its decline has largely been due to the introduction of low solute milks. However, concern remains that the use of high sodium oral rehydration solutions in certain European countries (where mortality from diarrhoea disease per se may be zero) could increase the incidence of hypernatremia, especially if stool sodium losses are low, as in noncholera diarrhoea. In fact, oral rehydration solutions with a sodium content of 60 or 90 mmol/ L have been safe and effective in treating hypernatraemic patients, but a single solution of 60 mmol/L sodium is recommended to rehydrate or maintain hydration without the need for free water
or high risks from errors in constitution (da Cunha Ferreira 1989). Therefore, the use in the developed world of a single solution with 60 mmol/L or less of sodium should be recommended for oral rehydration or maintenance of hydration, because of simplicity of instruction and avoidance of dangerous hypernatraemia. Such a solution can be used to replace stool losses in all viral and bacterial noncholera diarrhoea. 1.2 Potassium Substantial losses of potassium occur when children pass diarrhoeal stools (Molla et al. 1981), usually in the range 18 to 42 mmol/L per stool in noncholera diarrhoea. WHO oral rehydration solutions and most of the commercially available oral rehydration preparations contain at least 20 mmol/ L of potassium. Although it is unlikely that well nourished children with a single diarrhoeal episode would be adversely affected by mild potassium depletion, this may be problematic for dehydrated malnourished children. For example, 33% of children treated with oral rehydration solutions containing 20 mmol/L of potassium in one series developed hypokalaemia compared to none in the group receiving oral rehydration solutions contain-
Drugs 44 (1) 1992
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ing 35 mmol/L potassium (Nalin et al. 1980). Thus, adequate concentrations of potassium are necessary if oral rehydration solutions are to be safe and effective. 1.3 Base Base and base precursors have been included in oral rehydration solutions with the rationale that they correct any metabolic acidosis (probably resulting from poor tissue perfusion) and enhance sodium and water reabsorption, yet there is little clinical evidence to support their routine inclusion. Several clinical trials have indicated that the correction of metabolic acidosis was slower but just as effective with base-free oral rehydration solutions as with bicarbonate-containing solutions, and that the slower return of plasma bicarbonate levels to normal was of no clinical relevance in the face of a well rehydrated patient with a good urine output (Elliott et al. 1987, 1988; Islam & Ahmed 1984). Although bicarbonate was the original base included in oral rehydration solutions, it reacts with glucose when exposed to humidity or heat, and its limited shelf-life led to the development and inclusion of the base precursors acetate and citrate, which are equally effective (Islam 1985; Mazumder et al. 1990; Patra et al. 1982a). Acetate salts, however, gel after 12 hours' exposure to air and are thus not recommended in powdered oral rehydration formulations. Citrate is stable in bicarbonatecontaining oral rehydration solutions, but the advantage of citrate oral rehydration solution over base-free solution has not yet been established. 1.4 Carbohydrate Source Glucose is the carbohydrate source used in WHO oral rehydration solutions and in the majority of commercially available solutions. The process of coupled glucose/sodium absorption is intact in diarrhoeal states (leading to increased water absorption when oral rehydration solution is administered), and therefore glucose has been firmly established as the energy source in oral rehydration solutions. Concentrations of glucose used in clinical
trials range from 70 to 280 mmol/L, with many commercially produced solutions in the US and Europe being at the top of the range (200 to 280 mmol/L), aiming for high energy content, pleasant taste, and iso-osmolality. The question of optimal glucose concentration has been explored in several studies, and results have shown that, provided a sodium: glucose ratio of 1 : 1 to 1 : 1.5 is ensured, glucose concentrations of 60 to 140 mmol/L are most effective (Malawer et al. 1965; Sladen & Dawson 1969). Higher concentrations of glucose may lead to glucose malabsorption and osmotic diarrhoea, and lower concentrations of glucose may lead to poor sodium and water reabsorption. . Glucose polymers have also been used successfully as the carbohydrate source in oral rehydration solutions, and have been as effective as glucose monomers in clinical trials (Jones et al. 1981; Santosham et al. 1985). Disaccharides and a-I-41inked oligosaccharides may promote rapid water absorption largely because of the hypotonicity of the solution. The greater availability and lower cost of sucrose compared with glucose led to its use in early trials in cholera. Many treatment failures occurred, probably as a result of the massive stool purges rather than the solution itself. Other trials show that, in equivalent concentrations, sucrose can be at least as effective as glucose in the treatment of dehydration from cholera, and diarrhoea caused by noncholera pathogens (Molla et al. 1982; Palmer et al. 1977). Sucrose has been recommended by the WHO for home rehydration therapy when oral rehydration solutions or formulated brands are unavailable. 1.5 Amino Acids Absorption of amino acids takes place via a separate carrier mechanism and, as this is largely sodium-coupled (a mechanism which remains intact in most cases of diarrhoea), they have been included in oral rehydration solutions to enhance sodium and water reabsorption. Rehydration solutions with added glycine re-
Childhood Gastroenteritis
duced stool output and duration of diarrhoea, and enhanced water absorption in children with cholera, but had no beneficial effect (apart from shortening the duration of illness) in diarrhoeal illnesses not due to cholera (Nalin et al. 1970; Patra et al. 1984; Santosham et al. 1986). Although this may be explained by different mechanisms of damage depending on the pathogen (e.g. rotavirus damaging mucosa and impairing glycine reabsorption), osmotic diarrhoea was also described in some patients, and glycine is not recommended as a routine addition to oral rehydration solutions in these cases. Other amino acids, however, may yet prove to be beneficial. 1.6 Rice and Starch The composition of rice is predominantly starch, plus a small amount of protein (7 to 10%). The gradual release of glucose from starch via luminal and membrane-bound glucosidases means that the absorption of glucose can be immediate, the osmolality of the luminal contents can be low, and the number of glucose residues can be increased without osmotic 'overload'. This allows more efficient water and sodium reabsorption and a higher energy intake. It also allows the released amino acids to provide an additional source of sodium coupling, as well as providing a source of nitrogen. These theoretical advantages have been borne out in clinical practice with a reduction in stool outputs and a reduction in the quantity of oral rehydration solutions actually required (Molla et al. 1989; Patra et al. 1982). Reduction of stool output is gratifying for parents, particularly if the child is an outpatient, and home-made formulae based on rice and locally available cereals are now firmly established in the management of acute diarrhoea in the developing world (Editorial 1992).
2. Intravenous Fluid Replacement Although the use of oral rehydration solutions has been well established in developing countries, and has reduced morbidity and mortality dramatically, it is largely underused and undervalued in
61
the developed world. There is a tendency to overestimate the degree of dehydration in well nourished children (Mackenzie et al. 1989) and to give intravenous therapy (normal saline, or half normal saline with dextrose) to all those patients more than mildly dehydrated (Walker-Smith 1988). A recent randomised controlled trial in Australia showed that oral rehydration is as effective, both clinically and biochemically, as intravenous rehydration in children who are dehydrated (but not shocked), even if there is countinued vomiting (Mackenzie & Barnes 1991). The more widespread use of oral rehydration solutions in the hospital setting would reduce trauma for the child and lead to greater awareness of effective oral therapy in the community, thus reducing hospital admission rates.
3. Drug Therapy The routine use of drugs (usually antibiotics or antidiarrhoeal agents) in acute diarrhoea in children is rarely indicated, and certain drugs, particularly those that reduce motility, may be dangerous. A more profitable use of health resources is the adequate provision of oral rehydration therapy, with informed instruction regarding its use. Explanation can be given to the parents that the diarrhoea is the body's own mechanism for ridding itself of the harmful organism, and time can be spent instructing them in the use of oral rehydration solutions and in the planning of subsequent refeeding. 3.1 Antibiotics Antibiotics are not indicated as a first line treatment for diarrhoeal illness. For many of the responsible pathogens (e.g. the viruses rotavirus, adenovirus and Norwalk agent, and the parasite cryptosporidium) no agent will be effective,. The use of antibiotics is therefore a costly distraction from the main therapeutic priority which is adequate oral rehydration. There are, however, some specific indications for the use of antibiotics. Metronidazole may be effective in treating amoebiasis and giardiasis, and specific antibiotics
Drugs 44 (1) 1992
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may be of benefit it the child is systemically unwell and septicaemic. The use of antibiotics [chloramphenicol, ampicillin and cotrimoxazole (trimethoprim/sulfamethoxazole)] for Salmonella infection should be limited to those patients with typhoid fever, those with systemic infection (e.g. septicaemia and pyogenic infection or osteomyelitis), and to those in whom host resistance is poor (e.g. neonates and the immunosuppressed) [Pickering 1991]. For those patients with Salmonella gastroenteritis, antibiotics have in fact been known to produce symptomatic relapse (Aserkoff et al. 1969; Nelson et al. 1980) and to convert intestinal disease into systemic illness (Rosenthal 1969). The existence of chloramphenicol-resistant strains throughout the world has led to the suggestion that ampicillin should be the drug of choice where local sensitivities are unknown. In Shigella and enterotoxigenic Escherichia coli infections, cotrimoxazole may shorten the illness and reduce faecal organism shedding, but its use has encouraged multiple antibiotic resistance in what is usually an acute self-limiting disease. The value of antibiotics in Campylobacter and Yersinia infection has yet to be established, and the diarrhoea associated with Clostridium di./ficile (producing pseudomembranous colitis) may abate with the cessation of the existing antibiotic therapy, although vancomycin may be used for persisting symptoms. An additional indication is, of course, the sudden onset of diarrhoea which heralds an overwhelming generalised septicaemia, where the gut is not the primary organ of involvement. 3.2 Antidiarrhoeal Agents These drugs include adsorbents such as kaolin, antisecretory agents such as bismuth salicylate, and antimotility agents such as loperamide, and diphenoxylate plus atropine. These drugs are ineffective at best, and at worst can be harmful in childhood (Costello & Bhutta 1992; Motala et al. 1990). Those drugs altedng intestinal motility retard the movement of gut contents, thus restricting the distention which is often responsible for the pain
associated with gastroenteritis. In 19 young infants in Pakistan, abdominal distension and paralytic ileus was described after loperamide, resulting in 6 deaths on the ward (Bhutta 1990). Side effects of these drugs such as drowsiness, tachycardia and vomiting are common, and may be more pronounced in malnourished children. These antimotility agents should be avoided in children who are in shock or febrile, or who have evidence of colitis (bloody stools), since they may worsen the morbidity in shigellosis (Dupont & Hornick 1973). Adverse effects of bismuth salicylate relate to the absorption of salicylate and bismuth. Adsorbent agents such as kaolin may relieve symptoms by facilitating more formed stools, but few studies have shown a reduction in duration of diarrhoea, or a reduction in fluid and electrolyte losses, and they may interfere with nutrient and enzyme function by adsorption in the gut.
4. Feeding Following Acute Gastroenteritis Further controversy exists regarding nutrition in acute infantile diarrhoea and, as with oral rehydration solution formulation, there are differences in policies and guidelines between the developing and developed countries (Lifschitz & Schulman 1990). Once again, these differences are influenced by the pathogen involved, its mechanism of invasion, the state of nutrition of the child, and numerous cultural, economic and logistical factors, and are compounded by a relative deficit in conclusive research results. In developing countries where suboptimal nutrition may exist in the child's premorbid state, a prolonged period of time without adequate nutrition will clearly be detrimental. Certainly the continuation of uninterrupted breast feeding in addition to oral rehydration therapy should be encouraged in both industrialised and underdeveloped countries, since existing evidence points to a decrease in severity of diarrhoea and shortened duration of the illness with this practice (KhinMaung-U et al. 1985). Previous guidelines for the formula-fed infant have recommended a slow reintroduction of for-
63
Childhood Gastroenteritis
mula feeds after a temporary period of oral rehydration, with a gradual stepwise reintroduction of milk after initial hydration with rehydration solutions (i.e. one-quarter strength followed by onehalf, three-quarter and full strength milk over a 12to 72-hour period) [Wharton et al. 1988]. This regime gained popularity at a time when postgastroenteritis lactose intolerance complicated the illness in many cases, yet recent reports suggest that this is a declining problem (Editorial 1987), and also that the regrading process appears to make no difference to the incidence of lactose intolerance anyway (Fox et al. 1990). Recent work has questioned the need for a regrading process in infants over 6 months old and even now, for younger babies (under 6 months), an immediate return to formula feed has been recommended (Armistead et al. 1989; Brown 1991; Brown et a!. 1988; Fox et al. 1990). However, the incidence of lactose intolerance, and indeed of cow's milk protein intolerance (which may present as lactose intolerance), must be assessed in individual communities before a refeeding policy can be recommended. The lack of agreed definitions of lactose and cow's milk protein intolerance make firm policies for the introduction of substitute milks very difficult indeed. Further confusion may exist if a child's diarrhoea persists when regrading onto soya milk, as soya itself may cause persistent gut mucosal damage, and in these cases a protein hydrolysate feed may be indicated. The following management plan, based on existing data and personal clinical experience, is suitable for relatively well nourished children ill developed countries. 4.1 Breast-Fed Infants Breast feeding should be continued uninterrupted and be offered in addition to oral rehydration solutions. Breast feeding exerts a beneficial outcome on acute diarrhoea by reducing the number and volume of diarrhoeal stools (Khin-Maung U et al. 1985). Products of digestion in the gut lumen (amino acids, dipeptides and hexoses) may enhance the absorption of sodium and water, and
the benefits of continued nutritional intake from an uncontaminated source are important advantages, especially in the poorly nourished child. 4.2 Formula-Fed Infants I. A period of oral rehydration solutions alone for 6 to 24 hours, followed by reintroduction of normal full strength formula milk and solids is indicated. 2. If worsening of diarrhoea occurs, a further period of oral rehydration therapy should be given, followed by slow regrade up to full strength milk over 6 to 72 hours. 3. In the few infants who fail 2 regrades (these infants are usually less than 6 months of age), a change to a formula free from lactose and cow's milk protein is justified (i.e. a protein hydrolysate feed should be used). This is usually indicated for a temporary period only, but solids containing these substances (e.g. cheese, chocolate) must obviously also be avoided for 1 to 3 months when a rechallenge with a cow's milk-containing formula can be performed. 4. Previously unwell or malnourished children are at a higher risk from lactose and/or cow's milk protein intolerance and are more likely to develop a protracted illness/enteropathy. The failure of the first regrade may be an indication to start a lactose and cow's milk-free formula at an early stage.
References Armistead J, Kelly D, Walker-Smith JA. Evaluation of infant feeding in acute gastroenteritis. Journal of Pediatric Gastroenterology and Nutrition 8: 240-244, 1989 Aserkoff B, Bennett JV. Effect of antibiotic therapy in acute salmonellosis on the fecal excretion of salmonellae. New England Journal of Medicine 281: 636-640, 1969 Bhutta TI. Loperamide poisoning in children. Lancet I: 363, 1990 Brown KH. Dietary management of acute childhood diarrhoea: optimal timing of feeding and appropriate use of milks and mixed diets. Journal of Pediatrics 118: S92-98, 1991 Brown KH, Gastanaduy AS, Saavedra JM, Lembcke J, Rivas D, et al. Effect of continued oral feeding on clinical and nutritional outcomes of acute diarrhoea in children. Journal of Pediatrics 112: 191-200, 1988 Costella AM deL, Bhutta TI. Antidiarrhoeal drugs for acute diarrhoea in children. British Medical Journal 304: 1-2, 1992 da Cunha Ferreira RMC. Optimising oral rehydration solution composition for the children of Europe: clinical trials. Acta Paediatrica Scandinavica (Suppl.) 364: 40-50, 1989
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Dupont HL, Hornick RB. Adverse effect of'Lomotil' therapy in shigellosis. Journal of the American Medical Association 226: 1525-1528, 1973 Editorial. What has happened to carbohydrate intolerance following gastroenteritis? Lancet I: 23-24, 1987 Editorial. Cereal-based oral rehydration solutions - bridging the gap between fluid and food. Lancet 339: 219-220, 1992 Elliott EJ, Armistead JCM, Farthing MJG, Walker-Smith JA. Oral rehydration therapy without bicarbonate for prevention and treatment of dehydration: a double-blind controlled trial. Journal of Alimentary Pharmacology and Therapeutics 2: 253-262, 1988 Elliott EJ, Walker-Smith JA, Farthing MJG. The role of bicarbonate and base precursors in treatment of acute gastroenteritis. Archives of Disease in Childhood 62: 91-95, 1987 Finberg L. The role of electrolyte-glucose solutions in hydration for children - international and domestic aspects. Journal of Pediatrics 96: 51-54, 1980 Fox R, Leen CLS, Dunbar EM, Ellis ME, Mandai BK. Acute gastroenteritis in infants under 6 months old. Archives of Disease in Childhood 65: 936-938, 1990 Islam MR. Can potassium citrate replace sodium bicarbonate and potassium chloride in oral rehydration solution? Archives of Disease in Childhood 60: 852-855, 1985 Islam MR, Ahmed SM. Oral rehydration solution without bicarbonate. Archives of Disease in Childhood 59: 1072-1075, 1984 Jenkins HR, Ansari BM. Management of gastroenteritis. Archives of Disease in Childhood 65: 939-941,1990 Jones BMJ, Brown BE, Silk DBA. Intestinal absorption of maltotriose and a maltopentose-Iexose mixture in man. Gut 22: A868,1981 Khin Maung U, Nyunt Nyunt Wai, Myo Khin, Mu Mu Khin, Tin U, Thane toe. Effect on clinical outcome of breast feeding during acute diarrhoea. British Medical Journal 290: 587-589, 1985 Lifschitz CH, Schulman RJ. Nutritional therapy for infants with diarrhoea. Nutrition Reviews 48: 329-338, 1990 Mackenzie A, Barnes G, Shann F. Clinical signs of dehydration in children. Lancet 2: 605-607, 1989 Mackenzie A, Barnes G. Randomized controlled trial comparing oral and intravenous rehydration therapy in children with diarrhoea. British Medical Journal 303: 393-396, 1991 Malawer SJ, Ewton M, Fordtran JS, Ingelfurger FJ. Interrelation between jejunal absorption of sodium, glucose and water in man. Journal of Clinical Investigation 44: 1072-1073, 1965 Mazumder RN, Nath SK, Ashraf H, Patra FC, Alam AN. Oral rehydration solution containing trisodium citrate for treating severe diarrhoea: controlled clinical trial. British Medical Journal 302: 88-89, 1991 Molla AM, Molla A, Nath SK, Khatun M. Food-based oral rehydration salt solution for acute childhood diarrhoea. Lancet 2: 429-431, 1989 Molla AM, Rahman M, Sarker SA, Sack DA. Molla A. Stool electrolyte content and purging rates in diarrhoea by rotavirus, enterotoxigenic E. coli and Vibrio cholerae in children. Journal of Pediatrics 98: 835-838, 1981 Molla AM, Sarker SA, Hossain M, Molla A, Greenough III NB. Rice-poWder electrolyte solutions as oral therapy in diarrhoea due to Vibrio cholerae and Escherichia coli. Lancet 1: 13171319, 1982 Motala C, Hill 10, Mann MD, Bowie MD. Effect of loperamide on stool output and duration of acute infectious diarrhoea in infants. Journal of Pediatrics 117: 467-471, 1990
Drugs 44 (1) 1992
Nalin DR, Cash RA, Rahman M, Yurns MD. Effects of glycine and glucose on sodium and water absorption in patients with cholera. Gut II: 768-772, 1970 Nalin DR, Harland E, Ramlal A, Swaby D, McDonald J, et al. Comparison of low and high sodium and potassium content in oral rehydration solution. Journal of Pediatrics 97: 848-893, 1980 Nelson JD, Kusmiesz H, Jackson LH, Woodman E. Treatment of Salmonella gastroenteritis with ampicillin, amoxicillin, or placebo. Pediatrics 65: 1125-1130, 1980 Palmer DL, Koster FT, Islam AFMR, Raham ASMM, Sack RB. Comparison of sucrose and glucose in the oral electrolyte therapy of cholera and other severe diarrhoeas. New England Journal of Medicine 297: 1107-1110, 1977 Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P. Can acetate replace bicarbonate in oral rehydration solution for infantile diarrhoea? Archives of Disease in Childhood 57: 625627, 1982a Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P. Is oral rice electrolyte solution superior to glucose electrolyte solution in infantile diarrhoea? Archives of Disease in Childhood 57: 910-912, 1982b Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P. In search of a super solution: controlled trial of glycine-glucose oral rehydration solution in infantile diarrhoea. Acta Paediatrica Scandinavica 73: 18-21, 1984 Pickering LK. Therapy for acute infectious diarrhoea in children. Journal ofPedia1rics 118: SI18-128, 1991 Pizarro D, Posada G, Sandi L, Movon J R. Rice-based oral electrolyte solutions for the management of infantile diarrhoea. New England Journal of Medicine 324: 517-521, 1991 Rosenthal SL. Exacerbation of Salmonella enteritis due to ampicillin. New England Journal of Medicine 281: 636-640,1969 Santosham M, Bums B, Nadkarni Y, Foster S, Garrett S, et al. Oral rehydration therapy for acute diarrhoea in ambulatory children in the United States: a double-blind comparison of four different solutions. Pediatrics 76: 159-166, 1985 Santosham M, Burns BA, Reid R, Letson GW, Duncan B, et al. Glycine-based oral rehydration solution: reassessment of safety and efficacy. Journal of Pediatrics 109: 795-801, 1986 Semrad CE, Chang EB. Calcium-mediated cyclic AMP inhibition of Na+-H+ exchange in small intestine. American Journal of Physiology 242: C315-322, 1987 Siaden GE, Dawson AM. Interrelationships between the absorptions of glucose of sodium and water by the normal human jejunum. Clinical Science 36: 119-32, 1969 World Health Organization. The rational use of drugs in the management of acute diarrhoea in children. World Health Organization, Geneva 1990 Walker-Smith JA. Disease of the small intestine, 3rd ed., Butterworth & Co, London, 1988 Walker-Smith JA. Advances in oral rehydration. Drugs 36 (Suppl. 4): 99-108, 1988 Walker-Smith JA. Management of infantile gastroenteritis. Archives of Disease in Childhood 65: 917-918,1990 Wharton BA, Pugh RE, Taitz LS, Walker-Smith JA, Booth IW. Dietary management of gastroenteritis in Britain. British Medical Journal 296: 450-452, 1988
Correspondence and reprints: Dr Huw R. Jenkins, Department of Child Health, Cardiff Royal Infirmary, Newport Road, Cardiff CF2 1SZ, Wales.
Drugs 44 (I): 57-64, 1992 0012-6667/92/0007-0057/$04.00/0 © Adis International Limited. All rights reserved. DRUll64
Management of Gastroenteritis in Early Childhood Anne Davies and Huw R. Jenkins Department of Child Health, Cardiff Royal Infirmary, Cardiff, Wales
Contents 57 58 58 59 60 60 60 61 61 61 61 62 62 63 63
Summary
Summary I. Oral Rehydration Solutions 1.1 Sodium 1.2 Potassium 1.3 Base 1.4 Carbohydrate Source 1.5 Amino Acids 1.6 Rice and Starch 2. Intravenous Auid Replacement 3. Drug Therapy 3.1 Antibiotics 3.2 Antidiarrhoeal Agents 4. Feeding Following Acute Gastroenteritis 4.1 Breast-Fed Infants 4.2 Formula-Fed Infants
The most important aspect of modem management of acute diarrhoeal illness in children is that of oral rehydration therapy, and drug therapy is very rarely indicated. Despite the dramatic decline in mortality and morbidity in recent years, there is still the need for continuing education in the appropriate use of oral rehydration solutions. The constitution of oral rehydration solutions and policies of feeding practices during illness continue to be controversial, mainly because of wide variation in the aetiology ofthe diarrhoea, the nutrition of the child, and the economic and public health factors involved in any particular community. The priority of all healthcare workers is to provide simple guidelines in the use of a safe oral rehydration solution while discouraging unsafe treatments.
Drugs 44 (1) 1992
58
Acute gastroenteritis remains a major clinical problem, both in the developing world and in industrialised nations. With the widespread introduction of glucose-electrolyte oral rehydration solutions childhood mortality in developing countries has fallen dramatically, yet the appropriate use of oral rehydration in developed countries, where young children may experience approximately one diarrhoeal episode per year, is often neglected despite access to a primary healthcare system (Jenkins & Ansari 1990). However, there is continuing controversy regarding not only the nutritional management of the illness, but also the composition of the oral rehydration itself. Such controversy is compounded by many variables: the premorbid nutritional state of the child; the contributions of public sanitation and personal hygiene; the pathogen involved; and the availability of healthcare. Nevertheless, broad, safe guidelines are needed, based on existing data and experience.
1. Oral Rehydration Solutions There is no dotibt that the development of oral rehydration therapy has been of paramount importance in the reduction of morbidity and mortality from acute diarrhoeal states throughout the world. However, several aspects of controversy regarding its constitution still remain, and it is debatable whether one single solution would be applicable for worldwide use. In developed countries where diarrhoeal illness may be mild, juices or commercial carbonated drinks are often administered to children as 'rehydration' solutions. This is ill-advised, since they vary widely in osmolality and electrolyte composition, often being low in sodium and hyperosmolar (e.g. the sodium composition of 'Coca-Cola' is 3 mmol/L with an osmolality of 469 mOsm/kg). l.l Sodium
The inclusion of sodium in oral rehydration solutions is necessary to replace stool sodium losses and to promote water absorption. Ion exchange processes across the apical brush border of the en-
terocyte (whereby sodium is exchanged for hydrogen, and chloride is exchanged for bicarbonate) account for some sodium chloride absorption, but the sodium/hydrogen exchange process may be inhibited during intestinal secretion which occurs in diarrhoeal states (Semrad & Chang 1987) [fig. I]. Of greater implication for the formulation of oral rehydration solutions is the glucose- or amino acidcoupled sodium absorption process, which is unaffected by intestinal secretion. This depends on the maintenance of a low intracellular sodium concentration, so that sodium, linked to glucose, enters the cell across its apical membrane. The sodium/potassium ATPase (or sodium pump) at the basolateral membrane is responsible for maintaining the low intracellular sodium, and this is unaffected by a secretory state. The sodium content of oral rehydration solutions recommended by the World Health Organization (WHO) [90 mmol/L] was set to approximate the sodium losses in stools of cholera cases, yet the common pathogens responsible for diarrhoeal cases in Europe cause much lower sodium losses (e.g. 40 mmol/L in rotavirus diarrhoea, and 50 to 60 mmol/L for the invasive pathogens Shigella, Salmonella and Campylobacter). All clinical trials of oral rehydration solutions with lower sodium concentrations of 30 to 65 mmol/L have shown this constitution to be safe and effective for rehydration of mild, moderate and severe dehydration, with complications of little clinical relevance (e.g. asymptomatic hyponatraemia, periorbital oedema) reported in less than one-third of the trials (da Cunha Ferreira 1989). Furthermore, extensive clinical practice with the use of lower sodium oral rehydration solutions has lent further support to these findings (Walker-Smith 1988). Therefore, the use of WHO oral rehydration solution for children with diarrhoea caused by pathogens common to developed countries can only be recommended if it offers significant advantages over lower sodium oral rehydration solutions. The high sodium load of WHO oral rehydration solutions carries a risk of harmful retention of sodium and water, particularly in young infants who have higher insensible losses (e.g. through the skin), or
Childhood Gastroenteritis
I Lumen I
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--------.
..
-----..Na+-... ------------' ....
ISerosal
I Individual enterocyte Fig. 1. Diagrammatic representation of sodium (Na+) and chloride (CI-) absorption in the small intestine.
in mildly dehydrated children who may have only low faecal sodium losses from a viral-induced diarrhoea. Some would advocate the use of WHO oral rehydration solutions alternating with free water for clinical rehydration, and thereafter changing to a lower sodium oral rehydration solution for maintenance (Finberg 1980), but this regimen is more complicated for outpatient settings, and more likely to lead to errors of constitution and potentially dangerous hypernatraemia. Hypernatraemic dehydration was a significant cause of mortality and morbidity in the developed world during the 1970s. Some hypernatraemic episodes have been described following the improper use of oral rehydration solutions (without free water), but its decline has largely been due to the introduction of low solute milks. However, concern remains that the use of high sodium oral rehydration solutions in certain European countries (where mortality from diarrhoea disease per se may be zero) could increase the incidence of hypernatremia, especially if stool sodium losses are low, as in noncholera diarrhoea. In fact, oral rehydration solutions with a sodium content of 60 or 90 mmol/ L have been safe and effective in treating hypernatraemic patients, but a single solution of 60 mmol/L sodium is recommended to rehydrate or maintain hydration without the need for free water
or high risks from errors in constitution (da Cunha Ferreira 1989). Therefore, the use in the developed world of a single solution with 60 mmol/L or less of sodium should be recommended for oral rehydration or maintenance of hydration, because of simplicity of instruction and avoidance of dangerous hypernatraemia. Such a solution can be used to replace stool losses in all viral and bacterial noncholera diarrhoea. 1.2 Potassium Substantial losses of potassium occur when children pass diarrhoeal stools (Molla et al. 1981), usually in the range 18 to 42 mmol/L per stool in noncholera diarrhoea. WHO oral rehydration solutions and most of the commercially available oral rehydration preparations contain at least 20 mmol/ L of potassium. Although it is unlikely that well nourished children with a single diarrhoeal episode would be adversely affected by mild potassium depletion, this may be problematic for dehydrated malnourished children. For example, 33% of children treated with oral rehydration solutions containing 20 mmol/L of potassium in one series developed hypokalaemia compared to none in the group receiving oral rehydration solutions contain-
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ing 35 mmol/L potassium (Nalin et al. 1980). Thus, adequate concentrations of potassium are necessary if oral rehydration solutions are to be safe and effective. 1.3 Base Base and base precursors have been included in oral rehydration solutions with the rationale that they correct any metabolic acidosis (probably resulting from poor tissue perfusion) and enhance sodium and water reabsorption, yet there is little clinical evidence to support their routine inclusion. Several clinical trials have indicated that the correction of metabolic acidosis was slower but just as effective with base-free oral rehydration solutions as with bicarbonate-containing solutions, and that the slower return of plasma bicarbonate levels to normal was of no clinical relevance in the face of a well rehydrated patient with a good urine output (Elliott et al. 1987, 1988; Islam & Ahmed 1984). Although bicarbonate was the original base included in oral rehydration solutions, it reacts with glucose when exposed to humidity or heat, and its limited shelf-life led to the development and inclusion of the base precursors acetate and citrate, which are equally effective (Islam 1985; Mazumder et al. 1990; Patra et al. 1982a). Acetate salts, however, gel after 12 hours' exposure to air and are thus not recommended in powdered oral rehydration formulations. Citrate is stable in bicarbonatecontaining oral rehydration solutions, but the advantage of citrate oral rehydration solution over base-free solution has not yet been established. 1.4 Carbohydrate Source Glucose is the carbohydrate source used in WHO oral rehydration solutions and in the majority of commercially available solutions. The process of coupled glucose/sodium absorption is intact in diarrhoeal states (leading to increased water absorption when oral rehydration solution is administered), and therefore glucose has been firmly established as the energy source in oral rehydration solutions. Concentrations of glucose used in clinical
trials range from 70 to 280 mmol/L, with many commercially produced solutions in the US and Europe being at the top of the range (200 to 280 mmol/L), aiming for high energy content, pleasant taste, and iso-osmolality. The question of optimal glucose concentration has been explored in several studies, and results have shown that, provided a sodium: glucose ratio of 1 : 1 to 1 : 1.5 is ensured, glucose concentrations of 60 to 140 mmol/L are most effective (Malawer et al. 1965; Sladen & Dawson 1969). Higher concentrations of glucose may lead to glucose malabsorption and osmotic diarrhoea, and lower concentrations of glucose may lead to poor sodium and water reabsorption. . Glucose polymers have also been used successfully as the carbohydrate source in oral rehydration solutions, and have been as effective as glucose monomers in clinical trials (Jones et al. 1981; Santosham et al. 1985). Disaccharides and a-I-41inked oligosaccharides may promote rapid water absorption largely because of the hypotonicity of the solution. The greater availability and lower cost of sucrose compared with glucose led to its use in early trials in cholera. Many treatment failures occurred, probably as a result of the massive stool purges rather than the solution itself. Other trials show that, in equivalent concentrations, sucrose can be at least as effective as glucose in the treatment of dehydration from cholera, and diarrhoea caused by noncholera pathogens (Molla et al. 1982; Palmer et al. 1977). Sucrose has been recommended by the WHO for home rehydration therapy when oral rehydration solutions or formulated brands are unavailable. 1.5 Amino Acids Absorption of amino acids takes place via a separate carrier mechanism and, as this is largely sodium-coupled (a mechanism which remains intact in most cases of diarrhoea), they have been included in oral rehydration solutions to enhance sodium and water reabsorption. Rehydration solutions with added glycine re-
Childhood Gastroenteritis
duced stool output and duration of diarrhoea, and enhanced water absorption in children with cholera, but had no beneficial effect (apart from shortening the duration of illness) in diarrhoeal illnesses not due to cholera (Nalin et al. 1970; Patra et al. 1984; Santosham et al. 1986). Although this may be explained by different mechanisms of damage depending on the pathogen (e.g. rotavirus damaging mucosa and impairing glycine reabsorption), osmotic diarrhoea was also described in some patients, and glycine is not recommended as a routine addition to oral rehydration solutions in these cases. Other amino acids, however, may yet prove to be beneficial. 1.6 Rice and Starch The composition of rice is predominantly starch, plus a small amount of protein (7 to 10%). The gradual release of glucose from starch via luminal and membrane-bound glucosidases means that the absorption of glucose can be immediate, the osmolality of the luminal contents can be low, and the number of glucose residues can be increased without osmotic 'overload'. This allows more efficient water and sodium reabsorption and a higher energy intake. It also allows the released amino acids to provide an additional source of sodium coupling, as well as providing a source of nitrogen. These theoretical advantages have been borne out in clinical practice with a reduction in stool outputs and a reduction in the quantity of oral rehydration solutions actually required (Molla et al. 1989; Patra et al. 1982). Reduction of stool output is gratifying for parents, particularly if the child is an outpatient, and home-made formulae based on rice and locally available cereals are now firmly established in the management of acute diarrhoea in the developing world (Editorial 1992).
2. Intravenous Fluid Replacement Although the use of oral rehydration solutions has been well established in developing countries, and has reduced morbidity and mortality dramatically, it is largely underused and undervalued in
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the developed world. There is a tendency to overestimate the degree of dehydration in well nourished children (Mackenzie et al. 1989) and to give intravenous therapy (normal saline, or half normal saline with dextrose) to all those patients more than mildly dehydrated (Walker-Smith 1988). A recent randomised controlled trial in Australia showed that oral rehydration is as effective, both clinically and biochemically, as intravenous rehydration in children who are dehydrated (but not shocked), even if there is countinued vomiting (Mackenzie & Barnes 1991). The more widespread use of oral rehydration solutions in the hospital setting would reduce trauma for the child and lead to greater awareness of effective oral therapy in the community, thus reducing hospital admission rates.
3. Drug Therapy The routine use of drugs (usually antibiotics or antidiarrhoeal agents) in acute diarrhoea in children is rarely indicated, and certain drugs, particularly those that reduce motility, may be dangerous. A more profitable use of health resources is the adequate provision of oral rehydration therapy, with informed instruction regarding its use. Explanation can be given to the parents that the diarrhoea is the body's own mechanism for ridding itself of the harmful organism, and time can be spent instructing them in the use of oral rehydration solutions and in the planning of subsequent refeeding. 3.1 Antibiotics Antibiotics are not indicated as a first line treatment for diarrhoeal illness. For many of the responsible pathogens (e.g. the viruses rotavirus, adenovirus and Norwalk agent, and the parasite cryptosporidium) no agent will be effective,. The use of antibiotics is therefore a costly distraction from the main therapeutic priority which is adequate oral rehydration. There are, however, some specific indications for the use of antibiotics. Metronidazole may be effective in treating amoebiasis and giardiasis, and specific antibiotics
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may be of benefit it the child is systemically unwell and septicaemic. The use of antibiotics [chloramphenicol, ampicillin and cotrimoxazole (trimethoprim/sulfamethoxazole)] for Salmonella infection should be limited to those patients with typhoid fever, those with systemic infection (e.g. septicaemia and pyogenic infection or osteomyelitis), and to those in whom host resistance is poor (e.g. neonates and the immunosuppressed) [Pickering 1991]. For those patients with Salmonella gastroenteritis, antibiotics have in fact been known to produce symptomatic relapse (Aserkoff et al. 1969; Nelson et al. 1980) and to convert intestinal disease into systemic illness (Rosenthal 1969). The existence of chloramphenicol-resistant strains throughout the world has led to the suggestion that ampicillin should be the drug of choice where local sensitivities are unknown. In Shigella and enterotoxigenic Escherichia coli infections, cotrimoxazole may shorten the illness and reduce faecal organism shedding, but its use has encouraged multiple antibiotic resistance in what is usually an acute self-limiting disease. The value of antibiotics in Campylobacter and Yersinia infection has yet to be established, and the diarrhoea associated with Clostridium di./ficile (producing pseudomembranous colitis) may abate with the cessation of the existing antibiotic therapy, although vancomycin may be used for persisting symptoms. An additional indication is, of course, the sudden onset of diarrhoea which heralds an overwhelming generalised septicaemia, where the gut is not the primary organ of involvement. 3.2 Antidiarrhoeal Agents These drugs include adsorbents such as kaolin, antisecretory agents such as bismuth salicylate, and antimotility agents such as loperamide, and diphenoxylate plus atropine. These drugs are ineffective at best, and at worst can be harmful in childhood (Costello & Bhutta 1992; Motala et al. 1990). Those drugs altedng intestinal motility retard the movement of gut contents, thus restricting the distention which is often responsible for the pain
associated with gastroenteritis. In 19 young infants in Pakistan, abdominal distension and paralytic ileus was described after loperamide, resulting in 6 deaths on the ward (Bhutta 1990). Side effects of these drugs such as drowsiness, tachycardia and vomiting are common, and may be more pronounced in malnourished children. These antimotility agents should be avoided in children who are in shock or febrile, or who have evidence of colitis (bloody stools), since they may worsen the morbidity in shigellosis (Dupont & Hornick 1973). Adverse effects of bismuth salicylate relate to the absorption of salicylate and bismuth. Adsorbent agents such as kaolin may relieve symptoms by facilitating more formed stools, but few studies have shown a reduction in duration of diarrhoea, or a reduction in fluid and electrolyte losses, and they may interfere with nutrient and enzyme function by adsorption in the gut.
4. Feeding Following Acute Gastroenteritis Further controversy exists regarding nutrition in acute infantile diarrhoea and, as with oral rehydration solution formulation, there are differences in policies and guidelines between the developing and developed countries (Lifschitz & Schulman 1990). Once again, these differences are influenced by the pathogen involved, its mechanism of invasion, the state of nutrition of the child, and numerous cultural, economic and logistical factors, and are compounded by a relative deficit in conclusive research results. In developing countries where suboptimal nutrition may exist in the child's premorbid state, a prolonged period of time without adequate nutrition will clearly be detrimental. Certainly the continuation of uninterrupted breast feeding in addition to oral rehydration therapy should be encouraged in both industrialised and underdeveloped countries, since existing evidence points to a decrease in severity of diarrhoea and shortened duration of the illness with this practice (KhinMaung-U et al. 1985). Previous guidelines for the formula-fed infant have recommended a slow reintroduction of for-
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Childhood Gastroenteritis
mula feeds after a temporary period of oral rehydration, with a gradual stepwise reintroduction of milk after initial hydration with rehydration solutions (i.e. one-quarter strength followed by onehalf, three-quarter and full strength milk over a 12to 72-hour period) [Wharton et al. 1988]. This regime gained popularity at a time when postgastroenteritis lactose intolerance complicated the illness in many cases, yet recent reports suggest that this is a declining problem (Editorial 1987), and also that the regrading process appears to make no difference to the incidence of lactose intolerance anyway (Fox et al. 1990). Recent work has questioned the need for a regrading process in infants over 6 months old and even now, for younger babies (under 6 months), an immediate return to formula feed has been recommended (Armistead et al. 1989; Brown 1991; Brown et a!. 1988; Fox et al. 1990). However, the incidence of lactose intolerance, and indeed of cow's milk protein intolerance (which may present as lactose intolerance), must be assessed in individual communities before a refeeding policy can be recommended. The lack of agreed definitions of lactose and cow's milk protein intolerance make firm policies for the introduction of substitute milks very difficult indeed. Further confusion may exist if a child's diarrhoea persists when regrading onto soya milk, as soya itself may cause persistent gut mucosal damage, and in these cases a protein hydrolysate feed may be indicated. The following management plan, based on existing data and personal clinical experience, is suitable for relatively well nourished children ill developed countries. 4.1 Breast-Fed Infants Breast feeding should be continued uninterrupted and be offered in addition to oral rehydration solutions. Breast feeding exerts a beneficial outcome on acute diarrhoea by reducing the number and volume of diarrhoeal stools (Khin-Maung U et al. 1985). Products of digestion in the gut lumen (amino acids, dipeptides and hexoses) may enhance the absorption of sodium and water, and
the benefits of continued nutritional intake from an uncontaminated source are important advantages, especially in the poorly nourished child. 4.2 Formula-Fed Infants I. A period of oral rehydration solutions alone for 6 to 24 hours, followed by reintroduction of normal full strength formula milk and solids is indicated. 2. If worsening of diarrhoea occurs, a further period of oral rehydration therapy should be given, followed by slow regrade up to full strength milk over 6 to 72 hours. 3. In the few infants who fail 2 regrades (these infants are usually less than 6 months of age), a change to a formula free from lactose and cow's milk protein is justified (i.e. a protein hydrolysate feed should be used). This is usually indicated for a temporary period only, but solids containing these substances (e.g. cheese, chocolate) must obviously also be avoided for 1 to 3 months when a rechallenge with a cow's milk-containing formula can be performed. 4. Previously unwell or malnourished children are at a higher risk from lactose and/or cow's milk protein intolerance and are more likely to develop a protracted illness/enteropathy. The failure of the first regrade may be an indication to start a lactose and cow's milk-free formula at an early stage.
References Armistead J, Kelly D, Walker-Smith JA. Evaluation of infant feeding in acute gastroenteritis. Journal of Pediatric Gastroenterology and Nutrition 8: 240-244, 1989 Aserkoff B, Bennett JV. Effect of antibiotic therapy in acute salmonellosis on the fecal excretion of salmonellae. New England Journal of Medicine 281: 636-640, 1969 Bhutta TI. Loperamide poisoning in children. Lancet I: 363, 1990 Brown KH. Dietary management of acute childhood diarrhoea: optimal timing of feeding and appropriate use of milks and mixed diets. Journal of Pediatrics 118: S92-98, 1991 Brown KH, Gastanaduy AS, Saavedra JM, Lembcke J, Rivas D, et al. Effect of continued oral feeding on clinical and nutritional outcomes of acute diarrhoea in children. Journal of Pediatrics 112: 191-200, 1988 Costella AM deL, Bhutta TI. Antidiarrhoeal drugs for acute diarrhoea in children. British Medical Journal 304: 1-2, 1992 da Cunha Ferreira RMC. Optimising oral rehydration solution composition for the children of Europe: clinical trials. Acta Paediatrica Scandinavica (Suppl.) 364: 40-50, 1989
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Dupont HL, Hornick RB. Adverse effect of'Lomotil' therapy in shigellosis. Journal of the American Medical Association 226: 1525-1528, 1973 Editorial. What has happened to carbohydrate intolerance following gastroenteritis? Lancet I: 23-24, 1987 Editorial. Cereal-based oral rehydration solutions - bridging the gap between fluid and food. Lancet 339: 219-220, 1992 Elliott EJ, Armistead JCM, Farthing MJG, Walker-Smith JA. Oral rehydration therapy without bicarbonate for prevention and treatment of dehydration: a double-blind controlled trial. Journal of Alimentary Pharmacology and Therapeutics 2: 253-262, 1988 Elliott EJ, Walker-Smith JA, Farthing MJG. The role of bicarbonate and base precursors in treatment of acute gastroenteritis. Archives of Disease in Childhood 62: 91-95, 1987 Finberg L. The role of electrolyte-glucose solutions in hydration for children - international and domestic aspects. Journal of Pediatrics 96: 51-54, 1980 Fox R, Leen CLS, Dunbar EM, Ellis ME, Mandai BK. Acute gastroenteritis in infants under 6 months old. Archives of Disease in Childhood 65: 936-938, 1990 Islam MR. Can potassium citrate replace sodium bicarbonate and potassium chloride in oral rehydration solution? Archives of Disease in Childhood 60: 852-855, 1985 Islam MR, Ahmed SM. Oral rehydration solution without bicarbonate. Archives of Disease in Childhood 59: 1072-1075, 1984 Jenkins HR, Ansari BM. Management of gastroenteritis. Archives of Disease in Childhood 65: 939-941,1990 Jones BMJ, Brown BE, Silk DBA. Intestinal absorption of maltotriose and a maltopentose-Iexose mixture in man. Gut 22: A868,1981 Khin Maung U, Nyunt Nyunt Wai, Myo Khin, Mu Mu Khin, Tin U, Thane toe. Effect on clinical outcome of breast feeding during acute diarrhoea. British Medical Journal 290: 587-589, 1985 Lifschitz CH, Schulman RJ. Nutritional therapy for infants with diarrhoea. Nutrition Reviews 48: 329-338, 1990 Mackenzie A, Barnes G, Shann F. Clinical signs of dehydration in children. Lancet 2: 605-607, 1989 Mackenzie A, Barnes G. Randomized controlled trial comparing oral and intravenous rehydration therapy in children with diarrhoea. British Medical Journal 303: 393-396, 1991 Malawer SJ, Ewton M, Fordtran JS, Ingelfurger FJ. Interrelation between jejunal absorption of sodium, glucose and water in man. Journal of Clinical Investigation 44: 1072-1073, 1965 Mazumder RN, Nath SK, Ashraf H, Patra FC, Alam AN. Oral rehydration solution containing trisodium citrate for treating severe diarrhoea: controlled clinical trial. British Medical Journal 302: 88-89, 1991 Molla AM, Molla A, Nath SK, Khatun M. Food-based oral rehydration salt solution for acute childhood diarrhoea. Lancet 2: 429-431, 1989 Molla AM, Rahman M, Sarker SA, Sack DA. Molla A. Stool electrolyte content and purging rates in diarrhoea by rotavirus, enterotoxigenic E. coli and Vibrio cholerae in children. Journal of Pediatrics 98: 835-838, 1981 Molla AM, Sarker SA, Hossain M, Molla A, Greenough III NB. Rice-poWder electrolyte solutions as oral therapy in diarrhoea due to Vibrio cholerae and Escherichia coli. Lancet 1: 13171319, 1982 Motala C, Hill 10, Mann MD, Bowie MD. Effect of loperamide on stool output and duration of acute infectious diarrhoea in infants. Journal of Pediatrics 117: 467-471, 1990
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Nalin DR, Cash RA, Rahman M, Yurns MD. Effects of glycine and glucose on sodium and water absorption in patients with cholera. Gut II: 768-772, 1970 Nalin DR, Harland E, Ramlal A, Swaby D, McDonald J, et al. Comparison of low and high sodium and potassium content in oral rehydration solution. Journal of Pediatrics 97: 848-893, 1980 Nelson JD, Kusmiesz H, Jackson LH, Woodman E. Treatment of Salmonella gastroenteritis with ampicillin, amoxicillin, or placebo. Pediatrics 65: 1125-1130, 1980 Palmer DL, Koster FT, Islam AFMR, Raham ASMM, Sack RB. Comparison of sucrose and glucose in the oral electrolyte therapy of cholera and other severe diarrhoeas. New England Journal of Medicine 297: 1107-1110, 1977 Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P. Can acetate replace bicarbonate in oral rehydration solution for infantile diarrhoea? Archives of Disease in Childhood 57: 625627, 1982a Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P. Is oral rice electrolyte solution superior to glucose electrolyte solution in infantile diarrhoea? Archives of Disease in Childhood 57: 910-912, 1982b Patra FC, Mahalanabis D, Jalan KN, Sen A, Banerjee P. In search of a super solution: controlled trial of glycine-glucose oral rehydration solution in infantile diarrhoea. Acta Paediatrica Scandinavica 73: 18-21, 1984 Pickering LK. Therapy for acute infectious diarrhoea in children. Journal ofPedia1rics 118: SI18-128, 1991 Pizarro D, Posada G, Sandi L, Movon J R. Rice-based oral electrolyte solutions for the management of infantile diarrhoea. New England Journal of Medicine 324: 517-521, 1991 Rosenthal SL. Exacerbation of Salmonella enteritis due to ampicillin. New England Journal of Medicine 281: 636-640,1969 Santosham M, Bums B, Nadkarni Y, Foster S, Garrett S, et al. Oral rehydration therapy for acute diarrhoea in ambulatory children in the United States: a double-blind comparison of four different solutions. Pediatrics 76: 159-166, 1985 Santosham M, Burns BA, Reid R, Letson GW, Duncan B, et al. Glycine-based oral rehydration solution: reassessment of safety and efficacy. Journal of Pediatrics 109: 795-801, 1986 Semrad CE, Chang EB. Calcium-mediated cyclic AMP inhibition of Na+-H+ exchange in small intestine. American Journal of Physiology 242: C315-322, 1987 Siaden GE, Dawson AM. Interrelationships between the absorptions of glucose of sodium and water by the normal human jejunum. Clinical Science 36: 119-32, 1969 World Health Organization. The rational use of drugs in the management of acute diarrhoea in children. World Health Organization, Geneva 1990 Walker-Smith JA. Disease of the small intestine, 3rd ed., Butterworth & Co, London, 1988 Walker-Smith JA. Advances in oral rehydration. Drugs 36 (Suppl. 4): 99-108, 1988 Walker-Smith JA. Management of infantile gastroenteritis. Archives of Disease in Childhood 65: 917-918,1990 Wharton BA, Pugh RE, Taitz LS, Walker-Smith JA, Booth IW. Dietary management of gastroenteritis in Britain. British Medical Journal 296: 450-452, 1988
Correspondence and reprints: Dr Huw R. Jenkins, Department of Child Health, Cardiff Royal Infirmary, Newport Road, Cardiff CF2 1SZ, Wales.
